1
		DEPARTMENT OF HEALTH AND HUMAN SERVICES 
				FOOD AND DRUG ADMINISTRATION 
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
	PERIPHERAL AND CENTRAL NERVOUS SYSTEM DRUGS 
							ADVISORY COMMITTEE
								Volume II
						Friday, June 7, 1996 

								8:30 a.m.
	Holiday Inn Bethesda 8120 Wisconsin Avenue 

Versailles III and IV Ballrooms Bethesda, Maryland 

			2
PARTICIPANTS 
Sid Gilman, M.D., Chairperson 
Michael A. Bernstein, M.P.H., Executive Secretary 
MEMBERS 
	Harold P. Adams, Jr., M.D. 

Peggy J. Copple, M.D. Patricia K. Coyle, M.D. David A. Drachman, M.D. Chris Gennings, Ph.D. Claudia H. Kawas, M.D. 
Zaven S. Khachaturian, Ph.D. 
Ellyn C. Phillips (Consumer Representative) Orlando C. Snead III, M.D. 

	Justin A. Zivin, M.D., Ph.D. 
FDA 
	Russell Katz, M.D. 

Paul Leber, M.D. Robert Temple, M.D. 

		3 C O N T E N T S 
				PAGE 
Welcome and Information: Sid Gilman, M.D.	  5 
Opening Comments: Michael A. Bernstein, M.P.H.	  7
IND 39-927: MYOTROPHIN: TREATMENT USE UNDER AN INDIVIDUAL TREATMENT PROTOCOL FOR AMYOTROPHIC LATERAL SCLEROSIS (ALS) 
FDA Presentations 
	Welcome and Opening Comments: Paul Leber, M.D.	 11 
	Presentation and Analysis of the Data from Studies 

	1200 and 1202 on Myotrophin's Use in ALS: 
		John Feeney, M.D.	 26 
Sponsor Presentations: Cephalon, Inc. 
	Introduction: William F. Graney, M.D.	 76 
	Clinical Study Design: Deborah F. Gelinas, M.D.	 79 
	Myotrophin Data: 
		William F. Graney, M.D.	113 
		Thomas W. Dobbins, M.D.	161 
		William F. Graney, M.D.	175 
	Clinical Interpretation: Robert G. Miller, M.D.	195 
Committee Discussion  
Open Public Hearing 
Lynn Klein (for James Rather and Cary Green)  243 Janice Dorfman	252 
		Mary Beth Parks	253 
		Linda McKnight	255 
		Don Altier		259 
		Ben Gill		263 
		Christopher Pendergast	265 
		Dee Holden Norris	271 
		David Coleman (by Susan Grahn)	274 
		Steven Stricter	276 
		Joseph Polizzi	278 
		Frank and Karen Micale, Jr.	279 
		Fred Kanzler (read by Carl Mayle)	283 
		Dr. Gerald van der Vlugt	286 
		Dr. Theodore Munsat	289 
		Dr. Robert Brown	291 
		Dr. Benjamin Brooks	293 

				4 
C O N T E N T S (Continued) 
	Dr. Burt Jubelt	294  
	Abbie Myers	295 
	Dr. Barry Festoff	296 
Committee Discussion (Continued)	297 
Recommendations and Vote	306 
Closing Remarks		306 

				5 1		         P R O C E E D I N G S 

	2		        WELCOME AND INFORMATION 
	3		DR. GILMAN:  I would like to call this meeting to 
	4	order and welcome everyone to the 43rd meeting of the 

	5	Peripheral and Central Nervous System Drugs Advisory 
	6	Committee.
	7		My name is Sid Gilman.  I am from the University 
	8	of Michigan Medical Center in Ann Arbor, Michigan.  I am 
	9	Chair of this committee. 
10		I would like to introduce you to those seated 

11	around the table.  I will start with Dr. Harold Adams. 
12	Please identify yourself, your institution. 
13		DR. ADAMS:  I am Harold Adams.  I am Professor of 
14	Neurology at the University of Iowa. 
15		DR. DRACHMAN:  David Drachman, U. Mass Medical 
16	Center.
17		DR. COYLE:  Pat Coyle from SUNY Stony Brook. 
18		DR. SNEAD:  Carter Snead from the University of 
19	Toronto. 
20		DR. ZIVIN:  Justin Zivin, University of California 
21	at San Diego.
22		MR. BERNSTEIN:  Mike Bernstein, Executive 
23	Secretary, FDA. 
24		DR. GENNINGS:  Chris Gennings, Medical College of 
25	Virginia. 

				6 1		MS. PHILLIPS:  Ellyn Phillips, Consumer
	2	Representative. 
	3		DR. COPPLE:  Peggy Copple from the University of 
	4	Arizona Health Sciences Center in Tucson. 
	5		DR. KHACHATURIAN:  I am Zaven Khachaturian, 

	6	Director of the Ronald and Nancy Reagan Institute for
	7	Research. 
	8		DR. KAWAS:  I am Claudia Kawas, Johns Hopkins 
	9	School of Medicine. 
10		DR. KATZ:  Russ Katz, FDA. 

11		DR. LEBER:  Paul Leber, FDA.
12		DR. GILMAN:  Thank you all. 

13		I just wanted to make a few remarks to the 
14	audience and also to the members of the panel.  First, we 
15	will follow the agenda.  There is an agenda available for 
16	you.  If you don't have one, it is on the table outside.
17		I would like to delay voting on the issues on 
18	before us until the very end of the day.  First, I would 
19	like to have our committee hear the evidence to be 
20	presented, both from the sponsor and from the FDA panel. 
21		Then, we will have deliberations by the panel

22	about the evidence that we have heard.  Next, we will have 
23	an open public hearing.  Finally, we will resume our 

24	deliberations and at the end of the day we will vote. 
25		To the speakers from both the sponsor and the FDA, 

			7 1	I would ask that we be allowed to interrupt your
	2	presentations.  Any member of the committee who wishes to 

	3	interrupt, please do so.  It is important that we have our 
	4	questions answered at the time that you are presenting your 
	5	data. 
	6		I wish the committee members, though, would raise
	7	their hands to be recognized before they speak. If the 

	8	lights are out, of course, you can simply interrupt the 
	9	speaker and speak into the microphone. 
10		At this point, I would like to introduce Mr. 
11	Michael Bernstein, committee Executive Secretary, who has
12	asked for time to make a number of administrative 
13	announcements. 
14		            OPENING COMMENTS 
15		MR. BERNSTEIN:  Thanks, Dr. Gilman. 
16		I would like to welcome each of the committee

17	members and especially our new members to this 43rd meeting 
18	of the Peripheral and Central Nervous System Drugs Advisory 
19	Committee.  My name is Mike Bernstein and I am the Executive 
20	Secretary of this committee, which functions within the 
21	Division of Neuropharmacological Drug Products.
22		Please bear with me while I make a few 
23	administrative announcements. 
24		On the table by the entry are handouts of the 
25	agenda, question lists, and roster of committee membership.  

			8 1	I hope that everyone has picked up a package.
	2		We ask again that all speakers speak directly into 
	3	a microphone.  Individuals from the audience, following 
	4	recognition by the Chair, should come forward to a 
	5	microphone.  Unless one speaks directly into the mike, 
	6	comments cannot be heard by our transcriptionist or those
	7	sitting in the back of the room. 
	8		If anyone in the audience describes to make any 

	9	comments in the open public hearing, we ask that you wait 
10	until you have been recognized by the Chair before coming 
11	forth to a microphone.  Please identify yourself and your
12	affiliation before you begin your statement. 
13		Statements made in the open public hearing must 

14	relate to the issue being considered at this meeting and be 
15	of general interest to the committee members. 
16		A lunch break will be determined according to our
17	schedule.  There is a lunch break on the agenda, but that 

18	may have to fluctuate a little bit according to discussions. 
19		As this is an open meeting, a reminder that the 
20	proceedings may be tape recorded, but that the recording is 
21	considered to be unofficial until it has been approved by
22	the Commissioner of the Food and Drug. 
23		The following announcement addresses the issue of 
24	conflict of interest with regard to this meeting and is made 
25	part of the record to preclude even the appearance of such 

			9 1	at this meeting.
	2		Based on the submitted agenda made and information 
	3	provided by the participants, the agency has determined that 
	4	all reported interests in firms regulated by the Center for 
	5	Drug Evaluation and Research present no potential for a 

	6	conflict of interest at this meeting with the following
	7	exception. 
	8		In accordance with 18, U.S.C. 208(b)(3) a full 
	9	waiver has been granted to Ellyn Phillips.  A copy of this 
10	waiver statement may be obtained by submitting a written 
11	request to FDA's Freedom of Information Office located in
12	Room 12A-30 of the Parklawn building. 

13		We would also like to disclose for the record that 
14	Ms. Phillips, through her affiliation with the ALS 
15	Association, has been actively involved with Cephalon, Inc., 
16	one of the sponsors of Myotrophin, the product at issue
17	today, and with Rhone-Poulenc-Rorer Pharmaceuticals, a 
18	competing manufacturer to Cephalon's Myotrophin. 
19		Ms. Phillips has been actively involved in 
20	educating Cephalon, Inc., and Rhone-Poulenc-Rorer 
21	Pharmaceuticals concerning the ALS patient population and
22	its needs. 
23		Although these past involvements do not constitute 
24	a financial interest within the meaning of 18 U.S.C. 208(a), 
25	they could create the appearance of impartiality.  However, 

			10 1	the agency has determined notwithstanding these past
	2	involvements that the interest of the government and Ms. 
	3	Phillips' participation outweighs the concern that the 

	4	integrity of the agency's programs may be questioned. 
	5		Therefore, Ms. Phillips may participate fully in 
	6	today's discussions.
	7		In the event that the discussions involve any 
	8	other products or firms not already on the agenda for which 
	9	an FDA participant has a financial interest, the 
10	participants are aware of the need to exclude themselves 

11	from such involvement, and their exclusion will be noted on
12	the record. 
13		With respect to all other participants, we ask 
14	that in the interest of fairness that they address any 
15	current or previous financial involvement with any firm 
16	whose products they may wish to comment upon.
17		Lastly, IND 39-927, Myotrophin, will be the only 
18	issue discussed by the committee at this meeting. 
19		Thank you for your attention, and this concludes 
20	my comments, Dr. Gilman. 
21		DR. GILMAN:  Thank you, Mr. Bernstein.

22		IND 39-927:  MYOTROPHIN:  TREATMENT USE 
23	         UNDER AN INDIVIDUAL TREATMENT PROTOCOL FOR 
24		  AMYOTROPHIC LATERAL SCLEROSIS (ALS) 
25		           FDA PRESENTATIONS 

			11 1		DR. GILMAN:  As you heard, the topic for today's
	2	meeting is IND 39-927 Myotrophin. 
	3		Dr. Paul Leber, Director, Division of 
	4	Neuropharmacological Drug Products, has a few opening 
	5	comments. 
	6		Dr. Leber.
	7		      WELCOME AND OPENING COMMENTS 
	8		DR. PAUL LEBER:  Thank you, Sid. 
	9		Good morning, everybody.  I would like to welcome 
10	you, particularly the new members who have joined the 

11	committee.  Some of you we have known from the past, in
12	particular Dr. Drachman has served so often as a special 
13	consultant to the agency that he almost feels like he has 

14	been on the committee before.  But to everyone, welcome, and 
15	thank you for joining us. 
16		This, I believe is a relatively unusual question
17	for an advisory committee because it concerns the treatment 
18	use of an investigational drug.  Therefore, although many on 
19	the committee who are old hands probably know what we do 
20	with NDAs, there is a necessity that I take some time to try 
21	to explain, as we have done in our briefing manual, what it
22	is that makes treatment use different and what it is that 

23	makes it comparable to NDA decisions. 
24		In order to do that, I have to tell you something 
25	about the Act and something about the way in which we 

			12 1	interpret the regulations under that Act that deal with
	2	treatment use of a drug that is an investigational drug. 
	3		I would also like to take a little bit of time 
	4	after I do that to explain who we happen to choose to come 
	5	to the advisory committee, because we do not always do so in 
	6	the case of a treatment NDA decision, but that comes later.
	7		Finally, I would like to acknowledge before I 
	8	begin that is in any institution those who sometimes make 
	9	the presentation are not those who do the work.  In this 
10	particular occasion the lion's share -- and I take it in its 
11	full meaning, meaning almost all the work here -- has been

12	done by Dr. John Feeney.  He is a senior medical reviewer 
13	who has dealt with ALS products. 
14		And Dr. David Hoberman, a mathematical 
15	biometrician on our staff, who have worked to examine the 
16	evidence in this particular case.  And to them we owe really
17	most of what was done.  Russ Katz and myself, of course, 
18	have played our usual role as the "executives."  I will use 
19	that in quotation marks. 
20		To begin with, let's talk a bit about why we have 
21	INDs.  As many of you know here, the law of the land as

22	regards drugs deals with issues of premarket clearance.  The 
23	mechanism used is to require that no drug be in circulation 
24	unless it is safe for use and effective in use, and the 
25	device used in the 1938 version of the Federal Food, Drug, 

			13 1	and Cosmetic Act is the requirement that sponsors do test,

	2	submit reports of those tests to the agency in the form of 
	3	something called a New Drug Application, and initially it 
	4	became effective if the FDA didn't work, but since '62, it 
	5	has been required that the FDA review it and approve it 

	6	unless it finds that it does not meet the requirements of
	7	the law. 
	8		Accordingly, if you don't have an NDA, as a 
	9	sponsor, you can't ship a drug in interstate commerce.  But 
10	clearly, what do you do about investigational drugs?  So, 
11	since the 1938 version of the Act, there has been something
12	known as a Notice of Investigational Exemption for an 
13	Investigational Drug or something to that effect.  
14	Obviously, I am fumbling on it and over the years its use 
15	has changed and it has been called an Investigational New 
16	Drug Application.
17		This is a device that allows someone who wants to 
18	conduct trials with the drug, experiments, to obtain 

19	supplies of drug that moves in interstate commerce.  This is 
20	where the Federal Government's hook comes in, because it is 
21	interstate.
22		Well, in 1962, the IND, which between '38 and '62 
23	was largely a notice issued by someone who was going to move 
24	the drug that they were going to do so, the only provision 
25	is at that time that they had to label the drug as 

			14 1	investigational and keep records of what they had, got
	2	changed because of a number of events that I don't have time 
	3	to go into, but many of them concerned the widescale, 
	4	unsupervised distribution of thalidomide at the time the 
	5	thalidomide story broke. 
	6		It also probably concerned developments in the
	7	issue of human rights, knowledge of basically violations of 
	8	human rights in research, putting patients at risk for the 

	9	interest of society without due attention to the rights of 
10	individual patients that led to a whole new introduction or 
11	respecification, I should say, of the IND requirements.
12		[Slide.] 
13		So, in '62 you see a set of rules that give the 
14	FDA authority to monitor research that is going on and to 
15	specify and set forth in regulation, requirements that 
16	sponsors have to meet to set it.
17		This whole thing, as you know, you have to do 

18	testing before you put patients at risk.  You have got to do 
19	some testing.  It doesn't specify what it is, but you have 
20	to do something.  Control supplies of the drug, don't give 
21	it away to your neighbors, your friends, or anyone you want,
22	because then you have widescale distribution.  Keep records, 
23	so we will know what is going on in cases there is a 
24	disaster that happens in three patients, tell everybody, 
25	obvious reason protect us.  Finally you see the beginning of 

			15 1	informed consent.
	2		Now, the requirements of this particular IND are 
	3	interesting because they show how far we have come.  At that 
	4	point, a physician, in their judgment, could decide it would 
	5	not be in the interest of a patient to give informed consent 
	6	and could suspend it.  Clearly, that is not the rule today,
	7	and today we only have one exception under very, very 
	8	careful circumstances where you can't have informed consent. 
	9		Well, if you look at this regulation as it 
10	actually is in the Act, not the regulation but the law, it 
11	appears to be an exemption solely granted for
12	investigational use.  But clearly, since 1962, when controls 
13	became fairly demanding, people have used the 
14	investigational exemption as a device to treat patients who 
15	are sick.  In the brochure, we have given you an article 

16	published in '88 or '89 that gives some of the history, but
17	basically, it is obviously so that many drugs are not 
18	pursued commercially and they end up in this sort of never- 
19	never land state, having some evidence supporting their 

20	value, but they can't be moved in interstate commerce. 
21		So people gave them INDs, and this was known as
22	compassionate use, single investigator treatment use, and 
23	the like, but it was in sort of a limbo regarding the law. 
24	So when the FDA began in the early eighties to take a very 
25	serious look at what its regulations were in regard to 

			16 1	investigational use, a rewrite effort, it decided to settle
	2	once and for all treatment use under investigational 
	3	exemptions, and it came up with the notion and the device of 
	4	something called the treatment IND or the treatment protocol 
	5	under an existing IND that allowed the use of an 
	6	investigational drug.
	7		Now, this is very different.  It was done.  It was 
	8	in fact challenged as not being consistent with the law by 
	9	some commentators, but the FDA decided that it was, and we 
10	now have the regulation that is critical to today's 
11	discussion.
12		[Slide.] 
13		Now, this regulation lays out the conditions very 
14	carefully of when you can in fact have treatment use.  The 
15	reason for this is that we have a standard of an Act which 
16	we believe ensures the quality and performance of drugs that
17	are in the armamentarium.  That is set by the Act and we go 
18	through a process of approving NDAs that is supposed to 
19	guarantee that drugs are safe in use, effective in use, and 
20	labeled appropriately. 
21		If we were to allow treatment use, we could
22	generate in perpetuity the marketing of a whole new class of 
23	agents that had not met the test of law and would clearly 
24	violate the interests of society supposedly in the defending 
25	that Act. 

			17 1		So treatment INDs are set up under fairly
	2	stringent conditions that have to be met in order to allow 
	3	treatment use, also important to recognize that they are 
	4	intended not to allow use forever, a point I will come back 
	5	to. 
	6		Anyway, here are the conditions.  This is all part
	7	of concern that drugs that are going to be effective are 
	8	denied because of bureaucratic sloth and the like -- which I 
	9	deny, but that certainly was the assertion -- availability 
10	of drugs.  It takes too long to get them. 
11		So here are the conditions.  The drug has to be
12	intended to treat a serious or immediately life-threatening 
13	illness.  There is no comparable or satisfactory treatment 
14	available, marketed, to treat that condition. 
15		And here is an important thing.  The drug is under 
16	investigation in controlled trials or all controlled trials,
17	and it doesn't say it, but it means necessary probably for 
18	the submission and approval of an NDA have been completed 

19	and the sponsor is actively pursuing with diligence this 
20	development of the product so we are going to get an NDA. 
21		All of this points again to the point that this is
22	a transient state, it is not supposed to create a new drug 
23	class. 
24		[Slide.] 
25		Now, it is important, as always, to consider 

			18 1	definitions when people throw words around without defining
	2	them.  Remember, you have got to define what you mean by 
	3	serious disease and a life-threatening illness.  Without 
	4	doubt, ALS is a serious or life-threatening illness, but by 
	5	this test of regulation, it probably qualifies as a serious 
	6	disease.
	7		If you look at the definitions, immediately life- 
	8	threatening, it is down at the very bottom, it is a stage of 
	9	a disease in which there is a reasonable likelihood that 
10	death will occur within a matter of months or which 

11	premature death is likely without early treatment.
12		You could argue that ALS even fits that, but for 
13	purposes of the typical patient at the time of presentation 
14	has been treated with Myotrophin, I would argue we are at 

15	the stage we are talking about what would be classified as a 
16	serious disease.  It is a minor point, but therefore, the

17	test would be that no one can deny a request for treatment 
18	use those first four conditions having been met if there is 
19	insufficient -- you can only do it if there is insufficient 
20	evidence, which means you need sufficient evidence. 
21		[Slide.]
22		Now, here is the rub which is always true.  
23	Sufficient and substantial, they like to say are terms of 
24	art.  What does that mean?  It means that if you read the 

25	legislative history, the regulatory history, you may have an 

			19 1	opinion about what they mean.
	2		Substantial evidence, just to set where we are, 

	3	which is the requirement for approval of an NDA, has been 
	4	characterized as just such a term of art, but it has been 
	5	long used and I can tell you what its salient points are. 
	6		It basically says that in order to reach an

	7	affirmative decision that a drug will be effective for use, 
	8	experts qualified by experience and training in the 
	9	management of the illness for which the drug is being 
10	proffered, have to be able to conclude, not on the basis of 
11	this opinions, beliefs, prior experience, but on the basis
12	of evidence adduced in adequate and well-controlled trials, 

13	that the drug will do what the labeling the sponsor is going 
14	to use claims it will do. 
15		That is very important because it is not seeking 
16	testimony or belief, it is seeking a judgment by experts
17	qualified to make such judgments that evidence exists from a 
18	trial, which is deemed adequate and well controlled, that 
19	is, scientifically bona-fide trial, that supports the claims 
20	the sponsor makes. 
21		Now, that cuts two ways.  It means you need
22	evidence that comes from investigations that are 
23	scientifically valid, but it also means that you don't have 
24	to have a drug that work in everyone or in all conditions.  
25	You need only meet the requirements that the sponsor has 

			20 1	claimed for the drug.  So you can have very narrow.  That
	2	allows you to make decisions.  I mean you did one yesterday.  
	3	You don't think that that product works in every patient 
	4	with stroke.  You think it works in a selected subset, and 
	5	this is perfectly legal under substantial evidence. 
	6		[Slide.]
	7		Okay.  What is sufficient then?  The only thing I 

	8	can tell you about sufficient is that it has to be less than 
	9	or equal to substantial.  However, as a matter of practice, 
10	because we know where we are going and because you know what 
11	the intent of the regulation is, sufficient usually means
12	that one component of the evidence that we intend to rely 
13	upon has probably already been generated at the time we make 
14	the decision.  It needn't always be true, but in practice, 
15	in previous treatment INDs that has been the case, and it 
16	has often been the case that we have an expectation, a good
17	one based on the fact that trials are ongoing, that we will 
18	shortly have results -- it could be a matter of a couple of 
19	years -- of another trial of equal structural validity and 
20	the likelihood of success that will confirm the first, so we 
21	will have our investigations, plural, as required in most
22	cases under the current Act.  That is the best I can tell 
23	you. 
24		[Slide.] 
25		Actually, if you go back and saw what was going on 

			21 1	in June of 1995, Cephalon informed us that they had the
	2	results of Study 1200 -- this is the North American trial -- 
	3	in hand, and they were persuaded that they had met the test 
	4	of what would contribute to substantial evidence. 
	5		Upon review of that, we agreed.  In fact, we were 
	6	the ones, the agency, who encouraged the sponsor, as part of
	7	your role of trying to accelerate the availability of 
	8	promising drugs, to submit a treatment protocol, and the 
	9	sponsor agreed to do so. 
10		[Slide.] 
11		We didn't get that submission until October of
12	'95, and the points I probably should just reemphasize, what 
13	is probably obvious to all of you, the reason that we were 
14	able to make this suggestion and the sponsor could agree, is 
15	that it is a serious illness or worse, certainly a 
16	devastating one.  There was no fully satisfactory treatment
17	available.  That remains true to this day. 
18		We had the second trial underway.  It wasn't 
19	completed yet, but we knew it was going to complete, and we 
20	had every reason -- and I still do -- to believe that the 
21	sponsor is pursuing the development of the drug in the sense
22	that they will submit an NDA or want to submit an NDA. 
23		[Slide.] 
24		Now, in October of '95, however, just about at the 
25	time that we are going through the necessary internal 

			22 1	documentation to make a recommendation to the authority in
	2	FDA that can grant permission for a treatment IND, I believe 
	3	three or four days prior to the time this action had to be 

	4	taken, we received a copy of a press release that Cephalon 
	5	had issued. 
	6		In reviewing that, it basically said that the
	7	results of the European trial, 1202, formally and strongly 
	8	confirmed the results of 1200.  I have to admit we were 
	9	happy that was the case, but then we read it and we found 

10	that there appeared to be -- in fact there was -- a relative 
11	excess of deaths in Study 1202 among patients assigned to
12	Myotrophin as compared to those assigned to placebo. 
13		Well, that could always be due to chance.  In 
14	fact, on straight statistical analysis, it was, but one must 
15	remember that imbalances that aren't even statistically 

16	significant can have an impact on the interpretation of
17	other results because of the net effect that someone who 
18	dies may, in fact, have a score attributed to them, and 

19	there was a possibility, if one looks seriously, since there 
20	was a slight excess in Study 1200 of deaths, that something 
21	wasn't awry, and so we delayed making a treatment IND
22	decision. 
23		We asked the firm to submit more information, 
24	which they did, and there I think is the reason we come 
25	before you today, because in the course of looking over this 

		23 1	evidence, we were unable to reach the same conclusion as the
	2	firm in regard to whether or not 1202 was a confirmatory 
	3	trial.  In face, we viewed 1202 -- and to this day do -- as 
	4	a study which fails to confirm the results of Study 1200.  

	5	That is the Division's view.  The firm takes a different 
	6	stance.  They have been able to conduct analyses based not

	7	upon the initial described in the protocol, which convinced 
	8	them that the trial at worst is not contradictory and at 
	9	best is supportive. 
10	          That really is the issue before us today.  We 

11	thought that it would be impossible for us, given the fact
12	that we had spent several months with the firm going over 
13	the data, we were unable to reconcile our differences, we 

14	thought it was impossible to make a decision without sharing 
15	it in a public way with everyone here and gaining the 
16	opinion of experts who could look at this evidence in a
17	disinterested way and decide whether or not it met the test. 
18	          That is really what your charge is today, to look 
19	at the evidence and to decide whether it is sufficient for 
20	its treatment use.  The issue of the approvability of the 

21	NDA cannot technically be on the table, of course.  It
22	cannot be on the table at all because no NDA is pending 
23	before the agency.  But one has to consider the evidence 

24	nonetheless in its entirety, what it can support and what is 
25	likely in the future. 

			24 1		Clearly, that is the intent of the regulation, and
	2	within that context, we hope you can struggle with the data, 
	3	as we have, to see what it really means. 
	4		That concludes my opening remarks.  One thing I 

	5	would like to point out and ask the Chair's permission, we 
	6	had prepared our presentation on the basis largely of the
	7	briefing materials supplied by the firm some time ago. 
	8		As late as yesterday, we were receiving revised 
	9	presentations of arguments.  In addition, there are other 

10	points made that would take so much time for us to discuss, 
11	in fact, we would as a practical matter have to present the
12	firm's argument in order to explain what we find weak or 
13	deficient in it. 
14		So accordingly, I would like to ask the Chair if 
15	it is possible, after the committee and the firm have made 
16	their presentation, for us to be able to explain our view on
17	various arguments they are going to present for the first 
18	time today. 

19		They have already seen what our presentations are, 
20	so they will be fairly and directly prepared to discuss any 
21	of them.
22		DR. GILMAN:  That is perfectly acceptable.  Any 
23	concern from the committee about that request? 
24		Let's proceed in that fashion.  Dr. Leber, let you 
25	ask you about substantial and sufficient.  The way we 

			25 1	usually work in this committee is to see plural of trial, we
	2	wish to see at least two well-constructed, valid trials 

	3	showing evidence, and we then conclude if the data are 
	4	convincing that we have a substantial piece of evidence. 
	5		With the term "sufficient," would it be fair for 
	6	this committee to assume that a single trial, if it is
	7	convincing, does in fact provide sufficient evidence and 

	8	therefore would constitute enough evidence to approve an 
	9	IND? 
10		DR. LEBER:  It is a little more complicated.  Yes 
11	is the simple answer, but I suggest that it is a little more
12	complicated than that, because sufficiency regards the 
13	evidence.  It also regards the state of time the development 
14	of a drug where that judgment is made. 
15		The evidence, if we had but a single trial, as we 
16	did in June of 1995, we thought the evidence was sufficient
17	because all information bearing on the effectiveness of this 
18	drug and its safety was in our possession. 
19		What becomes more complicated is when you have 

20	contradictory evidence, and then the standard may shift 
21	slightly.  If you only had one study, and there was no other
22	evidence, it is clear that one study would be sufficient, 
23	and has been in the past. 
24		What the problem is now is that with the addition 

25	of conflicting evidence -- and you have to decide whether it 

			26 1	is truly conflicting, you may agree with the sponsor that it
	2	is not -- you may have to modify that view. 
	3		So again it may sound like I am trying to evade 

	4	the response, but I think it is a conditional thing in the 
	5	context of how much evidence you really have in your 
	6	possession.  If there was only one, it is enough, but it is
	7	than one, and it is not confirmatory, then, you have a 
	8	different level of problem. 
	9		DR. GILMAN:  I expect that if we had only one 
10	trial that were very convincing, you wouldn't need us here. 
11		DR. LEBER:  If we had only one trial, we probably
12	would not have come.  The minute we have two trials that do 
13	not appear to robustly confirm one another, there is always 
14	this question of what does the conflict mean, and I think 
15	that is why you are here. 
16		DR. GILMAN:  Thank you.  Any other questions for
17	Dr. Leber? 
18		Thank you very much. 
19		Let's proceed then.  John Feeney, M.D., medical 
20	reviewer, Neurology Drug Group, will make the presentation 
21	on behalf of the FDA.
22	         PRESENTATION AND ANALYSIS OF THE DATA FROM 
23	      STUDIES 1200 AND 1202 ON MYOTROPHIN'S USE IN ALS 

24		DR. JOHN FEENEY:  Good morning.  We are just going 
25	to get our slides together and get going in a few seconds 

			27 1	here.
	2		[Slide.] 
	3		I have a few introductory slides here.  Basically, 
	4	Myotrophin is insulin-like growth factor 1 or somatomedin C.  
	5	It is a 70-amino acid polypeptide that is produced in a 

	6	yeast culture system.   It share approximately 50 percent
	7	homology with insulin. 
	8		Circulating IGF-1 is produced almost entirely by 
	9	the liver in response to human growth factor and it is 
10	believed to mediate the majority of effects of human growth 
11	hormone.  IGF-1 can also be produced locally in a number of
12	other tissues. 
13		Cephalon undertook studies of Myotrophin in ALS 
14	after it was shown that Myotrophin promoted axonal sprouting 
15	in animal models of denervation and also prolonged neuronal 
16	survival in the chick embryo model of neuronal loss.
17		[Slide.] 
18		INDs for IGF-1 existed in the Division of 
19	Endocrine and Metabolism prior to 1992, but in 1992, when 

20	Cephalon opened its IND for the use of Myotrophin in ALS, 
21	the IND was submitted to the Division of
22	Neuropharmacological Drug Products. 
23		By mid-1995, two clinical trials that you have 
24	heard of, 1200 and 1202, had been completed and you just 
25	heard that the treatment IND was submitted in October with 

			28 1	the results of 1200.
	2		Then, on October 31st, the results of 1202 were 
	3	made public by Cephalon. 
	4		[Slide.] 
	5		I am sorry, this is kind of hard to read.  
	6	Basically, both of the trials, 1200 and 1202, are capably by
	7	design of demonstrating an effect of Myotrophin in ALS.  
	8	They are both double-blind, randomized, placebo-controlled 
	9	trials. 
10		They are both parallel in design with nine-month 
11	treatment periods.  Both of the trials include eight
12	centers.  1200 was conducted in North America.  1202 was 
13	conducted in Europe. 
14		The 266 patients in Study 1200 were equally 
15	divided among three treatment groups. The three treatment 
16	groups were placebo, low-dose Myotrophin, and high-dose
17	Myotrophin.  I will just tell you that the low dose was 0.05 
18	mg/kg/day given as a single sub-Q injection with a matching 
19	placebo injection later in the day, and the high dose was 

20	0.10 mg/kg/day divided into two equal injections. 
21		The 183 patients in Study 1202 were divided with a
22	2 to 1 randomization between Myotrophin and placebo.  The 
23	dose utilized in 1202 was 0.10 mg/kg/day, essentially the 
24	same as the high dose in Study 1200. 
25		I will just mention at this point that that dose 

			29 1	of 0.05 mg/kg comes from early Phase I testing where it was
	2	determined that higher doses caused an excess of symptomatic 
	3	hypoglycemia.  So that 0.05 mg/kg represents the maximal 
	4	single tolerated dose. 
	5		[Slide.] 
	6		Both of the trials relied heavily on the Appel
	7	Scale to grade patients' clinical status over time.  The 
	8	Appel Scale was developed at Baylor University in the early 
	9	1980s, and the experience with that was first published in 
10	an article by Appel, et al., in 1987. 
11		The Appel Scale grades patients with a range of
12	scores between 30, for best performance, and 164, for worst 
13	performance.  It consists of five components, three of which 
14	are shown here:  bulbar, respiratory, and muscle strength. 
15		The bulbar score consists of equal representation 
16	for swallowing and speech.  The swallowing is assessed by a
17	patient's diet and the speech is assessed at the time of the 
18	examination. 
19		The respiratory score is based on forced vital 

20	capacity, which is basically, as most of you know, the 
21	maximal amount of air that a patient can expire after a
22	maximal inspiration.  Basically, changes on forced vital 
23	capacity are mapped to six-point increments on the Appel 
24	Scale. 

25		I should mention that each of the components, each 

			30 1	of the five components contributes approximately 30 to 36
	2	points to the total Appel score. 
	3		Muscle strength is graded on the MRC zero to five 
	4	scale, the Medical Research Council scale.  Muscles are 
	5	graded zero to 5, and then the sum of numerous muscles are 
	6	mapped to a score on the Appel Scale.
	7		[Slide.] 
	8		The other two components of the Appel score are 
	9	upper extremity function and lower extremity function.  Each 
10	of these consists of four timed items, such as time to walk 
11	20 feet, time to cut some theraplast in occupational
12	therapy, time to perform some activities with a peg board, 
13	and then there are two functional items based on historic 
14	ability to do things, let's say, with the arms and shoulders 
15	or to dress and feed yourself. 
16		[Slide.]
17		In the 1987 publication, Appel, et al., compared 
18	their Appel scores to an independent five-point assessment 
19	of severity of ALS symptoms.  In doing this, they found that 
20	patients who were independent, still living alone, basically 
21	doing very well, had an average score of about 52, and the
22	range here was very tight. 
23		Patients who were no longer independent, might 

24	need a walker and some assistance, had an average score of 
25	75.  Patients who could usually no longer work, required a 

			31 1	caretaker for a lot of things, had an average score of about
	2	100.  Patients who were at the point where they might 
	3	require tracheostomy or a gastrostomy had an average score 
	4	of 120, and patients who were very severely affected had a 
	5	score of approximately 135. 
	6		[Slide.]
	7		Appel, et al., found that if they looked at Appel 
	8	scores over time for the 74 patients in their experience -- 
	9	they followed these 74 patients for up to two years -- they 
10	found that there was a remarkable linearity and that a 
11	linear slope could be fit to the scores over time.
12		Basically, this means that about 80 percent of the 
13	variability of the Appel scores for an individual patient 
14	could be accounted by fitting the line. 
15		This shows the distribution of Appel scores over 
16	time for 74 patients in that 1987 publication.  I want to

17	point out that the units here are represented in units per 
18	day.  This is in keeping with the original 1200 study 
19	report.  Unfortunately, you are going to have to deal with 
20	the fact that sometimes units you will see today will be 
21	expressed in units per month, and I don't think I have to
22	tell you that the conversion factor is about 30 there. 
23		So this is the distribution of slopes for the 74 
24	patients.  Let me tell you that for a slope of 0.14 units 

25	per day, basically, patients with this slope or greater will 

			32 1	experience approximately a 50-point or greater rise in their
	2	Appel score in the course of one year.  So these patients 

	3	are moving fairly quickly through their disease process. 
	4		Patients with a score of about 0.03 to 0.14 are 

	5	going to move approximately 10 to 50 points in the course of 
	6	a year, and about 50 percent of patients fall into that
	7	range. 
	8		Patients with scores of 0.03 and less are going to 
	9	move 10 points or less in the course of a year, and they 
10	might be considered slow progressors. 
11		In a 1995 publication, Appel tried to validate his
12	scale by using these slopes to predict time-to-death for 
13	patients with ALS.  Basically, what he found is that the 
14	higher the slope, the better the predictive value. 
15		Especially for patients in the slow-moving group 
16	of 0.03 units per day or less, they found that the
17	predictive value is very poor, and what you are going to see 
18	is that the inclusion/exclusion criteria of Studies 1200 and 
19	1202 basically tended to exclude these patients who were 
20	slowly moving. 
21		[Slide.]
22		These are the inclusion/exclusion criteria.  They 
23	are essentially the same for Studies 1200 and 1202.  
24	Patients had to be greater than 20 years of age, and they 
25	had to be diagnosed with classical, non-familial ALS.  There 

			33 1	was no operational definition of how to define classical
	2	ALS, but I would expect that most of the investigators were 
	3	using what has become accepted as the AALS score criteria 

	4	for diagnosing ALS.  Note that patients with familial ALS 
	5	were excluded. 
	6		Patients had to have a disease duration less than
	7	36 months and a forced vital capacity greater than 50 
	8	percent, and they have to have a score of 40 to 80 at the 
	9	time of screening on the Appel score. 
10		All of these criteria basically were meant to 
11	incorporate patients with mild to moderate ALS into the
12	trial. 
13		There is also a requirement that patients, once 
14	they were screened, they had to progress at least 5 points 
15	on the Appel Scale during a two- to three-month mandatory 
16	run-in period.
17		[Slide.] 
18		This is an outline of study events during both 
19	trials.  At month zero, this is the baseline visit or the 
20	time of randomization, and you will that once randomized, 

21	patients could continue on treatment for up to nine months. 
22	This represents a nine-month completer here. 
23		During the course of that nine months, if patients 
24	reached an Appel score of 115, they were allowed to be 
25	censored by protocol and basically leave the study.  They 

				34 1	were considered to be failures at that point, too sick to
	2	possibly return to the clinic for visits. 
	3		Not shown here is that independent of your Appel 
	4	score, you could also leave the trial, be censored early, or 
	5	a forced vital capacity of less than 39 percent. 
	6		So we have those categories, forced vital capacity
	7	and Appel score.  I should note that some people actually 
	8	endpointed for both of them at the same time. 
	9		Now, over here, to the left of the zero point, you 
10	will see this patient has a two-month run-in.  This patient 
11	has a three-month run-in.  Basically, this patient had met

12	the five-point criteria progression within two months, was 
13	randomized at that point. 
14		This patient took a full three months to progress 
15	five points and was randomized at that point. 
16		If a patient was screened, went three months,
17	hadn't progressed five points, they would not be randomized.  
18	They would not be eligible for entering into the trial. 
19		You can see on this slide basically the 
20	distribution of Appel scores that is collected over time 
21	with monthly Appel scores recorded for patients.

22		DR. GILMAN:  May I ask a question here. 
23		DR. FEENEY:  Sure. 
24		DR. GILMAN:  As I read the protocol, as I 
25	understand it, patients with primary lateral sclerosis and 

				35 1	patients with progressive bulbar palsy were excluded from
	2	that trial. 
	3		DR. FEENEY:  That is right. 
	4		DR. GILMAN:  My question is whether the original 
	5	Appel Scale also excluded those variants of ALS. 
	6		DR. FEENEY:  I don't know the answer to that.  I
	7	don't know if Dr. Appel is here today. 
	8		DR. GILMAN:  Please go to the microphone, Dr. 
	9	Appel. 
10		DR. STAN APPEL:  Patients with either of those 
11	have been included, but in our database can be separated out
12	by those criteria and can be looked at separately. 
13		DR. GILMAN:  So they are included in the original 
14	74, however, they are excluded in the trials of Myotrophin? 
15		DR. APPEL:  Excuse me.  No, the original 74 were 
16	patients that we were looking at collectively that had to
17	meet all the typical criteria, having all systems 
18	compromised, and by definition, they wouldn't fit, primary 
19	lateral sclerosis would not fit.  Primary bulbar palsy with 
20	no other involvement would not fit.  So they were excluded 
21	from the original 74.
22		My point is, in the whole database, we have them 
23	included and we have graded them, as well, but with respect 
24	to the 74, they are not included, and they are also excluded 
25	from the 1995 paper, because those criteria do not fit the 

					36 1	AALS criteria for classical ALS.
	2		DR. GILMAN:  The reason for that is, the question 
	3	about whether the patients examined with Myotrophin and 
	4	placebo are equivalent to the patients in the original 
	5	database, because those comparisons are made with slopes.  I 
	6	think the answer is yes, they did.
	7		DR. APPEL:  The answer is yes. 
	8		DR. GILMAN:  They do correspond well. 
	9		Another question.  Those cases that progressed 
10	more rapidly than others, were they people who had 
11	substantial bulbar involvement in both the original 74 and
12	also in the cases studied? 
13		DR. APPEL:  They may or may not.  Bulbar is a 
14	component. 
15		DR. GILMAN:  I know. 
16		DR. APPEL:  The point is to get that much
17	involvement and that rapid a progression, you usually have 
18	to have either bulbar and/or respiratory, or large 
19	respiratory component. 
20		DR. GILMAN:  So the answer is yes, they were more 
21	likely to have bulbar involvement than those who progressed
22	more slowly. 
23		DR. APPEL:  Yes. 
24		DR. GILMAN:  Thank you. 
25		Dr. Adams. 

				37 1		DR. ADAMS:  I have a question in regard to the
	2	inclusion/exclusion criteria.  It is stated that at 
	3	screening the patient had to have a score of 40 to 80, and 
	4	in the first two to three months, had to progress at least 
	5	five points. 
	6		DR. FEENEY:  Yes.
	7		DR. ADAMS:  Was there an exclusion for people that 
	8	may have progressed 40 points, we will say, in the first two 
	9	to three months, so that the very, very rapidly progressing 
10	patients at far extreme were excluded or included? 
11		DR. FEENEY:  No, I can tell you that I think in
12	Study 1200, at baseline, the highest total Appel score for 
13	any patient was I think about 110.  So there were some 
14	people who were moving pretty rapidly, not a lot, but there 
15	were some.  You will actually see the distribution of total 
16	Appel scores later at baseline.
17		[Slide.] 
18		You saw that Appel scores were collected monthly 
19	throughout the trial.  What do you do with those Appel 
20	scores?  Well, you can combine them into different outcome 
21	measures, and four of them are shown here.
22		The first two are last observation carried forward 
23	endpoints, where basically the last observed score for any 
24	patient during the course of the trial is carried forward 

25	for analysis purposes. 

			38 1		There are problems with LOCF analyses in studies
	2	of progressive illness because any score that you carry 

	3	forward would be expected to be less than the patient's 
	4	realized score had they been followed forward in time.  So 
	5	just keep that in the back of your mind whenever you are 
	6	looking at an LOCF analysis in an degenerative condition,
	7	anytime you have patients censored early, you are going to 
	8	have to think about your LOCF analysis. 
	9		The next are slopes analyses.  These basically 
10	compute slopes for patients over time, and then I want you 

11	to note that these two, this one here and this one, are both
12	related back to baseline pre-randomization levels of 
13	functioning for the patients.  So this is kind of a change 
14	from baseline, and this is a change from pre-randomization 
15	here. 
16		This one here, this slopes analysis, post-
17	randomization minus pre-randomization slope, is the analysis 
18	that incorporates all of the Appel scores over time for an 
19	individual patient as they were collected in the trial. 
20		Now, in Study 1200, the primary protocol-specified 
21	outcome measure were post-randomization slopes.
22		In Study 1202, the primary protocol-specified 

23	outcome measure was last Appel score minus baseline Appel 
24	score. 
25		You might ask why, in two studies that are 

			39 1	essentially the same, why the primary outcome measure
	2	differed, and to be honest with you, it has never been 

	3	totally clear to us, and when this was defined as the 
	4	primary outcome measure in Study 1202, we in discussions 
	5	with the sponsor let them know that we would be looking at 
	6	other analyses that might incorporate more data on patients
	7	over time.  Just a point worth remembering. 
	8		[Slide.] 
	9		What I want to do now, if we could back on the 
10	right there, to highlight the similarities and differences 
11	between Study 1200 and 1202.  I would like to present some

12	of the findings side by side here, so that you don't have to 
13	be thinking what happened in the other study on this 
14	particular measure. 

15		[Slide.] 
16		As mentioned earlier, both studies were capable by
17	design of demonstrating an effect of Myotrophin in ALS.  

18	Both were randomized, placebo-controlled trials, three 
19	treatment groups in Study 1200, two treatment groups in 
20	Study	1202. 

21		The randomization was unbalanced 2 to 1 here, and
22	was balanced here.  Not shown on the slides is that the 

23	randomization in Study 1200 was stratified based on the 
24	baseline Appel score.  That is, patients with a score of 61 
25	or greater were stratified, were considered in the upper 

			40 1	strata.  Patients with baseline scores of 60 or less were
	2	considered in the lower strata. 
	3		The reason for the stratified randomization was 
	4	simply to create a balance between the three treatment 
	5	groups.  It was never meant for analysis purposes.  In Study 
	6	1202, the randomization was never stratified.
	7		The primary outcome variable, we have already 

	8	talked about, differed between the two trials, and the 
	9	primary analysis, both of these studies by protocol had a 

10	covariate analysis.  The method for selecting the covariates 
11	was basically to look at from a preselected list of
12	covariates, to look at the results of the trial and examine 
13	which covariates had the most predictive value. 
14		In retrospect, we had to think that this method of 
15	selecting covariates had the potential to increase the 

16	chance for a false positive result, so that we chose to
17	create non-covariate analyses, which we consider better 

18	analyses, but we will present the results for both covariate 
19	and non-covariate analyses for both trials. 
20		DR. GILMAN:  Let me ask you a question about the 
21	primary outcome variables in the two studies.  It was not
22	clear to me from reading both materials why these two 
23	studies had difference primary outcome variables. 
24		What was the rationale? 
25		DR. FEENEY:  Not having done it myself, I think we 

				41 1	would have to defer to the sponsor.
	2		DR. GILMAN:  Please identify yourself at the 
	3	microphone. 
	4		DR. WILLIAM GRANEY:  I am Dr. William Graney from 
	5	Cephalon. 
	6		The change between the 1200 or North American
	7	trial, and the 1202, or European trial, was initiated at the 
	8	request of the European investigators.  The trial, as you 
	9	can see, had a slightly smaller number of patients, and 

10	their concern was that the number of patients required for 
11	the slopes or the number of measurements in each patient

12	required for the slopes, a minimum of three, would reduce 
13	the number of patients getting into the primary analysis. 

14		They felt that the use of the changed score, where 
15	it is only necessary to have a baseline and one successive 
16	measurement to be able to calculate the score, brought them
17	closer to an intent-to-treat approach. 
18		That really was the genesis of it and it arose 
19	from the European investigators themselves who, as you will 
20	see in our presentation, had a fair amount of input into the 
21	design decisions made in the European trial.
22		DR. GILMAN:  I am not sure I entirely understand 
23	that.  You mean that they wanted to have only a single 
24	observation before they randomized? 
25		DR. GRANEY:  They were concerned that during the 

				42 1	course of the trial, the dropouts that occurred would result
	2	in a relatively small number of patients or a smaller number 
	3	of patients who had three post-baseline evaluations.  In 
	4	other words who had an event or left the trial in months 1 
	5	or 2 would not have three post-baseline measurements to 
	6	allow the calculation of a slope.  It was specified in the
	7	protocol ahead of time.  As you can imagine, to get a 
	8	realistic slope or line, three points would be needed. 
	9		They were concerned, especially having a slightly 
10	smaller number of patients in the European trial than in the 
11	U.S., that the credibility and the acceptability of that

12	measurement would be lessened if there were a substantial 
13	number of patients who did not qualify for the primary 
14	endpoint. 
15		DR. GILMAN:  Are you referring to the pre- 
16	randomization or post-randomization, or both?
17		DR. GRANEY:  These are post-randomization 
18	measurements. 
19		DR. GILMAN:  Post. 
20		DR. GRANEY:  Yes, sir. 

21		DR. GILMAN:  Thank you.
22		Dr. Drachman. 
23		DR. DRACHMAN:  Would you clarify the way the slope 
24	was figured, was that done algebraically, was it a best-fit 
25	regression analysis, or how did they do that? 

				43 1		DR. FEENEY:  From my understanding, it was best-
	2	fit linear regression. 
	3		DR. DRACHMAN:  What did they do with the dropouts? 
	4		DR. FEENEY:  As Dr. Graney was just alluding to, 

	5	the slopes analysis in Study 1200 by protocol required that 
	6	patients have at least three post-baseline Appel scores to
	7	make the slope.  If somebody had fewer than three post- 

	8	baseline slope points, Appel points, they would not be 
	9	included in the analysis.  They were just not included. 
10		You will see later just how many patients that 
11	comprises.  It was about one out of nine patients in each

12	study did not have three post-baseline Appel scores, so they 
13	are not entered in the post-randomization slopes analysis. 
14		DR. DRACHMAN:  Was linearity an issue at all here? 
15		DR. FEENEY:  No.  I guess I failed to mention 
16	that, like the Baylor group, we found the linearity was very
17	good in about 80 percent of the variability was accounted 

18	for by these fitted lines in both Studies 1200 and 1202. 
19		DR. GILMAN:  Dr. Leber? 
20		DR. LEBER:  I just want to emphasize that what we 
21	are talking about is within-subject variance, having a very
22	high accountability.  The between-slope variance is quite 
23	large, as you saw. 
24		DR. GILMAN:  Please continue. 
25		[Slide.] 

			44 1		DR. FEENEY:  Both of the trials had some secondary
	2	outcome measures that I haven't mentioned yet.  In both 
	3	trials, clinical global impression was performed on a 
	4	monthly basis. 
	5		Basically, this had two components.  There was a 
	6	seven-point change from previous month scale and a five-
	7	point change from baseline scale, and patients were graded 
	8	on a monthly basis. 
	9		The sickness impact profile is a quality of life 
10	questionnaire that is comprised of about 136 questions that, 
11	for the most part, are yes/no type questions.  These 136
12	questions can then be broken down into I think about 12 
13	categories, which are then further broken down into domains, 
14	two or three big domains, such as physical impairment and 
15	psychosocial impairment. 
16		For treatment IND purposes, we have not performed
17	full analyses of these scales, and we have chosen to focus 
18	primarily on the Appel scores, but realize that these scales 
19	were utilized.  I think the sponsor will talk about some of 
20	those results. 
21		[Slide.]
22		Now, what about patient flow?  I know you can't 
23	read this, but take my word for it, for each of the five 
24	treatment groups across Study 1200, or I should say all of 
25	the slides on the left will be Study 1200, all the slides on 

			45 1	the right will be Study 1202.
	2		Approximately half of the patients in all of the 

	3	treatment groups were non-completers, so about half of the 
	4	patients completed a full nine months of treatment during 
	5	these trials. 
	6		The reasons for leaving the trial were mentioned

	7	earlier.  There could be an Appel endpoint, an FVC endpoint, 
	8	patients could die.  Patients could, like in any trial, 
	9	leave for adverse events, administrative reasons, and 
10	whatnot. 
11		If you look here, you can see in Study 1200 the
12	number of people censored early because of an Appel endpoint 
13	of 115 or a forced vital capacity of less than 39.  You can 
14	see that already you can tell that in the high-dose group 

15	here, there seems to be a benefit for the Myotrophin group 
16	compared to placebo over there.
17		It is hard in Study 1202.  You have to take into 
18	account the 2 to 1 randomization, but I think you can see 
19	that if you take that into account, there does seem to be 

20	some benefit on time to Appel endpoint and for FVC endpoints 
21	here, but unfortunately in 1202, this trend in favor of drug
22	is counterbalanced by an excess of deaths on drug. 
23		[Slides.] 
24		This just gets back to that point that if you are 
25	going to do a slopes analysis as per protocol, patients with 

			46 1	three post-randomization Appel scores, with less than three
	2	Appel scores after baseline are going to be excluded, and 
	3	you can see that roughly 1 out of 9 patients in all of these 
	4	treatment groups were excluded on that basis. 
	5		It is pretty well evened out among the three 
	6	treatment groups in Study 1200.  In 1202, remember 2 to 1
	7	randomization, there is a slight excess of patients on 
	8	Myotrophin who don't go into the slopes analysis, accounted 
	9	for by some adverse events. 
10		[Slides.] 
11		The next three slides are going to talk just about
12	baseline comparisons among the treatment groups, and you 

13	will see that all the way across, Study 1200, Study 1202, 
14	basically, the age, race, baseline weight, it is almost 

15	identical.  The patients on average were about 55 to 57, and 
16	the weight all seem to be about 155 to 160.
17		[Slides.] 
18		Baseline ALS history, you will see that again 

19	totally comparable across both studies.  Time since first 
20	symptom basically about the same.  Time since diagnosis 
21	basically about the same.  When you look at first ALS
22	symptom, I really don't know what to make of this scale, 
23	because it has some kind of idiosyncratic things like 
24	sensory symptoms, which I presume are cramps or whatnot. 
25		It does appear that in Study 1202, maybe more 

				47 1	patients had weakness as a first symptom and maybe more
	2	trouble with speech in 1202.  I don't know what to make of 
	3	all that. 
	4		DR. GILMAN:  Maybe we could ask the sponsor or the 
	5	investigators to comment on that.  Some people with ALS do, 
	6	in fact, complain about certain sensory symptoms.  I assume

	7	that that is what you were observing.  Will the sponsor 
	8	comment? 
	9		DR. GRANEY:  Yes.  In fact, that is correct.  
10	These were reports.  No patient, however, entered who had 

11	only sensory symptoms.  All of the patients had the classic
12	symptoms.  Some of the reported to their investigator that 
13	they had these sensory symptoms, as well, and those are the 
14	ones that are noted there. 
15		DR. GILMAN:  But it is to be emphasize that these 
16	were symptoms, and not signs.  They did not have sensory
17	loss as examined neurologically I assume. 

18		DR. GRANEY:  That is correct. 
19		[Slides.] 
20		DR. FEENEY:  Now, here are the baseline Appel 
21	comparisons across all five treatment groups.  You have got
22	to be impressed here that the average total Appel score at 
23	baseline for all treatment groups essentially identical, 70, 
24	and you have got to be impressed, too, that the component 

25	scores are essentially identical across all three treatment 

			48 1	groups.
	2		[Slides.] 
	3		Now. these slides illustrate distributions of the 
	4	pre-randomization slopes for different treatment groups.  
	5	Here, the high does Myotrophin group with the squares in the 
	6	placebo group with the circles and Myotrophin versus placebo
	7	here.  These are cumulative distributions which basically 

	8	means that any point here on the curve will tell you the 
	9	percentage of patients on the vertical axis that have a 
10	score on the horizontal axis down here or less than that 
11	score.

12		So let's say if we take the 50th percentile here, 
13	50 percent of patients really in both treatment groups had 
14	baseline or screening slopes of approximately 0.12 or 0.13.  
15	That is what that is telling you. 
16		Now, the advantage of looking at cumulative

17	distribution functions is that visually, it is easy to 
18	compare groups.  Basically, in this case, a shift to the 
19	left would represent a favorable shift, and a shift to the 
20	right of a curve would represent a change for the worse. 

21		For instance, here, there does seem to be a slight
22	shift to the left of Myotrophin screening slopes by about 
23	0.01 units per day, a slight shift there. 
24		[Slides.] 
25		These are more familiar distribution that you are 

			49 1	used to looking at.  These are the baseline Appel scores for
	2	the high dose Myotrophin group, placebo, in 1200; 
	3	Myotrophin, placebo in 1202. 
	4		Again, we already saw the means for these 
	5	distributions.  There are 70 at baseline.  You will notice 
	6	that the distributions here are fairly comparable,
	7	especially at the high range here. 
	8		You have to focus in that in the high range down 
	9	in 1200, for the placebo patients, there is a group of about 
10	7 or 8 patients here that seems to be outliers at their 
11	baseline Appel scores.  You don't see anybody really above,
12	about 95 here.  It is about 7 or 8 patients with scores 
13	above 95 over here. 
14		Now, this may not affect a slopes analysis, but 
15	this is going to kick in for your any time-to-event analysis 
16	that incorporates an Appel endpoint of 115.  You only have

17	to look at this patient right here to tell that he is going 
18	to endpoint very soon, and in fact, all these patients were 
19	early endpointers.  So just bear that in mind for the time- 
20	to-event analyses in Study 1200. 
21		[Slides.]
22		Every protocol should have a specified outcome 

23	variable and analysis, and that is what we are looking at 
24	here.  These are the protocol-specified analyses for Study 
25	1200 and 1202. 

			50 1		In 1200, the protocol said that the pooled doses,
	2	the high dose and low dose would be pooled and compared to 
	3	placebo.  Again, the covariate analysis without covariates, 
	4	the p values were 0.055, 0.05 for the pooled comparison. 
	5		The high dose comparison to placebo reached 
	6	statistical significance with a p value of 0.027.  It just
	7	reached statistical significance based on Dunnett's 
	8	correction for multiple dose comparisons.  The low dose did 
	9	not meet statistical significance. 
10		When  you come over to 1202, again, this is an 
11	LOCF change from baseline analysis.  You can see that
12	whether you use a covariate analysis or a non-covariate 
13	analysis, the difference did not reach statistical 
14	significance with a p value of 0.34 and a p value of 0.22. 
15		[Slides.] 
16		This actually shows you the mean slopes.  Now, we
17	are looking at slopes here for both Studies 1200 and 1202.  
18	This is the mean slope for the placebo group, mean slope for 
19	the high dose Myotrophin group.  This was the primary 
20	analysis in 1200, so you know that this difference between 
21	these two reached statistical significance, we just looked
22	at that. 
23		In Study 1202, this is the mean on-study slope for 
24	the placebo group and for the high dose group.  This 
25	difference did not reach statistical significance.  The p 

			51 1	value here was 0.40 with covariates that might have come
	2	down to 0.27 or so. 
	3		Also, note that the difference here, the on-study 
	4	slopes differ by an amount really very comparable to the 
	5	difference that was already present at baseline before 
	6	treatment began.
	7		[Slides.] 
	8		Again, let's look at some cumulative distributions 
	9	of on-study Appel slopes in 1200 and 1202.  You can see that 
10	a shift to the left for the high dose Myotrophin group has 
11	occurred in Study 1200 compared to the placebo group.  The

12	shift shows a beneficial trend of high dose Myotrophin 
13	compared to placebo. 
14		When you look at the distributions here for 1202, 
15	you see that the curves superimpose except for this one 
16	small area where there is a minimal separation.
17		[Slides.] 
18		Now, what about time-to-event analyses?  The 

19	sponsor in their briefing document has presented some 
20	results of Kaplan-Meier curves with an endpoint defined as 
21	the Appel or FVC.  If the reason for looking at Appel and

22	FVC endpoints is because you consider these failures or very 
23	poor responses, I think it is only right to incorporate 
24	death into that equation. 
25		So we have performed time-to-combined endpoint 

				52 1	analyses with death, Appel, and FVC.  You can see in Study

	2	1200, you get a separation of the curves with Myotrophin 
	3	favored up here compared to placebo. 
	4		When you look at the same analysis in Study 1202, 
	5	the curves basically superimpose. 
	6		[Slide.]
	7		You have to consider those outliers on the 
	8	baseline Appel scores in Study 1200 at some point, so as an 
	9	exploratory analysis, we did repeat the time-to-endpoint 
10	analysis in 1200, excluding patients with baseline Appel 
11	scores greater than 90, and what happens is you can compress
12	these curves fairly close together with a slight separation 
13	at the end. 
14		[Slide.] 
15		The sponsor also wanted to perform time-to-20- 
16	point change analyses.  If you remember the correlation
17	between the Appel scores and that 5-point scale in the 1987 
18	publication, the five groups based on ALS severity, spread 
19	out by about 20 points or 25 points.  So you might consider 
20	that a clinically relevant change in ALS status. 
21		So this is time-to-20-point change analysis in
22	Study 1200, and you can see that it favors Myotrophin here, 
23	high dose Myotrophin versus placebo.  We don't have a slide 
24	showing the same curves in Study 1202, but the curves 
25	essentially would not separate on this analysis. 

			53 1		DR. DRACHMAN:  In the 1200, weren't there
	2	inclusion criteria scores of 40 to 80? 
	3		DR. FEENEY:  A very good question.  Forty to 80 

	4	were the screening -- a patient came in, was screened, and 
	5	they had to have a score of 40 to 80.  They then were 

	6	followed for two to three months, had to demonstrate at
	7	least a 5-point progression. 
	8		So that if you look at scores at baseline, there 
	9	is no upper limit on what your baseline Appel score could 
10	be.  I pointed out there were some patients with baseline 
11	Appel scores in Study 1200 in the placebo group with scores
12	up around 110. 
13		DR. DRACHMAN:  So were those individuals with 
14	under 80 to begin with? 
15		DR. FEENEY:  Yes, that screen, they had to be 
16	under 80.  So those patients had progressed during the two t
17	three months screening period. 
18		[Slides.] 

19		These are the extended survival analyses from both 
20	studies.  I want to point out that the study was only 300 

21	days in duration, so 300 would cut you off right about here,
22	300 would cut you off right about here. 
23		What happened after day 300 is anybody's guess, 
24	because certainly patients after day 300 were not going to 
25	respect their treatment assignments.  Any patient who was 

			54 1	originally assigned to the placebo group, I am sure is
	2	crossing over to other experimental drug therapies, maybe 
	3	had crossed over to open label Myotrophin, whatever. 
	4		So it is very difficult to interpret anything that 
	5	happened after 300 days in both of these. 
	6		Now, the placebo group is the slope on the bottom

	7	here, and it is the slope on the top here.  You can see, at 
	8	300 days, there did seem to be a trend in favor of the 
	9	Myotrophin groups in Study 1200, but at 300 days in Study 
10	1202, the trend was reversed and was in favor of placebo. 
11		[Slides.]

12		Now, we are aware that the sponsor has a couple of 
13	arguments to explain the discrepancies between the results 
14	of Study 1200 and 1202.  One of them is that the placebo 
15	groups may have performed differently between the two 
16	trials, thereby diminishing any difference between
17	Myotrophin and placebo in Study 1202. 
18		We disagree.  You know, the baseline Appel scores 
19	were 70 in both trials, and if you look at the distributions 
20	of on-study Appel slopes for the placebo groups, these are 
21	the placebo groups on-study slopes for Study 1200 and 1202,
22	and you will see that the distributions of on-study slopes 
23	are exactly the same. 
24		So if you have the same baseline scores and you 

25	have the same slopes, it is hard for us to imagine how the 

			55 1	placebo groups differ.
	2		[Slide.] 
	3		Now, the other argument that the sponsor has made 
	4	is they would like to focus in on the upper strata now.  

	5	They want to focus in on patients who, at baseline, had 
	6	Appel scores of 61 or greater.
	7		Recall that in Study 1200, the randomization was 
	8	stratified for this upper strata and lower strata.  It was 
	9	stratified simply for balance between the two treatment 
10	groups, not for analysis purposes. 
11		Study 1202, the randomization was not stratified
12	and certainly there are no analysis plans that incorporated 
13	strata into the analysis. 
14		So basically, when you do an upper strata 
15	analysis, you are doing a post hoc analysis with data in 

16	hand, that is always problematic in any clinical trials.
17		Now, in trying to rationalize why we should look 
18	at the upper strata, one of the arguments that the sponsor 
19	would like to make is that people in the upper strata just 
20	have different slopes.  They are progressing more rapidly. 
21		To examine that question, what we did is we looked
22	at the placebo patients in the lower stratum of Study 1200, 
23	in placebo patients in the upper stratum, Study 1200, and we 
24	did the same in 1202. 
25		What you see is that the slopes really pretty much 

			56 1	-- the distributions overlap to a very great extent.  Now,

	2	we acknowledge that there is a group of outliers over here 
	3	with high slopes in the upper stratum.  These are going to 
	4	drive the means of the upper strata, the mean slope, a 
	5	little bit higher, but if you look at the medians for these 
	6	distributions, the median here, the median here, the median
	7	here, the median here, they are all going to be fairly 
	8	comparable. 

	9		So if you look at the upper strata, at least based 
10	on the data from these two studies, don't think that slopes 
11	are the difference.
12		Now, this is going to be carried forward by the 
13	sponsor, I am sure, because what they have done is looked at 
14	the Baylor database, and they found, using certain 
15	techniques of analysis, such as time-to-20-point change, 

16	that you can differentiate upper strata and lower strata
17	patients based on their rate of progression.  It just 
18	doesn't happen in Study 1200 and 1202. 

19		DR. GILMAN:  Could you go back on the left screen 
20	just one slide.  Is it the case that those curves also match 
21	the original 74 untreated patients?  In the original Appel

22	series of 74, do we have slopes like this that approximate 
23	this? 
24		DR. FEENEY:  Well, it is hard to compare because 
25	the distributions are done differently.  I would have a  

			57 1	hard time saying.  I mean it looks pretty comparable to me
	2	just eyeballing it. 
	3		DR. GILMAN:  Thank you. 
	4		DR. FEENEY:  You remember that most of the 
	5	patients, in the 74 patients, 50 percent had slopes between 
	6	0.03 and	0.14, and I think that is pretty much true here.
	7		So I just want to make the point that in 1200 and 
	8	1202, there is a big overlap in slopes between the upper 
	9	strata and lower strata.  It doesn't mean that there is not 
10	some other characteristic that differentiates the upper 
11	strata and lower strata, but it doesn't appear to be slopes.
12		[Slides.] 
13		Now, if you look at the upper strata this is the 
14	mean on-study slope for the placebo group and for the high 
15	dose group.  This is the slope for the placebo group and the 
16	Myotrophin group in 1202 here.
17		[Slides.] 
18		Now, if you look at the distributions, this is 
19	taking it a step farther.  We took the on-study slope for 
20	each patient and we looked at change in slope.  We looked at 
21	the on-study slope minus their screening slope for each

22	patient, and then we did distributions of these for high 
23	dose Myotrophin, placebo, and high dose Myotrophin and 
24	placebo here. 
25		You will see that in 1200, performing this 

			58 1	maneuver in the upper stratum, you get a separation, but
	2	when you look in 1202, the curves superimpose, and again, 
	3	this is the upper strata.  So even if you do look at the 
	4	upper strata, there are ways to look at it that just kind of 
	5	take away from any apparent effect there. 
	6		[Slides.]
	7		You can perform time-to-combined event analyses 

	8	for the upper strata.  Again, the combined event is death, 
	9	Appel, FVC, and you will see that for the upper strata in 
10	1200, the high dose Myotrophin group performed better than 
11	placebo, but for the upper strata in 1202, the curves are
12	pretty much superimposable. 
13		[Slides.] 
14		Another big problem if you want to just focus on 

15	the upper strata in 1202 -- and again, you don't really need 
16	to focus on the upper strata in 1200 because the overall
17	results seem to favor high dose Myotrophin over placebo -- 
18	but if you want to look in 1202 and focus on the upper 
19	stratum, you can see that the slopes favor Myotrophin here. 
20		The problem is that when you look at the lower 

21	stratum, it goes in the other direction, and it goes in the
22	other direction by an order of magnitude that is comparable 
23	to the effect up here. 
24		So it is just another problem in focusing out a 
25	subgroup analysis in 1202. 

			59 1		[Slides.]
	2		So take a step back and I think in our memo to the 
	3	committee, you saw that we seem to favor these analyses 
	4	where we take the on-study slope minus the screening slope 
	5	and look at change in slope. 
	6		These are the distributions for those changes for
	7	both strata combined in Study 1200, and you can see that for 
	8	change in slope, there was a beneficial effect of high dose 
	9	Myotrophin versus placebo, but for the combined strata in 
10	1202, the curves superimpose. 
11		[Slide.]
12		So where are we with regards to the efficacy of 
13	Myotrophin?  Our conclusion is that in Study 1200, a 
14	difference between high dose Myotrophin and placebo that 
15	favored the Myotrophin was demonstrated, but in Study 1202, 
16	when we looked for independent corroboration of the results
17	of 1200, unfortunately, we didn't find them, and we didn't 
18	find them based -- remember, for primary analysis, the 
19	primary analysis reached statistical significance in 1200, 
20	did not in 1202.  Post-randomization slopes analysis reached 
21	statistical significance, was a primary analysis in 1200,
22	for 1202 did not reach statistical significance. 
23		Change in slope, the trend on those cumulative 

24	distributions was in favor of Myotrophin in 1200, other 
25	direction was -- there is no separation in 1202.  I don't 

			60 1	think I need to go on.  You get the drift.
	2		The only other thing I haven't covered is safety.  
	3	At this point in time, at the level of the treatment IND, we 
	4	really haven't examined all of the safety data in great 
	5	detail.  In fact, we don't have the full safety data from 
	6	1202 in-house yet.
	7		I can tell you that in a review of all the deaths 
	8	from both studies, there was nothing that would make us 

	9	think that use of Myotrophin should be precluded.  There 
10	were a lot of deaths, obviously.  Most of them seemed to be 
11	in line with the disease process.
12		For Study 1200, a review of discontinuations for 
13	adverse events and whatnot didn't seem to raise any undue 
14	alarm on our part.  I think the sponsor will probably 

15	present some of the more common adverse events.  They can go 
16	into some detail on that if you want to hear more about
17	that. 
18		DR. GILMAN:  Thanks, Dr. Feeney. 
19		Let's take a couple of questions now.  First, 
20	there is a commentary in the narrative on page 15 by the FDA 
21	about difficulty with blinding because of inflammation
22	occurring at the site of injection. 
23		I thought I had understood from the sponsor's 
24	statements that inflammation resulted from the vehicle, not 
25	from the primary agent, and therefore, I would assume 

			61 1	inflammation might have occurred on the skin in both placebo
	2	and active drug injections. 
	3		Can you comment on that or can the sponsor? 
	4		DR. FEENEY:  I will just say from what I know, I 

	5	think about 7 percent of patients in Study 1200 experienced 
	6	what are called inflammation, redness, induration, whatnot,
	7	and for the Myotrophin groups I think it was about 35 to 40 
	8	percent of patients had that. 

	9		DR. GRANEY:  If I could comment on that.  In fact, 
10	there is a fair amount more of detail relating to injection 
11	site related reactions.
12		They were fairly numerous when you look across the 
13	whole possible classifications of them, which included 

14	bleeding, complaints of pain, swelling.  We set up a 
15	collection of terms which we could put them.  One of them 
16	was the one which we called "injection site inflammation."
17		That included, in general, terms which tended to 
18	involve redness or some swelling.  However, it is really 
19	clear on looking at the data that the individual patients 
20	having these injection site reactions were quite complex.  
21	They had combinations of pain, bleeding on one occasion. 
22	They had swelling. 

23		When the classifications were done, they were not 
24	exclusive.  We have items like swelling occurring in a 
25	couple of the different classifications.  We, in fact, took 

				62 1	a look at all of the patients who reported injection site
	2	reactions, and I can show you the slide later as part of y 
	3	presentation or following it. 
	4		When we look at all injection site related 
	5	complaints that bring these together, they are very evenly 
	6	divided between the treatment groups at all of the
	7	individual sites, and I do have a slide I can show that. 

	8		DR. GILMAN:  But what about the placebo cases? 
	9		DR. GRANEY:  They are very similar.  They are 

10	quite similar.  In fact, as you will see when I present the 
11	overall safety, injection site pain was actually more common
12	in placebo patients. 
13		DR. GILMAN:  Dr. Feeney mentioned that there is a 
14	very big difference in the number that experienced 
15	inflammation at the site of injection, in the placebo group 
16	much smaller, in the treatment group much higher, is that
17	correct? 
18		DR. GRANEY:  I think that is correct.  What I 

19	would like to do, if I could, a little later is point out 
20	the relative difficulty with that classification.  It is 
21	post hoc, was done at the time of data entry, and I think
22	really does not have the apparent strength that it might 

23	from the simple display of the data, and we have other data 
24	to show you. 
25		DR. GILMAN:  Also, for Dr. Feeney, we heard from 

				63 1	Dr. Leber earlier that there was some concern about the
	2	number of deaths in Study 1202.  I don't remember exactly 
	3	the numbers, 18 I think it was or something like that, a 
	4	much higher number than in 1200. 
	5		Can you comment on that? 
	6		DR. GRANEY:  Well, the first comment you always
	7	have to make in talking about the excess deaths in 1202 is 
	8	that the 2 to 1 randomization, remember, you know, the 18 is 
	9	just because of the 2 to 1 randomization it is not totally 
10	out of line. 
11		There was an excess of deaths.  It wasn't
12	statistically significant.  A review of the causes of death 
13	doesn't raise any obvious drug-induced mechanism.  It was 
14	there, it trended in the opposite direction from what we saw 
15	in 1200.  That is really where we are at. 
16		DR. GILMAN:  I did want to ask about that point
17	also.  Do you have a cause of death -- and will the sponsor 
18	show that -- do we have autopsy verification in the patients 
19	who died, both of the disease process, do we have 
20	neuropathological diagnosis in these cases? 
21		DR. GRANEY:  Yes, we don't really have extensive
22	autopsy or neuropathological, but we are prepared to provide 
23	extensive clinical information on the individual deaths. 

24		In my presentation, in the safety I have a basic 
25	discussion of it from an overview point of view and with an 

				64 1	analysis that we performed.  Additionally, we can provide
	2	information to you on the individual deaths, and I think you 
	3	will see, as Dr. Feeney, mentioned that the deaths really 
	4	appear from the clinical point of view to be quite 
	5	characteristic of the ALS deaths that we saw elsewhere. 
	6		DR. GILMAN:  Do you also have neuropathological
	7	information on these cases? 
	8		DR. GRANEY:  We do not. 
	9		DR. GILMAN:  On any of them? 
10		DR. GRANEY:  I would have to check and find out.  
11	We certainly don't have it on the majority of them, and I
12	will determine what we have. 
13		DR. GILMAN:  All right. 
14		Dr. Leber first and then Dr. Temple. 
15		DR. LEBER:  Since I made the statement, I probably 
16	should put it in the appropriate context timewise.  We
17	received three days before we were about to take action on 
18	the basis of 1200, a description of Study 1202, which is 

19	brief. 
20		It provides raw information about 18 deaths 
21	occurring among the patients who were assigned to the high
22	dose, single dose of Myotrophin in Study 1202, and 5 or 4 
23	deaths at the time, I don't remember exactly. 
24		Even if you double that, that is an excess.  Now, 
25	we weren't only concerned about the possibility, the study 

			65 1	is not powered to look at mortality in the time frame that
	2	that could be a signal of concern, but also the effects of 
	3	when the deaths occurred. 
	4		If you look at the survival analysis presented for 
	5	1202, you will notice there was a period during the trial 
	6	where there were a great number of survivors, and therefore
	7	earlier deaths occurring on Myotrophin. 
	8		So part of our concern was the biasing effect in 
	9	potential analyses of having people leave early by virtue of 
10	dying, and therefore their scores being carried forward.  So 
11	it was a mixture of things.
12		Now, what John is telling you, of course, is in 
13	retrospect, now six months later, after looking at all the 
14	data, we are not willing to say what we think those deaths 
15	mean although I want to correct something.  In terms accrued 
16	incidence, the number of deaths on Myotrophin is always
17	greater.  That includes 1200.  I don't think it is 
18	meaningful, but I believe the lowest number is 7 deaths 
19	occurred in the placebo arm and maybe 8 and 11 in the other 
20	doses, and if you come to the other study, it is 18 versus 
21	5.
22		So there is this.  It could be statistically 
23	significant if you ran the numbers up, and it is always 
24	possible that the drug may benefit some and harm others, but 
25	we are not able, given the amount of information, to make 

				66 1	that judgment.
	2		DR. GILMAN:  Thank you. 
	3		Dr. Temple. 
	4		DR. TEMPLE:  Dr. Leber made my point. 
	5		DR. GILMAN:  Ms. Phillips. 
	6		MS. PHILLIPS:  Just a question about the deaths. 

	7	Has there been an analysis of where the people were on the 
	8	Appel score when they entered the study? 
	9		DR. FEENEY:  When they entered the study? 
10		MS. PHILLIPS:  In other words, were they sicker 
11	when they entered the study and therefore they were dying at
12	a -- 
13		DR. FEENEY:  Let me just make one comment along 

14	those lines.  To say that people on the Appel score only die 
15	with high scores would be incorrect.  People die on the 
16	Appel score who have low Appel scores.
17		DR. GRANEY:  I think you will find that we cover 
18	that topic in Dr. Gelinas' presentation, and we have 
19	additional information that we can make available for you. 
20		DR. GILMAN:  Thank you. 
21		Dr. Zivin.
22		DR. ZIVIN:  In the analysis of covariates, the 

23	order in which the covariates are considered is of some 
24	importance, and I didn't exactly understand how that order 
25	was selected. 

			67 1		Can you explain that to me a little bit better?
	2		DR. FEENEY:  I think Dr. Hoberman was the 
	3	statistician in our division.  He could probably explain it 
	4	much better than me. 
	5		DR. HOBERMAN:  The order was actually selected by 
	6	the sponsor.  The one document that we received that gives a
	7	hint is there were simply a list of covariates one after the 
	8	other down the page. 
	9		This list was a list of covariates that presumably 
10	were entered into the model in that sequence by the sponsor 
11	at the time they did the analysis.  Now, I tried to repeat
12	an analysis, but I did not use the same order, and I got a 
13	different result, and that is what you found in the 
14	document. 
15		The purpose of explaining that in the document was 
16	not so much to say that the statistical significance should
17	be at tremendous jeopardy, but to explain that the method in 
18	the protocol was not a really well-defined method to give an 
19	unambiguous result from two aspects. 
20		Number one, the result could depend on the order 
21	of the covariates as it did in the case when I did the
22	analysis, but I think even more importantly, or at least as 
23	important, it is not a method which is known to control Type 
24	1 error at 0.05. 
25		Now, let me just say a little history.  This plan 

			68 1	was in the protocol.  At the time that I learned about it

	2	after taking over this project, I communicated with the 
	3	sponsor and said that I did have an objection to this plan, 
	4	and at least I think I learned about it for the purposes of 
	5	1202, and subsequently decided to do independent analyses. 
	6		As far as the substantiality of this issue for

	7	1200, I don't believe it is a terribly substantial issue 
	8	because of the independent analyses.  For 1202, I don't 

	9	think it is a really substantial issue because again if you 
10	do what was actually stated in the protocol, you don't get 
11	close to statistical significance.
12		DR. GILMAN:  Can I just follow up with a question. 
13		It is stated in the protocol to be a computer 
14	generated algorithm.  Is that a fixed algorithm or did it 
15	vary? 
16		DR. HOBERMAN:  It all depended on entering. 
17	First, you enter a variable.  Then, you see whether or not 
18	that is statistically significant.  If that is statistically 
19	significant to some extent, it could be at the 0.05 level, 
20	it could be at the 0.10 level, whatever you dictate. 
21		Then, the next variable is entered into the model. 
22	If that is statistically significant, that will be entered 
23	into the model.  However, there is also a criteria, so that 
24	if the first one that you entered one now rises above a 

25	certain level and loses its statistical significance, it 

				69 1	could be kicked out of the model.
	2		So what it is, is this algorithm of playing with 
	3	the data and building up a series of covariates and ending 
	4	when you have a whole bunch that do meet a criterion and 
	5	along the way some are kicked out, some are brought in, and 
	6	you can get kicked out at any time.  It is like musical
	7	chairs. 
	8		DR. GILMAN:  So it is a search for something that 
	9	will turn up? 
10		DR. HOBERMAN:  Right, it is a search that depends 
11	on the data that was gathered.
12		DR. GILMAN:  It is almost a post hoc analysis in a 
13	sense. 
14		DR. GRANEY:  If we could, we would like to make a 
15	comment about that. 
16		DR. GILMAN:  Please.
17		DR. TOM DOBBINS:  Tom Dobbins, Cephalon. 
18		I think that the order per se is not the issue.  
19	An analysis of covariates with the specified criteria should 
20	not be order-dependent in the variables, and the potential 
21	dependence of that order may be some other aspect that maybe
22	we could answer that question separately, but I think that 
23	as far as the statistical method of stepwise selection in a 
24	regression procedure, that is completely determinable. 

25		So it should not depend upon the order of the 

			70 1	variables entering or leaving the model.  As a practical

	2	matter and I think as a scientific matter, there will be 
	3	ordering in the list that we chose where the variables are 
	4	most relevant to the disease. 
	5		So, for example, we would enter something like 
	6	bulbar score as opposed to country of origin in the European
	7	study, for example. 
	8		DR. GILMAN:  Dr. Leber first and then Dr. 
	9	Gennings. 
10		DR. LEBER:  I want to emphasize what Dave said 

11	earlier, that this has no substantial effect on anything
12	that is in dispute before us.  Whether you use this analysis 
13	method or not, with all its well-known generic flaws, it 

14	does not affect the judgment on Study 1200, and if you use 
15	it on 1202, it doesn't affect the judgment from our view 

16	because it isn't statistically significant either way on the
17	primary specification. 
18		I will say for the record that the way the 
19	protocols were written the precise listing of covariates 

20	that would be entered are not identified, and as I believe 
21	Dr. Gilman points out, to some extent there is a flavor

22	there for data conditioning because it depends upon the 
23	realized set of individuals randomized and what they display 
24	as personal attributes that will determine what order of 
25	entering you do. 

					71 1		You don't know on the next occasion that you
	2	repeat this experiment mythically that you would end up with 
	3	the same set of covariates in the model, and I don't think 
	4	you could know because they might have different 
	5	distributions of attributes in the patients entered. 
	6		I think that is just the problem of this type of
	7	analysis. 
	8		DR. GILMAN:  Dr. Gennings and then Dr. Temple. 
	9		DR. GENNINGS:  I just wanted to emphasize that the 
10	algorithm is also going to be conditional on the selection 
11	criteria for what goes in and what goes out, and those
12	numbers can change, and that could change the results. 
13		DR. DOBBINS:  That is true, and I think that that 
14	might be part of the issue with regard to the discrepancies. 
15		DR. GENNINGS:  And were those numbers specified to 
16	begin with?
17		DR. DOBBINS:  Yes. 
18		DR. GENNINGS:  And what were they? 
19		DR. DOBBINS:		0.1. 
20		DR. GILMAN:  Dr. Temple. 
21		DR. TEMPLE:  I think what is being said is typical
22	of many covariate analyses and it is one of the reasons that 
23	people get nervous when a finding of no significant 

24	difference becomes significant based on a covariate 
25	analysis.  That doesn't happen very often, fortunately, so 

					72 1	we don't have to bear the burden of worrying what it means.

	2		My feeling is it may help you get a better point 
	3	estimate of something if you already have made it on the 
	4	primary and adjusted analysis, but it is treacherous 
	5	business, this is not an unusual problem. 
	6		DR. GILMAN:  Dr. Adams.
	7		DR. ADAMS:  I would like to change the topic.  I 
	8	would like to go to Section D in your briefing, page 15. 

	9		DR. GILMAN:  Which briefing, the FDA briefing? 
10		DR. ADAMS:  The FDA briefing, Section D, page	15. 
11		DR. GILMAN:  Tab?

12		DR. ADAMS:  Tab D. 
13		There is a discussion of 7 patients in the placebo 
14	arm who have a baseline score of 95 and greater, and I would 
15	like some more discussion from you and from the sponsor in 
16	regard to these 7 patients because 6 of these had endpoints,
17	1 death, 5 Appel endpoints.  One of these apparently had an 
18	Appel score of 115 at time of randomization, and I would 

19	like some more discussion on those patients and how it 
20	affects the overall results of 1200. 
21		DR. FEENEY:  Let me tell you those patients affect
22	the time-to-endpoint analysis, as I showed here, and they 
23	affect it greatly.  It is an exploratory maneuver, but you 
24	have to think of it because there are outliers in the 
25	placebo group compared to the high dose Myotrophin group. 

			73 1		Now, an interesting phenomenon happens.  The
	2	primary analysis is based on slopes, and as you heard, in 

	3	order to enter the slopes analysis, you have to have three 
	4	Appel scores during the treatment period. 
	5		If you look at those 7 outliers, at least a fair 
	6	number of them aren't even in the slopes analysis because

	7	they were out so quickly that they did not have three on- 
	8	study Appel scores. 
	9		So although if you start exploring the slopes 
10	analysis and the effect of those patients on them, you might 
11	whittle down the treatment difference a little bit, you do

12	not seem to affect the overall statistical properties of 
13	this primary analysis. 
14		DR. LEBER:  On the fly, I don't want to disagree 
15	with you because I haven't thought about it all that 

16	carefully, but it dawns on me that you have a slope
17	analysis, and the individuals who had high slopes, if in 
18	this case they were more rapidly progressing, and on the 

19	basis of arguments John has made, that someone to get to an 
20	Appel of 115, who had to enter with an Appel of no more 

21	than, what, 80 at screen, has to have a very high slope to
22	get there over the time. 
23		Accordingly, these individuals with high slope 
24	aren't included in the slope analysis, and if that is the 
25	case, it is biasing against the drug, because they are on 

			74 1	placebo, so it is the opposite effect of what you are
	2	suggesting. 
	3		But I think this is the treachery.  If you now 
	4	turn to a time-to-event analysis, you have a different bias 
	5	arising from the same censoring process, and that is why I 

	6	think the evaluation of trials becomes analysis-dependent.
	7		You have to decide how it is operating, not in a 
	8	general way, but specific to the analysis being examined, 
	9	and here you can see it going in opposite directions.  It 
10	just makes it so complex. 
11		DR. GILMAN:  Dr. Snead.
12		DR. SNEAD:  I would like some clarification on a 
13	comment made on page 12 at Tab C of the agency handout 
14	regarding the placebo patients, in which it is stated that 
15	they are really not a valid statistical analysis of the 

16	population of the patients with ALS because they are samples
17	of convenience, and not truly representative of the 
18	population. 
19		What exactly does that mean? 
20		DR. FEENEY:  I will let Dr. Leber. 
21		DR. LEBER:  I wrote a good part of this document,
22	and I think it is very important that I step back again, and 
23	I will go into the heuristic mode -- I apologize for needing 
24	to do this. 
25		If you were going to forecast an election, what 

			75 1	would you do?  You would make very certain that the
	2	individuals in your sample on which you are basing your poll 
	3	reflect very much the public that is voting.  If not, you 
	4	run into the Dewey-Truman or Netanyahu-Peres type problems. 
	5		If you think what we do in clinical trials, we 
	6	obtain patients that are available to us.  They on face may
	7	look something like the population because we pick them on 
	8	the basis of various attributes we find appealing, but in no 
	9	way are they a true statistically random sample of the 
10	population. 
11		That is one of the reasons why we always want to

12	look within a study, because we don't really know about how 
13	representative the sample we capture for study is of the 
14	population as a whole. 
15		So ergo, when you start looking between studies 
16	back to the Baylor database, which, in fact is a registry,
17	you run into all sorts of kinds of problems, and I was 
18	really trying to make the case that the way we sample for 
19	our trials is for our convenience.  It is not, in a 
20	statistical sense, a stratified random sample or a random 
21	sample of the population.
22		That is what that is all about.  That makes it 
23	very difficult compare one study to another or one study to 
24	a registry, and that was the thrust of that argument. 
25		DR. SNEAD:  So that was a generic comment rather 

				76 1	than a specific one.
	2		DR. LEBER:  A generic comment, which I think you 
	3	have got to worry about all the time. 
	4		DR. GILMAN:  Dr. Temple. 
	5		DR. TEMPLE:  I am sure this is clear, but it is 
	6	not a complaint about the study because all studies partake
	7	of this problem, it's a warning against crossing between 
	8	studies. 
	9		DR. LEBER:  Well, it is really a warning about 
10	explanations offered that turn on the idea that we really do 
11	have a random sample when in fact we don't.
12		DR. GILMAN:  That is helpful.  Any other questions 
13	from the committee? 
14		If not, Dr. Feeney, thank you very much. 
15		It is 10:15.  Let's take a 15-minute break.  We 
16	will convene at 10:30 sharp.
17		[Recess.] 
18		DR. GILMAN:  The meeting is about to begin again.  
19	Please take your seats. 
20		This is time for the sponsor's presentation.  Dr. 
21	William F. Graney will make the introductions for Cephalon.
22		         SPONSOR'S PRESENTATION 
23			 INTRODUCTION 
24		DR. GRANEY:  Thank you.  I would like to thank the 
25	committee and therapy agency for the opportunity to present 

			77 1	the Myotrophin clinical program today.
	2		[Slide.] 
	3		Dr. Feeney did a very fine presentation of the 
	4	protocol designs and the results, and before beginning our 

	5	presentation, I would like to review the areas of agreement 
	6	between Cephalon and the Division.
	7		We agree that the AALS total score is an 
	8	appropriate measure for the trials, that the North American 
	9	trial was positive, and that safety is not an issue for us 
10	here today. 
11		We are here today to discuss the two studies as
12	sufficient evidence for the safety and efficacy of 
13	Myotrophin in the treatment of ALS.  We maintain the 
14	European trial is supportive of the positive North American 
15	trial and that Myotrophin's effect is most evident in the 
16	majority of the patients who have rapidly progressing
17	disease. 
18		[Slide.] 
19		Our speakers this morning will present the 
20	evidence for this position.  Dr. Deborah Gelinas, of the 
21	California Pacific Medical Center, will review the Appel ALS
22	Scale as a measure of the progress of disease and will 
23	discuss its application in the current trials.  Dr. Gelinas 
24	will also review the variation of disease progression 
25	between patients. 

			78 1		I will then review the efficacy from both trials,
	2	and Dr. Thomas Dobbins, of Cephalon, will review related 
	3	statistical points which require consideration. 
	4		Following a review of the safety of Myotrophin, 
	5	and the body of evidence for its efficacy and safety in ALS, 
	6	Dr. Robert Miller, of the California Pacific Medical Center

	7	and the University of California, will provide a clinical 
	8	interpretation of the results of the program. 
	9		[Slide.] 
10		As Dr. Feeney noted, Myotrophin is recombinant 
11	human insulin-like growth factor 1 or IGF-1, a 7 kilodalton,
12	70 amino acid protein.  The preclinical studies that led to 
13	the clinical program for Myotrophin indicated multiple 
14	activities of the drug which could be of benefit in ALS. 
15		Myotrophin promotes the survival of motor neurons 
16	in cell culture and in animal models where motor neuron
17	death can be quantified.  Myotrophin is essential in the 
18	maintenance, growth, and myelination of nerve axons and is 
19	the primary contributor to nerve sprouting in response to 
20	various injurious or pathologic stimuli. 
21		Myotrophin enhances functional recovery following
22	nerve injury, promoting reinnervation and increasing muscle 
23	plate size. 

24		Finally, Myotrophin has profound effects on muscle 
25	catabolism, increasing muscle mass, and decreasing muscle 

			79 1	atrophy.
	2		These diverse activities in preclinical work led 

	3	us to develop the clinical program for Myotrophin in ALS. 
	4		I will now ask Dr. Gelinas to discuss the use of 

	5	the AALS Scale in that program and the features of ALS which 
	6	affected the design of the clinical studies.
	7		         CLINICAL STUDY DESIGN 
	8		[Slide.] 
	9		DR. GELINAS:  Good morning.  I am a neurologist at 
10	the Forbes North MDA/ALS Center and I see many patients with 
11	ALS.  I was also a principal investigator of the North
12	American Myotrophin study. 
13		[Slide.] 
14		Amyotrophic lateral sclerosis is a progressive 
15	degenerative disorder of motor neurons in the motor cortex, 
16	spinal cord, and brainstem.  It is characterized by muscle
17	wasting, weakness, and spasticity.  There are no significant 
18	sensory, bowel, bladder, or cognitive abnormalities in this 
19	disease. 
20		[Slide.] 
21		The diagnosis of ALS is a clinical one and it is

22	confirmed by the concomitant presence of upper and lower 
23	motor neuron signs in two or more body regions.  The 

24	diagnosis ultimately becomes evident by progression of 
25	symptoms. 

			80 1		[Slide.]
	2		Initially, symptoms of ALS may be quite focal.  A 
	3	patient may present with a footdrop or a hand clumsiness or 
	4	some slurring of speech.  However, with time, there will be 
	5	contiguous spread of disease to previously unaffected areas 
	6	and ultimately, all patients with ALS with look clinically
	7	alike. 
	8		[Slide.] 
	9		The natural history of ALS is that there is a 

10	steady decline in strength and respiratory function, and 
11	that decline is linear throughout the majority of the course
12	of disease.  The rate of decline, however, varies greatly 
13	from patient to patient, and those of us who care for 
14	patients with ALS know that some patients go from the time 
15	of diagnosis to death within a year, and other patients are 
16	still ambulating more than five years out from diagnosis.
17		[Slide.] 
18		Our objective as investigators in designing this 
19	study in ALS was to examine whether Myotrophin could slow 
20	the rate of disease progression in ALS.  To demonstrate 

21	this, we chose to measure progression with a functional
22	rating scale that could evaluate both upper motor neuron 

23	abnormalities with slowness and spasticity, and lower motor 
24	neuron abnormalities with its inherent weakness. 
25		[Slide.] 

			81 1		The scale that was chosen was the Baylor AALS
	2	Scale, which was developed by Stan and Vickie Appel.  This 

	3	scale has been validated in over 1,200 patients with motor 
	4	neuron disease over a 10-year period. 
	5		The AALS is a quantitative measure of clinical 

	6	disease in ALS.  It is a comprehensive disease-specific,
	7	objectively measured scale which provides a single total 
	8	index of disability regardless of the site of onset of 
	9	symptoms. 
10		The rate of change of the AALS correlates with 
11	disease progression, and is an important co-predictor of

12	patient survival along with the rate of change of pulmonary 
13	function and the age of a patient at the time of 
14	presentation of diagnosis. 
15		[Slide.] 
16		The AALS is compose of five separate scales:  the
17	bulbar, which evaluates the ability to swallow and to speak; 
18	respiratory, which evaluates forced vital capacity; muscle 
19	strength, which is composite of a manual muscle exam, as 

20	well as grip strength and pinch strength; upper extremity 
21	function, which are an accumulation of time-to-test which
22	look at manual dexterity; and lower extremity function, 
23	which again are time-to-test which look at functional 

24	ability to walk, sit, climb stairs, and stand. 
25		A normal person would have a score of 30 points.  

			82 1	A patient with maximal disability would have a score as high
	2	as 164 points. 
	3		[Slide.] 
	4		This table illustrates the correlation between the 
	5	AALS score and disease severity.  A patient who presents to 
	6	an ALS clinic initially, typically has an AALS of between 40
	7	and 80. 
	8		Let's take an example of one of these scores.  A 
	9	patient with a score of 75 would typically be eating a 
10	dental soft diet, would have some slurring of speech, would 
11	have a forced vital capacity that is slightly down, but
12	probably would have no symptoms whatsoever, and would be 
13	walking with a walker or occasionally, for longer 
14	excursions, with a wheelchair.  They would need some minimal 
15	caretaker assistance perhaps for bathing. 
16		Some months later, when that same patient comes

17	back to clinic, the score might be 99.  At that point, the 
18	patient would be eating a pureed diet only.  The speech 
19	would be quite slurred, and the forced vital capacity would 
20	be down, such that they might have difficulties with 
21	coughing and clearing the upper airway.  The patient at this
22	point would be spending most of the time in the wheelchair 
23	and would be fairly dependent on a caretaker for activities 
24	of daily living. 
25		It is rare to see patients at these extremes in 

			83 1	the center because of the fact that the disability becomes
	2	so great that it becomes a coordinated family effort to the 
	3	patients to get into clinic for evaluation. 
	4		However, at above 115, patients typically are 
	5	drinking only a liquid diet or else they have a feeding 
	6	gastrostomy.  They not longer have useful speech.  They are
	7	wheelchair-bound or, if they are not able to leave the home, 
	8	bedridden, and they are always considering or facing major 
	9	life issues of tracheostomy and dependence. 
10		The thing that I wish to emphasize is that a 
11	particular AALS score is a snapshot in time of how a patient
12	looks.  However, the rate of change of score is a moving 

13	picture over time of how the disease progresses in one 
14	person's life. 
15		To illustrate this, I would like to give two 
16	patient examples.

17		[Slide.] 
18		This patient is a 39-year-old man whose symptoms 
19	of ALS began in 1991 with cramps and weakness in his left 
20	leg.  He was first seen for evaluation at the ALS center in 
21	February of 1993.

22		He was found at that time to have mild weakness in 
23	the upper extremity, and in the lower extremity, fairly good 
24	strength proximally, but a great deal of weakness distally, 
25	such that he could not ambulate on his heels. 

			84 1		His reflexes were brisk, he had Babinski and
	2	clonus.  He would walk, however, with the assistance of a 
	3	walker.  He was diagnosed as having ALS and has been 
	4	followed since that time. 
	5		He has shown a very gradual progression of his 

	6	difficulties, always more marked in the lower extremities,
	7	and he has been able to participate in a number of drug 
	8	trials for ALS. 
	9		He continues to work, although part time, at home 
10	as an accountant, and he is working at home because the 
11	disability makes it so difficult for him to get out to his
12	office. 
13		His rate of change of his AALS score is linear, 
14	and the slope is 0.9 points per month.  We would term him a 
15	moderate progressor. 
16		[Slide.]

17		In contrast, this 56-year-old woman, who was first 
18	seen in November of '95 for evaluation of weakness in her 

19	right arm, had only symptoms that started July of that same 
20	year.  She noted a gradual weakness, progressing however to 
21	the point where she could no longer brush her hair or feed
22	herself or dress herself. 
23		At the time she was first seen, she too had mild 
24	proximal weakness and some distal weakness in the upper 

25	extremities, as well as in the lower extremities.  Her 

			85 1	reflexes also were brisk, she had crossed adductors and she
	2	had positive Babinski bilaterally.  She too was able to 
	3	ambulate on her own. 
	4		She had a borderline normal vital capacity at that 
	5	time and had virtually no pulmonary symptoms.  However, her 
	6	progression has been extremely rapid, and she is currently
	7	wheelchair-bound and unable to ambulate. 
	8		Her AALS slope is 7.8 points her month, and we 
	9	would term her a rapid progressor. 
10		[Slide.] 
11		The Baylor Natural History database has been
12	validated in more than 1,200 patients with motor neuron 
13	disease for over 10 years.  831 of those patients have been 
14	diagnosed as having classical sporadic ALS. 
15		This cohort provides a longitudinal scale on the 
16	relationship between disease progression and AALS score and
17	slope.  The database offers a pool of patients from which to 
18	reference and match the patients who were enrolled in our 
19	study. 
20		A review of this database revealed 181 patients 

21	who were matched both in terms of clinical presentation and
22	inclusion and exclusion criteria to the patients who were 
23	enrolled in the Myotrophin studies. 
24		These patients were further subdivided into 
25	moderate progressors, those with an AALS of less than or 

					86 1	equal to 60, and rapid progressors, those with an AALS score
	2	of greater than 60. 
	3		DR. GILMAN:  Dr. Gelinas, I wonder if you could 
	4	tell us how many or what percentage of these patients who 
	5	expired have come to autopsy examination of the Baylor 
	6	database.
	7		DR. GELINAS:  I cannot answer that.  Perhaps Dr. 
	8	Appel can answer that. 
	9		DR. APPEL:  In approximately five years ago, when 
10	we had a database of about 500 patients at that time, Dr. 
11	Gilman, we were running an autopsy rate of about 60 percent. 
12	Since that time, it has dropped considerably even though we 
13	are making every effort to keep it up, so that the number is 
14	less than that for now 1,500 patients. 
15		DR. GILMAN:  Are you able to verify classical ALS 
16	in those autopsies that you had performed?
17		DR. APPEL:  Absolutely. 
18		DR. GILMAN:  And no other modifying features, no 
19	dementia, no parkinsonism, on cerebellar degenerations in 

20	those cases? 
21		DR. APPEL:  In a rare number of cases, less than 5
22	percent, we have made the diagnosis of neuropathological 
23	Alzheimer's with no verification that they truly with 
24	Alzheimer's by clinical criteria because we had not studied 
25	it extensively.  This is in a very, very small number of 

				87 1	such cases.
	2		The remaining 95 percent are free of those 
	3	changes. 
	4		DR. GILMAN:  Thank you. 
	5		[Slide.] 
	6		DR. GELINAS:  In this review of the database, two-
	7	third fell into the rapid progression category, one-third 
	8	fell into the moderate progression category. Symptoms which 
	9	identified moderate progression were a greater bulbar 
10	involvement and a greater pulmonary involvement, as well as 
11	an older age.
12		DR. DRACHMAN:  Was the gender difference 
13	significant? 
14		DR. GELINAS:  I cannot answer if it was -- you 
15	mean statistically significant? 
16		DR. DRACHMAN:  Yes.
17		DR. GELINAS:  I don't know.  It looks like it 
18	would statistically significant, but I don't know that that 
19	was run, that analysis. 
20		DR. GILMAN:  We heard from the sponsor that the 
21	answer is no.
22		DR. GELINAS:  In the North American study, we 
23	stratified patients a priori to ensure proper distribution 
24	of both moderate and rapid progressors, and we stratified 

25	according to the AALS score.  In the European study, this 

			88 1	stratification scheme was adopted post hoc.
	2		Trial design in ALS necessitates that one look at 
	3	rate of progression of disease and that one evaluate 
	4	patients who are progressing in order to detect a change in 
	5	the short study, such as a nine-month study. 
	6		DR. ADAMS:  Dr. Gelinas, would you explain to me
	7	how the score of 60 was used to determine moderate versus 
	8	rapid progressors? 
	9		DR. GELINAS:  Initially, that score was rather 
10	empirically chosen, and based on the Baylor database and the 
11	characteristics of a great deal of variability, also based
12	on the fact that initial presentation to ALS center was 
13	between 40 and 80, and so 60 was the middle point. 
14		DR. ADAMS:  Well, the question is that some people 
15	that got to the centers may have had symptoms for nine 
16	months, when they came in at 60, and others may have had
17	symptoms for two months when they arrived at 60. 
18		To me, 60 -- and I am learning here -- 60 seems to 
19	be a score of severity, and really not a score of 
20	progression. 
21		DR. GELINAS:  You are absolutely right, and a much
22	better way to have done it would have been to divide them 

23	into two cohorts based on rate of progression, but we 
24	weren't that knowledgeable at the time of design of this 
25	study. 

			89 1		DR. GILMAN:  Dr. Khachaturian has a question.
	2		DR. KHACHATURIAN:  Is the rate of change linear 

	3	over time on the two groups?  Do they change at any time, 
	4	that is, a slow progressor would become rapid, and vice 
	5	versa?  Is there any data on that? 
	6		DR. GELINAS:  That is actually a rather hot
	7	debate.  There are those who say that maybe at the very far 
	8	edges of disease, at the terminal phases of disease, that 
	9	there is a more precipitous drop-off and a more rapid slope.  
10	However, during the phase of illness that most physicians 

11	are able to evaluate and study the patients, the rate of
12	progression is linear. 
13		DR. DOBBINS:  We are going to address directly the 
14	stratification in terms of disease severity versus disease 
15	progression in our remarks in a few moments. 
16		DR. GILMAN:  Dr. Katz, did you have a question or
17	comment? 
18		DR. KATZ:  I was just going to say given the 

19	acknowledgment that ALS score above or below 60 isn't 
20	necessarily the same thing as moderate and progressive 
21	patients with regard to slope.

22		It is not really accurate to equate the two, and 
23	to speak about moderate and rapid progressors as if that is 
24	the same thing as categorization by above or below 60. 
25		DR. LEBER:  I have another I think technical point 

			90 1	here.  When you talk about slope, there is pre-slope and
	2	there is post-randomization slopes, and there probably is a 
	3	relationship between the attained baseline score which is 
	4	related to the rate you progress during screening, and there 
	5	is a correlation there, but there is a much lesser 
	6	correlation between what your baseline attained score is and
	7	your post-randomization slope, and we are prepared to 

	8	discuss this because I think you have got to be very 
	9	careful, once again, of what you are talking about when you 
10	say things predict other things. 
11		But I guess we take the point that baseline score,
12	which everyone passes through eventually, is a poor 
13	predictor of rate of progression, a very important point. 
14		DR. GILMAN:  Dr. Zivin. 
15		DR. ZIVIN:  Can you or Dr. Appel please tell me 
16	how the items for the scale were chosen, and more important,
17	how the weightings were chosen? 

18		DR. GELINAS:  Perhaps with the initial development 
19	of the scale, Dr. Appel can answer that better than I.  I 
20	can tell you that the weightings, each of the five 
21	categories, would be given a potential of 6 points per
22	category. 
23		DR. ZIVIN:  But the question is how were those 

24	points chosen, why is swallowing more important than stair 
25	climbing, and by what factor. 

				91 1		DR. GILMAN:  Dr. Appel.
	2		DR. APPEL:  The tests were administered to 30 
	3	patients prior to our establishing the weighting.  Based on 
	4	those 30 patients, we established a weighting, such that no 
	5	individual component would override the scale and such that 
	6	the total score would be an accurate reflect.
	7		In fact, we had to change the weighting slightly 
	8	as we went on before it was actually adopted, so that we 
	9	were assessing clinical parameters, how the patient walks, 
10	how they talk, how they communicate, how they breathe, and, 
11	in essence, give relevant information of clinical importance
12	that would be reflected in the score and the rate of change 
13	of the score. 
14		DR. ZIVIN:  But the question is by what process 
15	were the weightings selected. 
16		DR. APPEL:  They were first selected arbitrarily

17	to be somewhat unequal and then they were weighted, such 
18	that one could have a total score that monitored the rate of 
19	progression of the patients and the rate of clinical change.  
20	This was done in 1981, 1982, and 1983, before we even 

21	adopted this based on the fact that, in ALS, you need to
22	monitor what is happening in terms of function in upper and 
23	lower extremities, strength in upper and lower extremities, 
24	distal musculature, as well as proximal musculature, speech, 
25	swallowing, and breathing. 

				92 1		DR. ZIVIN:  How did you decide how to change the
	2	weightings from your initial arbitrary decisions? 
	3		DR. APPEL:  Well, what happened is we didn't have 
	4	a linear scale initially when we started before we 
	5	established this, and so what we did is, by playing with 
	6	this -- and we are not statisticians -- but by playing with
	7	this and doing the weightings slightly differently, we found 
	8	that by giving relatively equivalent weightings to important 
	9	clinical parameters, the most important of which is 
10	respiration, less of importance going down the scale, being 
11	speech and swallowing, because these are things that get
12	these patients into trouble, and then going down from that 
13	to upper and lower extremities, strength and function, we 

14	came out with a balanced approach. 
15		DR. GILMAN:  Dr. Drachman. 

16		DR. DRACHMAN:  Would you look back at your mild
17	patient and that slide several back? 
18		DR. GELINAS:  Would you like us to go back to it? 
19		DR. DRACHMAN:  Could you please, yes. 
20		DR. GELINAS:  Go back to the mild patient, please, 
21	or the moderate progressor, the patient picture with the
22	man. 
23		[Slide.] 
24		DR. DRACHMAN:  When you look at the curve, I would 
25	think that you might pick various 3-point intervals and get 

				93 1	very different slopes.  How do you deal with that?  I mean
	2	if you look at the first three points, that would be very 
	3	different from the three points at 35 to 40, very different 
	4	from those from 45 to	50.  How do you deal with those aspect 
	5	of slope? 
	6		DR. GELINAS:  First, let me state that I am not a
	7	statistician, but secondly, let me state that what I have 
	8	gleaned from statisticians is that the more points you have, 
	9	the more accuracy you have in predicting a slope, and then 
10	we did a best-fitted regression analysis. 
11		DR. DRACHMAN:  Yes, but in the study, you are
12	willing to use three points to determine -- or at least 
13	three -- but somewhere no more than. 
14		DR. GELINAS:  Some completed the study, so we were 
15	able to have a better fit of slope. 
16		DR. GILMAN:  Dr. Dobbins wants to comment.
17		DR. DOBBINS:  Yes.  This is a very important point 
18	here.  When you look at this graph, you are looking at the 
19	disease in months over a 60-month period versus a 9-month 
20	window in our studies. 
21		In the course of that 9-month window, the Appel
22	Scale score is highly linear, and that was evident from the 
23	slide that Dr. Feeney showed earlier of two types of 
24	patients, a more rapidly progressing patient, if you recall, 
25	and a less rapidly progressing patient. 

				94 1		So within the 9-month window, in particular, of

	2	the North American and European studies, the Appel Scale 
	3	score is highly linear.  I would like to address that point 
	4	even further with regard to the remark made regarding pre- 
	5	slope scores versus post-slope scores. 
	6		A particular patient within pre-study score is

	7	highly predictive of his post-baseline score precisely 
	8	because of this linearity. 
	9		DR. GILMAN:  Dr. Leber. 
10		DR. LEBER:  I actually had a question of Dr. 
11	Appel, which I just wonder for clarification if you have

12	changed the weightings over time in the scale.  Has there 
13	been a period where the published results of this scale 

14	represented different, or has, since its publication, been 
15	stable?  That is for historical purposes. 
16		DR. APPEL:  The scale was never changed from the
17	time that we adopted it, and all publications are the same 
18	in 1984 as they are at the present time.  I was addressing 
19	Dr. Zivin's question, which was how did we start in the 

20	beginning and how did we come with the idea of weighting it. 
21		From 1984, and all publications since that time,
22	this is exactly the same scale that we have today. 
23		DR. GILMAN:  Dr. Temple. 
24		DR. TEMPLE:  It is perfectly true that if you only 
25	have three points, and they are all fairly close together, 

			95 1	there is going to be some imprecision in what the person's
	2	rate of change is.  Probably the further apart they are, the 
	3	longer the experience, the better.  But that is just where 
	4	the variance comes from, there is an error rate in these 
	5	slopes, and the presumption is that you have the same 
	6	problem in both placebo and treatment group, and that is why
	7	you need relatively large numbers, because it is not a very 
	8	precise measurement if you only have three points and if 
	9	they are taken fairly close together.  So it is true, but 
10	that is what you deal with.  That is the nature of the data. 
11		DR. GILMAN:  I think Dr. Dobbins wanted to
12	respond. 
13		DR. DOBBINS:  Two points at the moment with regard 
14	to that.  Among the patients with at least three post- 
15	baseline scores, the majority of the patients overwhelmingly 
16	had much more than three point post-baseline.
17		In fact, in both the North American and European 
18	studies, 60 percent of the patients in that group had at 

19	least eight or nine observations, in fact, the entire study.  
20	About the percentage of patients with only three 
21	observations in the analysis in both studies, it is less
22	than 10 percent, it is about 5 percent and evenly balanced 
23	between the treatment groups. 
24		In fact, in both studies, patients excluded from 
25	the three-point slope analysis, were balanced among the 

					96 1	treatment groups, and we can show that specifically.

	2		DR. GILMAN:  Could you comment on why you 
	3	established more in some cases than in others before 
	4	randomization and treatment? 

	5		DR. DOBBINS:  More? 
	6		DR. GILMAN:  Oh, you are talking about post-
	7	randomization, I am sorry. 
	8		DR. DOBBINS:  I was talking about post- 
	9	randomization, yes, because that is a key point with regard 
10	to the amount of data that we have on patients.  The thought 
11	may be that if we require three post post-baseline, that
12	there are a lot of patients in the sample who only had three 
13	points, and we want to be very clear in that matter that the 
14	majority of patients had large numbers of points, again 60 
15	percent with at least eight. 
16		DR. GILMAN:  Yes.  All right.  Please continue.
17		[Slide.] 
18		DR. GELINAS:  There are other important study 
19	design elements which are mandated by the disease ALS, based 
20	again on the Baylor historic database, it was observed that 
21	patients with scores, AALS scores above 115, often were not
22	able to get into clinic.  When they got to clinic, they were 

23	too tired or too weak to be able to complete the entire AALS  
24	assortment, and that slopes, which would be derived at this 
25	late stage of disease, were no longer linear. 

			97 1		Due to this, we decided to address this issue
	2	directly and we defined protocol-specified termination 
	3	points, such that patients would be able to complete as much 
	4	as possible a reliable AALS score, and we terminated 
	5	patients who had an AALS score of greater than 115 or a 
	6	forced vital capacity of less than 39 percent or predicted.
	7		[Slide.] 
	8		Because ALS is a uniformly fatal disease, it was 

	9	anticipated that some patients would die during the course 
10	of the study.  This graph from the Baylor database shows us 
11	that the total AALS score per se does not predict patient
12	death and that, in reality, death is not infrequent at any 
13	point along the time one is diagnosed with ALS, but 
14	especially is not infrequent with an AALS score of greater 
15	than 80. 
16		DR. DRACHMAN:  That table gives the number of
17	deaths, but it does not give the percent by score.  Are you 
18	saying that the percentage of deaths for those under 80 and 
19	those at 100, and so on, are equivalent, or how would you 
20	view that? 
21		DR. GELINAS:  I can view this only by the patients
22	evaluated in this database, and actually I would defer for 
23	the statistics to Dr. Dobbins. 

24		DR. DRACHMAN:  There is no denominator there, so I 
25	don't know what to make of those numbers. 

			98 1		DR. DOBBINS:  The figure is only meant to
	2	illustrate that within two months proximal to death, the 
	3	Appel score can vary greatly over the range.  So, for 
	4	example, a patient, if you look at one month prior to death, 
	5	based on that chart, patients are relatively equally likely 
	6	to have an Appel ALS score as low as 80 and as high as	120.
	7		DR. DRACHMAN:  How likely? 
	8		DR. GELINAS:  The denominator is 34. 
	9		DR. GILMAN:  Let's halt there.  Dr. Leber is next, 
10	then, Dr. Temple. 
11		DR. LEBER:  I think what we are struggling with,
12	and which Dr. Drachman is picking up, is the issue of 

13	conditioning upon who was available to suffer the event 
14	given a score of a certain size. 
15		It is very much like a survival analysis.  You 
16	can't look the accrued rate because you really want to look
17	at the hazard, that is, the likelihood of suffering the 

18	event having survived to a point in time where you have a 
19	given score. 
20		Now, what will happen, that there will probably be 
21	many, many fewer people available who have a score that is
22	very high compared to a score that is very low.  So when you 
23	do the rate of death, instantaneous, conditioned upon an 
24	attained score, that would be a different display than this 
25	one, which doesn't provide the denominator and doesn't 

			99 1	condition the proportion on how far along you have gone in
	2	the disease. 
	3		So it fundamentally doesn't provide the answer 
	4	that you want. 
	5		DR. GILMAN:  Dr. Appel. 
	6		DR. APPEL:  I just wanted to concur with Dr.
	7	Leber's point, that the point here is that the reason you 
	8	have fewer people -- and I think this is what caught Dr. 
	9	Drachman's eye -- appearing in the 121 to 130, 131 to 140, 
10	is these patients were not coming back, were not able to be 
11	assessed, and therefore, could not be included.
12		We are talking about an n of 181 that matched 
13	things, and in fact, the sole point of this slide is to show 
14	that patients can die at 80, they can die at 85, they can 
15	die at 95, and you can't do the kind of analysis Dr. 
16	Drachman would like because of what Dr. Leber said, and you
17	can see it in the graph here, fewer patients are coming 
18	back. 
19		DR. GILMAN:  You could input those scores, though, 
20	surely. 
21		Dr. Leber.
22		DR. LEBER:  I think I agree entirely with what Dr. 
23	Appel is saying.  It is not that you can't do it.  That is 
24	not the issue here.  The issue is that this is presented to 
25	imply that one has information that one does not, and I 

			100 1	think that is what we were responding to, and what Dr.
	2	Drachman was responding to. 
	3		You can't tell from this what proportion of 
	4	individuals would die had they had that score.  All you can 
	5	say is this is what they saw, but it is not a complete 
	6	accounting of everyone in the race, and I think that is the
	7	problem. 
	8		DR. DRACHMAN:  The fundamental issue is whether 

	9	death is a surrogate measure for the degree of severity of 
10	the illness, and whether the Appel Scale is comparable in 
11	that way.  One would ordinarily guess with very mild ALS,

12	they will not die of the disease, whereas, with very severe 
13	ALS measured by the Appel Scale or any other means, they 
14	would be more likely to die, so that death is not an 
15	independent factor.  That is the point that I am addressing. 
16		DR. APPEL:  May I make the point, I wish Dr.
17	Drachman's statement were true, that with a mild rate of 

18	progression, the patient would not die of this disease.  
19	Unfortunately, it is not true.  Even with a mild rate of 
20	progression, patients will die with ALS. 
21		DR. DRACHMAN:  Not rate, but severity, not rate,
22	severity. 
23		DR. APPEL:  And will progress to a severe score 
24	which cannot be monitored because we don't have the 
25	information here. 

				101 1		DR. GILMAN:  Dr. Temple and then Dr. Leber.
	2		DR. TEMPLE:  That still isn't the question that I 
	3	think is being raised.  The question is what sort of scores 
	4	should you attribute to someone who turns up dead when you 
	5	haven't seen them for a few months. 
	6		It must be true that between a score that is not
	7	associated with dying, it is very early, and a score that is 
	8	very high where people die.  There must be some increase in 
	9	risk with score.  It is just, unfortunately, not very 
10	precise and you can't make the observations to really pin it 
11	down, but it is inconceivable that there isn't a rising risk
12	with score. 
13		At some point there has got to be a steep curve, 
14	because you have got to go from zero to a risk, and you have 
15	got to get there by going through some numbers.  It is just 
16	that, as you said, you can't quite pin it down because they
17	are not coming to clinic. 
18		DR. GILMAN:  Dr. Appel. 
19		DR. APPEL:  Let me try and get my point across.  I 
20	guess I am not succeeding here, but I really do want to 
21	succeed.
22		The point here is that one cannot impute a score 
23	of 130 or 140 based on this information.  The fact that when 
24	we looked in our database, it was random, means that you 

25	cannot take a fixed score and say the patients will die at 

			102 1	that point.
	2		DR. GILMAN:  Well, the cause of death is another 
	3	factor in here, and the frequency of autopsy examination is 
	4	an important factor, so that one can establish the cause of 
	5	death if possible. 
	6		For example, some of these people may have had
	7	acute pulmonary emboli and thereby expired with a score that 
	8	is very low as one example. 
	9		Dr. Leber. 
10		DR. LEBER:  I think this is the usual confusion 

11	between reverse and direct probabilities.  We are interested
12	in assigning score for people who died that is 
13	representative of their condition at the time of their 
14	death. 
15		The LOCF analysis, which is based upon a score 

16	they attained earlier than the time of death, may somewhat
17	predict what they are likely, if a long time elapsed, we 

18	expect them to deteriorate.  Whether they deteriorate along 
19	the slope they had prior to that time or they accelerate is 
20	an open question.  I don't think we have enough information. 
21		The trouble is that the representative score for a
22	person that is dying is not available from this.  What you 
23	really want probably is to start out and say, having 
24	survived to a given score on the Appel score, what is the 

25	probability that you will die in some forward interval of 

			103 1	time having attained that score.
	2		I would argue logically that I would expect it to 
	3	be higher having attained a higher score than if you only 
	4	had a score of, say, 50 or so.  I mean that just stands to 
	5	reason. 
	6		DR. GILMAN:  Given probability, however, the
	7	patient may have an acute myocardial infarction or pulmonary 
	8	embolus or pneumonia. 
	9		Dr. Temple, then Dr. Dobbins. 
10		DR. TEMPLE:  I guess, Dr. Appel, I don't 
11	understand why the question that is being raised can't be
12	answered.  There must be a denominator for the population 
13	less than 80, the population 81 to 90, 91 to 100.  You could 
14	at the bottom of that put the number of people. 
15		It is censored, but you can say of the people who 
16	achieved this number, how many then died in the subsequent
17	one or two months.  That is an available number.  
18	Everybody's guess is that the number for less than 80 is a 
19	lot larger than all the other numbers, so the percentage of 
20	people who died in the next one or two months is smaller.  I 
21	mean that seems almost inevitable.
22		So if that were true, then, there would be a 
23	relationship between what your score is and the probability 
24	of dying.  It seems almost inconceivable that there is no 

25	relationship.  I mean it has almost got to be. 

			104 1		DR. GILMAN:  Dr. Dobbins, do you want to respond
	2	to that? 
	3		DR. DOBBINS:  Yes.  I think we are overlooking a 
	4	very important point, and it was brought forth in the 1995 
	5	Brain paper by Havercamp and Appel, and that shows that the 
	6	survival is directly related to the rate of disease
	7	progression, and not disease severity at a particular point. 
	8	That is a very fundamental point.  As measured by the Appel 
	9	score slope. 
10		DR. GILMAN:  Dr. Leber. 
11		DR. LEBER:  John made this point earlier in his

12	presentation that the predictive value of time-to-death is 
13	much better when you are progressing more rapidly, and in 
14	fact you are shooting at a much closer target, to use a bad 
15	metaphor. 
16		If, in fact, you have a very slow slope, the
17	opportunity for slight deflections in error to predict the 
18	time five years hence is going to be off, so the quality of 

19	prediction is terrible, the precision of prediction.  If you 
20	are just about on death's door, and you are very rapidly 

21	progressing toward it, obviously, your prediction will be
22	off by less.  This is question of shooting at the moon 
23	versus shooting at Uranus. 

24		I think the problem for us, however, is not that. 
25		[Laughter.] 

				105 1		DR. LEBER:  Well, perhaps you would like the
	2	galaxy.  I mean I think this is going beyond the evidence to 
	3	such a point.  Neptune?  You pick your planet, you pick your 
	4	star. 
	5		I guess what we wanted to do, all of us, is to be 
	6	able to fairly provide an estimate for the state of patients
	7	who were censored.  All of this is an attempt to get at the 
	8	question of what is the fair comparison when you have 
	9	missing data, and I think that neither of us, the firm or 
10	the agency, have found a way to do it. 
11		However, we tried one way based upon what we
12	thought were basically in Dr. Appel's paper, a description 
13	of what the typical patient -- I use his words, I think, or 
14	their words -- would be like at about the time you begin to 
15	discuss tracheostomy and you are really far advanced.  I 

16	think that number was about 130 to 135, wasn't it?  I think
17	that is described in your paper. 

18		DR. APPEL:  Absolutely. 
19		DR. GILMAN:  Dr. Appel, maybe you should respond 
20	directly to that. 
21		DR. APPEL:  What Dr. Leber is saying is true.  In
22	the paper, we used 140 to predict that, but let me read the 
23	last part of the sentence that was in the legend to that 
24	paper.  The first part is just what Dr. Leber is saying, the 
25	score of 140 used here in predicting survival is based on 

				106 1	clinical experience.  Use of a different score would not
	2	alter the nature of the relationship between predicted and 
	3	actual survival, and in fact, we have run it all the way 
	4	from about 100 all the way up, and it is the same.  So you 
	5	get the same prediction, and that is one of the reasons that 
	6	I don't think it is valid to use 140 per se.
	7		DR. GILMAN:  Dr. Dobbins and then Dr. Temple. 

	8		DR. DOBBINS:  I would just like to follow that 
	9	from the statistical standpoint, and the other, I think 

10	sentence in that article that we have referred to -- and I 
11	will quote from it because I think it is very instructive --
12	says, "When patients have reached a total ALS score of 120, 
13	they are usually incapacitated and returning to the clinic 
14	for scoring is difficult." 
15		That is related to our clinical trials where the 
16	patients are terminating the study at 115.  So it is
17	representative of late stage disease, and not necessarily 
18	end stage disease. 
19		DR. GILMAN:  Dr. Temple. 
20		DR. TEMPLE:  Obviously, there is going to be a 
21	relationship between how rapidly you progress and how
22	rapidly you die.  That doesn't mean the basis for that 
23	relationship isn't that you achieve a score associated with 
24	death more rapidly.  That is perfectly possible.  The two 
25	are not inconsistent. 

			107 1		I guess I still don't understand why there can't
	2	be a presentation something like what you had there with 
	3	some denominators in it, so that you could say, of 100 
	4	people whose score is 80, here is the fraction that will die 
	5	in two months, of a fraction of people with a score of 100, 
	6	here is the fraction who will die within the two months, et
	7	cetera.  You can do that. 
	8		DR. LEBER:  Because the denominator you use there, 
	9	on the ones you have in your hand, it doesn't take into 
10	account the numbers that have been lost along the way. 
11		Say we change metaphors.  We are looking at who
12	finishes the marathon in New York City, and you stand at the 
13	finish line and you count the number who ran and the number 
14	who finish that cross that point.  You get a different 
15	proportion than if you looked at the numbers who started at 
16	Verazano Bridge and across that point.
17		DR. TEMPLE:  That is just the censoring problem. 
18		DR. LEBER:  Well, the censoring is enormous here 
19	because those patients aren't coming back, so you have no 

20	idea who is at risk in the interval.  Let's not think of it 
21	in time, think of it in scores.  Of those who achieve a
22	score of 120, how many of those who achieve that score can 
23	be accounted for in the next interval, how many who achieve 
24	the score of 130, the interval now in progression of ALS, 

25	and I think there is high censoring, so you don't know those 

			108 1	numbers.
	2		But, frankly, this is all irrelevant because none 
	3	of us are contending the imputation business right now. 
	4		DR. GILMAN:  Dr. Hoberman. 
	5		DR. HOBERMAN:  Dr. Leber just basically made my 
	6	point.  The purpose of the imputation was a sensitivity
	7	analysis on results that we already regarded as negative.  
	8	So therefore, it is essentially saying that if you see 
	9	something on these screens and something reported by the 
10	sponsor, we found that this kind of imputation further 
11	weakens the case.
12		But as far as what Dr. Appel said, I think the 
13	issue is not the issue of prediction of death for rate.  
14	Remember, the endpoint for which the imputation was made was 
15	change from baseline, not for slope. 
16		So when we used 140 in the paper, it was simply a
17	stand-in for the worst score that you regarded clinically 

18	when you are on a respirator.  It was simply substituting 
19	something for death. 
20		Now, as I wrote in my review, if you impute all 
21	the deaths as 115, you don't get anything different from the
22	regular LOCF.  The point is that if you impute anything 

23	between 115 and 140, you get a worse result, but again, this 
24	is not a statistically relevant issue as far as formal 
25	statistics is concerned.  It is simply an issue about trying 

			109 1	to see whether if there is some difference between
	2	treatments, in what trending direction would it go if you 
	3	try to account for deaths on study. 
	4		DR. GILMAN:  We have ground to a halt here over a 
	5	point that is not particularly directly relevant to our 

	6	decision.  So I would like arbitrarily to say that last
	7	slide demonstrated that people with a score of 80 can die, 
	8	and let's move on. 
	9		Please continue. 
10		DR. GELINAS:  The point that I actually wanted to 
11	make was that although the AALS score per se is not

12	predictive, how fast you get there is predictive. 
13		If you look here at two different patient 

14	populations, based on the rate of change, with a slope of 
15	3.3 or less, they are in the moderate progression category, 
16	and above 3.3 points per month, they are in the rapid
17	progression category. 
18		The median benefit, the median increased survival 
19	between these two is about two years. 
20		[Slide.] 
21		The AALS, because of its clinical relevance and

22	its ability to measure deterioration in function in a linear 
23	fashion in ALS, lends itself to several analyses to assess 
24	the effect of Myotrophin on ALS. 
25		Dr. Graney will show you slopes which indicate the 

			110 1	rate of disease progression, as well as total change in AALS
	2	scores. 
	3		Because early termination events were specified a 
	4	priori in the North American trial, Dr. Graney will be able 
	5	to review time-to-event analysis and to show the difference 
	6	between groups until severe final impairment.
	7		In summary, the AALS is an objective physician- 

	8	based assessment of illness and a single index of disease 
	9	severity and progression that is of clinical relevance.  
10	Therefore, these analyses and any therapeutic benefit 

11	derived from them are of direct clinical importance.
12		The SIP, the Sickness Impact Profile, in contrast, 
13	is a patient-based assessment of disease. 
14		[Slide.] 
15		The SIP was an independent assessment composed of 
16	136 questions which related to daily activities of living,

17	such as the ability to walk, to talk, and to go out and 
18	enjoy yourself. 
19		The SIP survey was conducted by independent 
20	consultants who had no other relationship to the Myotrophin 
21	ALS study.  Dr. Graney will also review these important
22	results which demonstrate that for the first time in the 
23	clinical research study in ALS, a slower decline in health- 
24	related quality of life was demonstrated. 
25		[Slide.] 

			111 1		In conclusion, ALS is a relentlessly progressive
	2	neurodegenerative disease which is uniformly fatal.  Loss of 
	3	function over time is the hallmark of ALS and it is the 
	4	reality for patients, week by week, month by month. 
	5		The AALS is a valid measurement of this disease 
	6	progression, and for the purpose of design of clinical
	7	trials in ALS, the partitioning of patients into moderate 
	8	and rapid progression is clinically meaningful and 
	9	prognostically important. 
10		Of greatest importance, there is currently no 
11	therapy which halts the disability in ALS.
12		Drs. Graney and Dobbins will present data to 
13	demonstrate that Myotrophin does delay disability. 
14		DR. GILMAN:  Thank you, Dr. Gelinas. 
15		Can I ask you why or how the team decided to use 
16	nine months as the interval that people would be studied
17	here? 
18		DR. GELINAS:  There is a lot of debate among 
19	leaders in ALS as to what is the right study length.  The 

20	RPR people did a study which was much longer.  They were 
21	looking for survival, so they needed to be powered with a
22	much longer study in order to detect a change. 
23		As a rule, in functional studies, you can get by 
24	with a shorter study, and when you look at times shorter 

25	than six months, you don't have a chance to really detect a 

			112 1	change.  So nine months is probably the shortest that you
	2	can run a study and hope to detect a change. 
	3		From a patient perspective, when you go to a study 
	4	that is longer than nine months, it is a very desperate time 
	5	because patients feel that this may be their last chance, so 
	6	that the shortest study that you can offer a patient is
	7	really the most attractive to them, because then they have 

	8	hopes that if this one doesn't show it, maybe they will be 
	9	in another one that will. 
10		DR. GILMAN:  Dr. Coyle. 
11		DR. COYLE:  Just as a point of clarification, why
12	was forced vital capacity used as a termination factor in 
13	addition to the score? 
14		DR. GELINAS:  At forced vital capacities of less 
15	than 39 percent, it has been shown by many different 
16	experienced clinicians in ALS that death becomes likely.  At
17	forced vital capacities of less than 39 percent of 

18	predicted, a patient can no longer blow their nose, they can 
19	no longer cough, they can't clear their airway.  They get 

20	definitely a dyspnea on exertion.  They are often lost to 
21	follow-up at that point, and they often don't have the
22	strength and the reserve to be able to comply with a set of 
23	examinations. 
24		DR. COYLE:  Right, and you would have a fair 

25	proportion of them that would have a score below the 115 

			113 1	cutoff, but might have that lower forced vital capacity?

	2		DR. GELINAS:  No, the majority of patients who 
	3	would have a very low FVC would also have a high AALS. 
	4		DR. COYLE:  I see. 
	5		DR. GILMAN:  Any other questions from the 
	6	committee?
	7		If not, thank you very much. 
	8		Dr. Graney. 
	9		            MYOTROPHIN DATA 
10		DR. GRANEY:  Thank you for that presentation, Dr. 
11	Gelinas.
12		[Slide.] 
13		By agreement with the Division, our presentation 
14	today will focus on analyses using base statistical models 
15	except for the protocol specified primary analyses as we 

16	review the data on the efficacy of Myotrophin in the two
17	clinical trials. 

18		[Slide.] 
19		We believe that both clinical studies provide 
20	evidence that Myotrophin is effective in slowing the 
21	progression of disease in ALS.  Three findings support this
22	position. 
23		First, the study endpoints derived from the AALS 
24	total score, the measure of functional impairment are 

25	positive and directionally consistent between the two 

			114 1	studies.
	2		Second, the time until the occurrence of one of 
	3	the protocol-specified termination criteria indicating 
	4	advanced disability is increased in both studies. 
	5		Third, in both studies, the therapeutic effect is 
	6	most evident in the rapidly progressing patients, and the
	7	size of the effect in these patients is similar between the 
	8	two studies. 
	9		As Dr. Gelinas noted, the AALS total score is our 
10	primary measure of disease progression.  Our presentation 

11	will examine the rate of change of that score or slope, as
12	well as the actual change in the score from baseline to 
13	endpoint. 

14		We will also examine the occurrence of the events 
15	defined prospectively as mandating termination.  An AALS 

16	score of 115 or more or an FVC of 39 percent or less of
17	predicted. 
18		Throughout the presentation today, in our slides, 
19	the results for placebo will be indicated by the yellow, for 
20	the low dose Myotrophin by the orange, and the high dose by 
21	the pink.
22		[Slide.] 
23		In the North American study, the slope or the rate 
24	of change of the score shows a dose-response relationship, 
25	with the high dose producing a 21 percent reduction in the 

			115 1	slope.
	2		The protocol-specified analysis comparing the 
	3	combined Myotrophin groups with the placebo-treated group 

	4	yielded a p value of 0.055.  A pairwise comparison of the 
	5	high dose group with the placebo group was statistically 
	6	significant with a p value of 0.009.

	7		As you can see, the treatment groups are equally 
	8	represented in this analysis which, as I noted, requires at 
	9	least three evaluations.  You will see that about 10 
10	patients in each of the groups did not have a sufficient 

11	number of points to qualify for this three-point slope.
12		[Slide.] 
13		As in Dr. Feeney's presentation, we were also 
14	interested in whether Myotrophin altered patient slopes from 
15	the pre-treatment or screening period to the treatment 
16	period.
17		We examined this within-group effect by looking at 
18	the slopes for each of the treatments before and after 

19	randomization, and we display here the difference.  A 
20	negative value for the difference indicates a favorable 
21	treatment effect.

22		In the North American trial, there was a favorable 
23	effect in both of the treatment groups, and this was absent 
24	in the placebo group. 
25		DR. GILMAN:  Dr. Graney, could you go back two 

				116 1	slides, please.  I wanted to ask you how you established the
	2	dose.  Why did you double the dose?  You used 0.05 and 0.10. 
	3		DR. GRANEY:  Yes.  The dose is based upon blood 
	4	levels that were seen in preclinical models as giving 

	5	effects, showing a response of the nervous system to 
	6	Myotrophin in some standard mouse models of injury.
	7		When we looked at our Phase I studies and at the 
	8	mouse levels, the dose in man that produced blood levels 
	9	equivalent to the effect of animal levels was 0.10 mg/kg.  
10	As Dr. Feeney noted, from our Phase I studies also, it was 
11	noted that this dose does produce hypoglycemia or it does

12	produce episodes of hypoglycemia in a limited number of the 
13	volunteers.  Only 8 or 10 patients got it, I think 25 
14	percent had evidence of hypoglycemia.  So we decided that 
15	that, as a dose, was not workable.  The decision was then 
16	made to go ahead and split that dose into two during the

17	day.  The 0.5 was chosen as a logical intermediate between 
18	the placebo and those dose. 
19		DR. GILMAN:  Oh, the idea was that you wanted 
20	three arms.  I don't understand why you didn't just go ahead 
21	with 0.1 in divided does.
22		DR. GRANEY:  I think part of the concern -- and 
23	there were many factors that went into it -- was even at the 
24	beginning of the study, an underlying concern that the 0.1 
25	dose in these debilitated patients, where there might be 

			117 1	some problems with nutrition, would give problems in
	2	hypoglycemia and cause problems with the progress of the 

	3	trial.  The 0.5 dose would provide some cover for that. 
	4		Exactly your point came up and was brought up the 
	5	by European investigators, and that is one of the reasons 

	6	that the	0.1 was used alone.  At the time that the European
	7	trial was being designed and fleshed out, there was enough 

	8	experience, although double-blinded still, from the American 
	9	trial, to indicate that the 0.1 must be well tolerated.  In 
10	effect, the change that was then made in the European study 
11	was to just take both of the groups that would have gotten

12	the two different doses of Myotrophin and assign them both 
13	to the 0.10, effectively giving us the 2 to 1 randomization 
14	we see in Europe. 
15		DR. GILMAN:  Also, did you test the difference 
16	between placebo and 0.05?
17		DR. GRANEY:  Yes, and it was not significant. 
18		[Slide.] 
19		We see here the change in the AALS total score 
20	from baseline.  This analysis, although you will hear more 
21	discussion of the LOCF by Dr. Dobbins, does include
22	virtually all of the patients by virtue of the activity of 
23	this analysis. 
24		In the LOCF, patient scores are carried forward 
25	beyond the point where they have ended the trial as if they 

			118 1	continued in the trial, so a patient that ends at an early
	2	point will be carried forward in the analysis, and 
	3	effectively, all of the patients are represented in all of 
	4	the months. 
	5		I think the significant finding here is that there 
	6	is a dose-related effect of Myotrophin, that it emerges as
	7	early as the first month, and that at baseline, we have 
	8	about a 24 percent reduction in the change of the score from 
	9	baseline in the high dose as compared to the placebo-treated 
10	group. 
11		[Slide.]
12		Myotrophin increased the time until the 
13	development of advanced disability as indicated by the 

14	occurrence of one of the protocol-specified termination 
15	criteria, and we have certainly talked about this at length 
16	at several points in the discussion today, but we are
17	looking here at a display of basically the surviving 
18	patients who have not reached 115 of an FVC of less than 39 
19	percent. 
20		The effect is significant in the high dose group 
21	and dose related.  The difference between the high dose
22	group and the placebo begins to emerge relatively early in 
23	the study. 
24		A Cox proportional hazards analysis of this data 
25	shows that the risk of an event in the high dose group as 

			119 1	compared with the placebo is reduced by 44 percent.
	2		[Slide.] 
	3		Now, we will go to the Sickness Impact Profile, an 
	4	alternate means of evaluation that Dr. Gelinas described to 
	5	you.  I think the important point here is that this profile 
	6	is independent of the effect on the AALS total score, and
	7	yet it is confirmatory. 
	8		Remember we are looking now to determine the 

	9	effect of the drug on the patients' quality of life as 
10	perceived and reported by the patient.  The overall SIP, 
11	which includes 12 items, showed a dose-related effect with
12	significance in the high dose. 

13		We also saw a dose-related effect in the physical 
14	and the psychosocial domains that you saw described earlier. 
15		[Slide.] 
16		In summary, in the North American trial,
17	Myotrophin produced dose-related slowing of the progress of 
18	disease.  The magnitude of the effect was about a 20 to 25 
19	percent reduction from the values seen in the placebo- 
20	treated groups. 
21		We saw these effects in the reductions of the rate
22	of change of the AALS score or slope, and in the change of 
23	the score from baseline.  Further, we saw a change in the 

24	time to the development of the pre-specified events. 
25		The Sickness Impact Profile does give us another 

				120 1	measure.  I would point out that this is an independently
	2	administered evaluation.  Interviewers contact the patients 
	3	by phone, and so were not subject to getting information 
	4	from the investigator sites on other elements of the 
	5	patient's well-being, and again, what we saw was a dose- 
	6	related effect significant in the high dose compared to
	7	placebo. 
	8		[Slide.] 
	9		The effects of Myotrophin on disease progression 
10	were also seen in the second multicenter trial.  As Dr. 
11	Feeney pointed out --
12		DR. GILMAN:  Can I interrupt you there to ask, you 
13	also administered the Clinicians' Global Assessment? 
14		DR. GRANEY:  Yes, we did. 
15		DR. GILMAN:  And what were the results of that? 
16		DR. GRANEY:  We have scattered elements of
17	significance over time, and I can show you the data later if 
18	you would like.  After the start of the study, it was 
19	recognized that the CGI was probably not well suited to ALS. 
20		If you will recall, on the CGI, basically, half of 
21	the extent of the scale is used to record improvement, and I
22	think, as our clinicians would tell you, there really is no 
23	prospect even with therapy of ALS patients having a 
24	measurable degree of improvement or reporting improvement in 
25	their well-being. 

					121 1		With the becoming clear, the CGI was actually
	2	removed as one of the primary endpoints before the end of 
	3	the study.  We do have data.  There was some scattered 

	4	evidence of effect, but we don't believe that it was a 
	5	particularly good tool for this protocol. 
	6		DR. GILMAN:  Was that a prospectively determined
	7	tool? 
	8		DR. GRANEY:  Yes. The CGI was included in the 
	9	protocol at the time it was put together. 
10		DR. GILMAN:  Dr. Kawas. 
11		DR. KAWAS:  Just a clarification.  On the Sickness
12	Impact Profile, the 20 percent of patients that aren't in 
13	those results, who are they? 
14		DR. GRANEY:  In the Sickness Impact Profile, the 
15	studies were conducted at months 3, 6, and 9, so that we 
16	don't have as many measures as we had in the Appel Scale. 
17	Patients who ended the trial without having had a Sickness 
18	Impact Profile after baseline simply don't have a score 
19	available. 
20		DR. KAWAS:  So that 20 percent of people who 
21	didn't make it to three months, is that --
22		DR. GRANEY:  I will have to look at that specific 
23	analysis.  Yes, that is the case. 

24		DR. KAWAS:  Thank you. 
25		DR. GILMAN:  Dr. Adams. 

					122 1		DR. ADAMS:  In regard to the Sickness Impact
	2	Profile again, you said there were three assessments, at 3, 
	3	6, and 9 months, and the change in score from baseline 
	4	reflects which of those assessments, or is that an aggregate 
	5	value? 
	6		DR. GRANEY:  I am almost certain that is an
	7	endpoint that we are looking at. 
	8		DR. ADAMS:  So that is at 9 months. 
	9		DR. GRANEY:  Yes.  Just a second, let me ask Dr. 
10	Dobbins on that. 
11		DR. GILMAN:  Please identify yourself.
12		MR. MICHAEL MURPHY:  Michael Murphy, Senior Vice 
13	President, Cephalon.  I wanted to address the CGI measure 
14	and then I can also comment on the SIP.  Perhaps it would be 
15	of interest. 
16		In both protocols, two different measures of
17	global improvement were employed.  One was identified as a 
18	clinical global impression of change from a previous visit.  
19	The second was identified as a clinical global impression of 
20	therapeutic response which was from baseline. 
21		In the North American trial, both of those
22	measures yield fairly consistent results through time and/or 
23	at endpoint, and we obviously can show you the data. 
24		In the European study, only one of the measures is 
25	significant at endpoint. 

					123 1		On the Sickness Impact Profile, the results which

	2	Bill showed were endpoint analyses which only requires that 
	3	a patient have a baseline in at least one post-baseline 
	4	evaluation.  So it is the maximum sample size permitted by 
	5	the analysis, and the missing patients simply reflect those 
	6	who do not have either a baseline or a post-baseline
	7	measure. 
	8		DR. GILMAN:  Dr. Zivin. 
	9		DR. ZIVIN:  I am not sure that the question I had 
10	was answered or not, which is in the Sickness Impact 
11	Profile, was the analysis done with the last observation
12	carried forward? 
13		DR. DOBBINS:  Yes. 
14		DR. GILMAN:  Dr. Drachman. 
15		DR. DRACHMAN:  In the AALS scale, then, would one 
16	be accurate to say that there is roughly a two- to three-

17	month advantage for those on full dose versus placebo, is 
18	that the way you read that? 
19		DR. GRANEY:  It is somewhat difficult to convert 
20	the slope exactly to time and event, but -- 
21		DR. DRACHMAN:  Not slope, but the score.
22		DR. DOBBINS:  Yes.  Within the context of the nine 
23	months, the hypothesis being that it would be greater going 
24	beyond the nine months.  In the window in which we captured 
25	the differential progression, that would be correct. 

				124 1		DR. GILMAN:  Dr. Temple.
	2		DR. TEMPLE:  I didn't understand that last part.  
	3	most of the differences that were seen did not continue to 

	4	get larger with time, differences on slope, and things like 
	5	that, did they?  So why would one expect that it would grow 
	6	with time?
	7		DR. DOBBINS:  The slope would not change with 
	8	time, but a one-point change in the slope over time is 10 
	9	points at 10 months, 20 points at 20 months, and so on. 

10		DR. GILMAN:  Thank you.  Please continue, Dr. 
11	Graney.
12		DR. GRANEY:  Thank you. 
13		[Slide.] 
14		We will talk now about our European trial, 
15	contrasting it with the North American. Again, the overall 
16	design was similar with several differences that I would

17	like to note.  Only a single dose of Myotrophin, the 0.1 
18	mg/kg/day was studied and I briefly revealed the reasons for 
19	that.  The European investigators also preferred a trial 
20	that treated a larger number of patients with the high dose. 
21		At randomization, as a result of the compression
22	of groups that we just talked about, two patients were 

23	assigned to the single Myotrophin dose for each patient 
24	assigned to placebo. 
25		The protocol-specified endpoint for the European 

			125 1	trial was the change in the ALS score from baseline, and as

	2	I mentioned in answering one of the earlier questions, this 
	3	analysis does include a larger percentage of patients than 
	4	the slopes analysis chosen for the U.S. study, because of 
	5	course you can't generate a three-point slope without three 
	6	post-baseline slopes.
	7		However, in order to provide a more extensive 
	8	comparison of the trials, I will also present the slopes 
	9	analysis and the times-to-event for the European trial as I 
10	did for the North American. 
11		[Slide.]
12		In looking at the change in the score from 
13	baseline, as compared to placebo, Myotrophin produced a 

14	decrease in the change of the AALS score from baseline at 
15	endpoint of 3.3 points or 13.1 percent at endpoint.  This 
16	compares to a reduction of 5.9 points or 24 percent in the
17	North American trial. 
18		You will see that this pattern of a drug effect, 
19	which although statistically significant is in the same 
20	direction as the North American trial with a lesser 

21	magnitude as seen across the AALS-related measures.
22		[Slide.] 
23		Again, because of the interest that we had in 
24	slopes, as well as the Division, we did calculate slopes for 
25	the European trial, and I will turn first to the slope that 

				126 1	we calculated with three observations.
	2		Myotrophin produced a reduction of 0.6 points per 
	3	month or 16 percent, about 50 or 60 percent of the change we 
	4	saw in the U.S. trial.  The p value on this was 0.063.  You 
	5	can see here that we had about 85 percent of the patients 
	6	involved.
	7		We did go ahead in this study to do a two-point 

	8	slope, recognizing the limitations of that.  When we did 
	9	that analysis, we had basically the same magnitude, but we 
10	did get a p value of 0.047. 
11		The difference between the two analyses in terms
12	of the patients included is 168 patients with the two-point 

13	slope as compared to 155 for the three-point.  I think it is 
14	notable that the magnitude of change is really the same 
15	between the two even when we include more patients. 
16		DR. GILMAN:  Could you go back one slide, please. 
17	It looks as if you are not getting much difference if one 
18	just looks at the difference until six months from the first 
19	observations, whereas, with the slopes in the North American 
20	trial, there was a change from the very beginning. 
21		DR. GRANEY:  Yes.
22		DR. GILMAN:  Could you comment on that? 
23		DR. GRANEY:  We have looked at it extensively in 
24	our effort to try to determine the difference between the 

25	two studies, and I really don't have a specific answer for 

			127 1	the delay that we see.
	2		DR. DOBBINS:  Just to add a little to that. 
	3		DR. GILMAN:  Dr. Dobbins. 
	4		DR. DOBBINS:  We do note in the North American 
	5	study, although significance begins earlier, that the break 
	6	actually begins to magnify at around five to six months.  So
	7	the same phenomenon to some extent is observed in the North 
	8	American study. 
	9		DR. GILMAN:  Dr. Leber. 
10		DR. LEBER:  It is not just that the statistical 

11	significance changes, but the directionality shifts here,
12	which is the kind of thing you often see because of 
13	dropouts, but I am not going to argue that that is the 
14	explanation. 
15		I would also like to point out something that I 
16	think important as you hear it presented.  The slopes

17	analysis the firm is presenting has p values that are 
18	nominally in the range of statistical significance or 
19	statistically significant. 

20		The slopes analysis done by the FDA on the same 
21	data has p values of what, around 0.22 to 0.4.  I would like
22	to call everyone's attention to that because it suggests 
23	very strongly that the differences are analysis-dependent, 
24	and it might be useful, while the firm is here, to explain 
25	how that came about, where these models they are using came 

					128 1	from before they just present it as, in fact, the result of
	2	the slope analysis. 
	3		DR. GILMAN:  Can you respond, Dr. Dobbins? 
	4		DR. DOBBINS:  Yes, we would be perfectly happy to 
	5	do that at the appropriate time. 
	6		DR. GILMAN:  Well, why not now?
	7		[Laughter.] 
	8		DR. DOBBINS:  Dr. Gilman, may I suggest that I 

	9	include those remarks in my discussion with the efficacy 
10	issues that is part of my discussion.  The short answer to 
11	the question is that we used a more sensitive method, and

12	actually the best method for analyzing longitudinal data in 
13	a clinical trial, which although unfortunately was not a 

14	method that was chosen at the time prior to the studies 
15	being analyzed, in the end is the most efficient method. 
16		And this method I refer to is a repeated measures
17	analysis of variance. 
18		DR. GILMAN:  I think we need a little discussion 
19	on that.  Dr. Leber. 

20		DR. LEBER:  Well, I don't challenge the idea that 
21	it is a different method.  I just wonder by what criteria
22	you say it is the best method. 
23		DR. DOBBINS:  It is the statistically most 
24	efficient method for this kind of problem. 
25		DR. LEBER:  Does that mean it is the most valid 

			129 1	method or the most efficient method?  Are the two the same?
	2		DR. DOBBINS:  Yes, I think it is.  I think it is 
	3	most efficient and most valid. 
	4		DR. LEBER:  I would suggest this battle is on the 
	5	biometric plane and we need to bring out biometrician 
	6	champion.
	7		DR. GILMAN:  Dr. Hoberman. 
	8		DR. HOBERMAN:  When I saw this slide presented, I 
	9	was disturbed because I have the impression that the sponsor 
10	was presenting this as a primary analysis, that is, the 
11	results of getting the data in, unlocking the data set, and
12	then doing something that was in a protocol.  That is not 
13	true. 
14		This analysis was done quite recently, and it is a 
15	technical issue, and the last thing I want to do is turn 

16	this into dueling statisticians, but it is going to educate
17	nobody. 
18		The issue here is that the sponsor, after many, 
19	many covariate analyses in all kinds of models that have 

20	been unspecified, some of which have been submitted, decided 
21	to do an analysis which accounts for more information about
22	what happens from time point to time point, then simply 
23	fitting straight lines to each individual and then doing an 
24	analysis of variance to decide whether the averages of those 
25	slopes are different. 

			130 1		That is basically what was in the protocol for
	2	both studies in terms of analyzing slopes. 
	3		Now, what the sponsor did was take into account 
	4	the degree to which if a person was above a mean at one 
	5	time, above the group mean at one time, that they tended to 
	6	be above the group mean at the next time.
	7		In this way, when Dr. Dobbins measures efficiency, 
	8	what he means is that it tends to cut down on the estimate 

	9	of noise in the data, and all a statistic is, is a ratio of 
10	signal to noise.  You try to find a signal.  Then, we have 
11	to relate that to a measure of noise, and the larger the

12	signal is compared to the noise, the more we say this 
13	couldn't have happened by chance, it is not noise. 
14		So what this model tries to do is incorporate 
15	information which decreases the amount of noise in the 
16	problem.  It is a sensible thing to do.

17		Now, when I found that they had done this rather 
18	late in the game, I went back and I did another analysis.  
19	Now, the analysis that the sponsor did prescribes a certain 
20	pattern of this correlation that I spoke about over time. 
21		You simply say to the computer find me a
22	correlation, do a goodness-of-fit test, then, use that one 
23	in order to get the efficient analysis. 
24		Now, we are not God, neither is the computer God, 
25	and we don't really know what the correct one is, but what 

			131 1	the sponsor did was use the data in order to estimate this
	2	pattern of correlation over time. 
	3		Now, that was all done by the computer.  What I 
	4	did was use a slightly different method which has been 
	5	extensively used in the literature, reported on the 
	6	literature, and I don't want to give you the name because it
	7	is just going to make you mad, and what it does is account 

	8	for any misspecification of this correlation structure. 
	9		So, in other words, it uses more of the data to 

10	get an arguably more accurate estimate of the noise.  When I 
11	did that, the p value for the same analysis, the same data
12	set, was	0.16 using the same correlation structure that they 
13	hypothesized only I used more information to correct for the 
14	degree to which that was incorrect. 
15		It went up to 0.16.  If I used another correlation 
16	structure, it went up to 0.21.  If I used another one, it
17	went up to 0.23. 
18		There is another issue.  The other issue is the 
19	estimate of the signal.  Now, there are many ways to get 
20	statistically valid, unbiased estimates of the signal.  Now, 
21	it turns out that the sponsor's measurement of the signal,

22	when using this result that they got with the 0.06, was 
23	minus 0.58. 
24		However, if you do other analyses, this can go 
25	down to 0.5 and in fact, I did an analysis where it went 

			132 1	back down to minus 0.46.
	2		The upshot of all of this is that when the sponsor 
	3	shows you p values at or near 0.05, I want you to be aware 
	4	that this not a robust result, and by "robust," when I was a 
	5	kid, robustness had something to do with coffee.  Now I am a 
	6	statistician it has to do with the degree to which you can
	7	slightly perturb the problem, ask a slightly different 
	8	question, do a slightly different analysis, and come up with 
	9	a conclusion that is congruent with the one that you have 
10	done initially. 
11		In this case, there is no robust analysis of a p

12	value less than 0.05 no matter what analysis you do.  Now, 
13	the 0.047 is a late entry, late entry within the last 24 
14	hours.  So I haven't been able to look at that one, but my 
15	comment is precisely the same, you can always perturb the 
16	data in a way to get a better result -- and obviously the

17	sponsor is doing that -- and you can do other analyses that 
18	make the case much less compelling. 
19		DR. GILMAN:  Dr. Dobbins. 
20		DR. DOBBINS:  Yes, I would like to respond to 
21	that.  We take great issue with the implication that somehow
22	we picked a particular correlation structure which best 
23	suited our needs. 
24		In fact, and before I respond to that, I think a 
25	little mixing in the beginning with some kind of 

			133 1	sophistication and that this method is not well known or
	2	well established in the literature, repeated measures 
	3	analysis of variance has been around a long time and is 
	4	widely regarded as the most efficient method for this. 
	5		Secondly, if I may, Dr. Hoberman, you have had 
	6	your comments, I would like to respond.  With regard to his
	7	statement with the use of covariates the models that we used 
	8	for repeated measures include no covariates.  They included 
	9	simply the design parameters of study site and treatment.  
10	So it is a very simple model which exploits the information 
11	within a patient over time, that correlation.
12		Our analysis showed, an analysis very similar to 
13	what Dr. Hoberman which we are prepared to present today, 

14	showed that we had robust results.  We are not talking in 
15	everything less than a 0.05, but what we saw was in the 
16	range of actually 0.001 to about 0.14 assuming several

17	different kinds of variability structures for the data, the 
18	essential point being is when you use a more efficient 
19	method which better distinguishes the signal from the noise, 
20	treatment effect is more apparent. 
21		Secondly, the treatment effects that we observed,
22	the treatment estimates that we observed, as Dr. Hoberman 

23	pointed, one being around 0.4 or 0.5, we would argue that 
24	the range 0.4 or 0.5 to about 0.7 that we saw is a very 
25	tight range, and in fact, the optimal models, the optimal 

			134 1	correlation structure we saw had essentially identical
	2	treatment estimate to the simple linear method, what is 
	3	called the naive linear regression, which is the ordinary 
	4	least squares. 
	5		We can discuss the issue of the robustness of the 
	6	results.  We are simply saying that we used a better
	7	statistical method, and I don't think we can be faulted for 
	8	using the best method available even if we didn't specify it 
	9	pre-hoc.  If we are taking an x-ray of a tumor and we have a 
10	CT scan available, I don't think because the protocol said 
11	that we have an x-ray, that we should continue to use the x-
12	ray, and that is effectively what we have done with this 
13	analysis and this method. 
14		DR. GILMAN:  First, Dr. Hoberman, then Dr. Temple, 
15	then Dr. Leber, then Dr. Drachman, and please be brief. 
16		DR. HOBERMAN:  I think Dr. Dobbins has
17	misunderstood my criticism.  First of all, when I was 
18	talking about your using the pattern that was most 
19	advantageous, I thought, and I am sorry if I didn't make it 
20	clear, that the computer chose that with the goodness-of-fit 
21	criteria.  I have the printout.
22		DR. DOBBINS:  Yes, that is correct, but it wasn't 
23	arbitrarily chosen by -- 
24		DR. GILMAN:  Dr. Dobbins, please wait until he is 
25	finished. 

			135 1		DR. HOBERMAN:  So it was not a prespecified
	2	structure, it was determined by the computer, and I thought 
	3	I had said that. 
	4		The second thing is I did not mean to imply that 
	5	the model had covariates in it.  I was referring to the 
	6	panoply of covariate models that have been submitted and
	7	that I know have been done aside from the repeated measures. 
	8		Third, I was not referring to the repeated 
	9	measures model in the literature, I was referring to, pardon 
10	the expression, GEE, so there is no issue about repeated 

11	measures, it is older than time.  So that is not the issue.
12		I also concur that, yes, if you have a more 

13	efficient method, do it, fine, and you did it, but you 
14	yourself have stated that there is a wide range of values 
15	that you can get from this analysis, and I think that minus 
16	0.4 to 0.7, I am not exactly sure why you say it is tight,
17	because if you apply those to all the different standard 

18	errors, you are going to have an incredible range of p 
19	values. 
20		So the idea that somehow there is a p value of 
21	0.06 or 0.04 that you are stating is the result of this

22	trial in slopes, I don't think it gives a full picture, and 
23	I simply wanted to point out that this is not a robust 
24	result in the sense that you can take these results and say 
25	wow, this study was statistically significant. 

			136 1		DR. GILMAN:  Dr. Dobbins, would you respond?  I
	2	see from your body language you would like to do that. 
	3		DR. DOBBINS:  I think I can simply say that we 
	4	agree to disagree on that point.  We believe that the 
	5	results are robust and that the p values and the level of 
	6	significance are substantially reduced with this method
	7	based on what we saw for the ordinary least-squares method 
	8	in the European study. 
	9		We do have a slide where we could show the range 
10	of values, the results that we had from these various 
11	correlation structures, but I guess the simple point being
12	is that where we disagree is that Dr. Hoberman, and I 

13	presume the agency, feel that that is a relatively wide 
14	range. 
15		We don't feel that it is such a wide range.  In 
16	the application of this method, we had significance levels
17	ranging between 0.01 and about 0.14 in our analysis of the 
18	robustness of various structures. 
19		With regard to the treatment effect in the range 
20	of about	0.45 to 0.7, given that the results in this study 
21	is about	0.58 based on the naive method, we don't consider
22	that to be a large variation in the range. 
23		The key point is the variability was reduced, not 
24	the treatment estimate.  The method reduces the variability 
25	and therefore makes the signal, which is arguably weaker in 

					137 1	the European study, more clear, and that is what the method
	2	does. 
	3		DR. GILMAN:  Would you define robust? 
	4		DR. DOBBINS:  In the sense of values, significance 
	5	levels in the range of about 0.001 to 0.14.  We would 
	6	expect, if the method was not actually taking more
	7	information from the data, then, we would expect that 
	8	significant levels to vary much more widely. 
	9		DR. GILMAN:  Are you saying that robust in your 
10	mind is a significance level of 0.001? 
11		DR. DOBBINS:  Yes, that relatively tight range.

12		DR. GILMAN:  But that is not what we are seeing. 
13		DR. DOBBINS:  This particular analysis being at 
14	0.06, our optimal analysis, yes. 
15		DR. GILMAN:  Dr. Temple first, then, Dr. Leber, 
16	then, Dr. Drachman.
17		DR. TEMPLE:  Not burdened with any comprehension 
18	of the specifics of this, I don't have to worry about the 
19	intimate details. 
20		What I think the message that David is presenting 
21	is that the result is analysis-dependent and is after the

22	fact.  If the obviously correct analysis to have done is the 
23	one that was finally done, it would have been specified.  
24	Now, maybe people learn more and then get better at it, but 
25	if it was always the right thing to do the repeated measures 

			138 1	analysis, then, everybody would do it, but actually things
	2	don't always work out that that is the most favorable.  
	3	Sometimes something else is more favorable.  So people make 
	4	a judgment about what overall the best analysis is. 
	5		No one would say that any given analysis or the 
	6	one that was done is obviously wrong, foolish,
	7	unprecedented, or anything like that.  The point is that it 
	8	is one of a variety of analyses that are plausible, and once 
	9	the data are in hand, it gets very hard to say how exactly 
10	one makes the judgment about which one to choose. 
11		I don't think it is an insult to a company to say
12	that they like the analyses better that make the drug look 
13	better.  I mean how could it be any other way? 
14		The point is that once you have the data in hand, 
15	it becomes very hard to say which analysis is self-evidently 
16	the most logistical, which one is the best, et cetera.  That
17	is why you specify the analysis beforehand.  I don't see 
18	David is saying anything more than that, and illustrating 
19	that fact by saying he could some fairly plausible analyses, 
20	too, and they don't look as good, which just shows that 
21	there is judgment involved, and when there is judgment
22	involved, it is a difficult question to say what your true p 
23	value or alpha level is. 
24		I think that is what everybody is saying. 
25		DR. GILMAN:  Good.  Thank you. 

			139 1		Dr. Leber.
	2		DR. LEBER:  Basically, the points that Dr. Temple 
	3	just made.  I brought all this up because I wanted to call 

	4	attention to the analysis dependency of the p value here, 
	5	and very frankly, once you start modeling something -- and 
	6	these are all models whether we like it or not, some of it

	7	is the evidence, but some of it is also the model we apply, 
	8	and by changing models you can often get different numbers. 
	9		I just wanted to point that out because we think 
10	we guard against that usually by specifying in protocols 

11	what we intend to do, and no more intended.  I didn't want
12	to insult anybody either.  I just wanted to call attention 
13	to the numbers, you know, flashing before your eyes changing 
14	and why. 
15		DR. GILMAN:  Dr. Drachman. 
16		DR. DRACHMAN:  I was just a little bit puzzled
17	because earlier on, when I asked Dr. Gelinas about how many 
18	points make a slope, the reply that I got, not from Dr. 
19	Gelinas but from Dr. Dobbins, was, well, we had many more 
20	than three points. 
21		Here, however, I see that there are two
22	observations that are being used to determine the slope also 
23	-- or maybe used -- also, in a group of people in whom 
24	baseline slopes were not known, so we have no idea whether 
25	this was a change of slope or what. 

			140 1		Could you comment on that?
	2		DR. GRANEY:  Yes, I can, thank you.  Part of the 

	3	problem may arise from my not repeating clearly enough how 
	4	Dr. Gelinas' description does indeed echo in here.  When I 
	5	say three-point slopes, these were all the patients who had 
	6	at least three post-baseline slopes.
	7		The two simply gave us additional numbers and 
	8	added a total of about 15 patients because it did include 
	9	those patients who had only two.  The same thing still 
10	holds.  The majority of the patients in both of these 
11	analyses have a much larger number of points going into
12	their slopes.  All points available were used in the slope. 
13		DR. DRACHMAN:  Would you regard the two as being 
14	reliable?  I mean is that a reasonable way of determining 
15	slope? 
16		DR. GRANEY:  Just to give you a brief answer, I

17	will tell you that it really comes down to a question of the 
18	statistical mechanism used.  The tools that were used with 
19	the two-point slope were felt to draw enough in terms of the 
20	internal consistency of patients' behavior or patients' 

21	slopes behavior that it was a good basis to draw a line on
22	the basis of just two points. 
23		Maybe Dr. Dobbins can comment a little further. 
24		DR. DOBBINS:  It is a minor point with regard to 

25	it was just intended to include as many patients as possible 

			141 1	in the analysis.  We believed that at least three-point
	2	post-baseline observations is the better analysis from the 
	3	standpoint that it captures more of a patient's information, 
	4	and I just elaborate or reiterate a point I mentioned before 
	5	is that for the difference between the two analyses is the 

	6	addition of about 11 patients, I think, who had two points
	7	post-baseline, but the overwhelming majority of patients 
	8	again had much greater than three points post-baseline. 

	9		So there really is not much difference in any 
10	regard between the two analyses although we prefer, as the 
11	literature has shown, at least three points post-baseline.
12		DR. GILMAN:  Dr. Leber. 
13		DR. LEBER:  This is a point I think Dr. Drachman 

14	started to bring up, and I would like to pursue it a moment. 
15		It is conceivable that all these differences exist 
16	on a post-measure, that is, post-randomization slope, that
17	they actually existed on pe-slope and account for the 
18	differences seen between the groups. 
19		One of the reasons we have looked at the 
20	difference between groups on pre-slope minus post-slope, or 
21	vice versa, was to see whether or not you could correct for
22	the fact that patients might differ by chance a little bit 
23	in terms of how well they were doing when they began, 

24	because clearly, these differences could pre-exist the 
25	assignment of treatment. 

			142 1		So one of the things these are not adjusted for is
	2	what these patients were like at baseline, and that is 
	3	something I would like to find out, if you have done this on 
	4	a change from slope measure, that is, pre-slope versus post- 
	5	slope. 
	6		DR. GILMAN:  Dr. Dobbins, can you answer that?

	7		DR. GRANEY:  I am not it answers exactly your 
	8	question, Dr. Leber, but our next slide does give the 
	9	difference between the pre-slope and the on-treatment slope 
10	for the two groups in this study. 
11		[Slide.]
12		Here, we have the total number of patients 
13	contributed 155.  We are looking at the high dose and the 
14	placebo.  We are looking at the treatment slope, the post- 

15	slope minus the pre-treatment slope, and we see the negative 
16	value as we did with the treatment groups in the North
17	American trial. 
18		We thought that it was certainly interesting that 
19	we get a negative value, as well, for the placebo group.  

20	This is in contrast with the number that you saw in North 
21	America and does suggest to us that there is some difference
22	in the populations that could contribute to the difference 
23	that we saw between the trials. 
24		We would certainly hesitate to try to quantitate 
25	that over, say, what portion is based on that. 

			143 1		DR. GILMAN:  Dr. Leber.
	2		DR. LEBER:  Do you have a p value for this? 
	3		DR. DOBBINS:  The p value between treatments is 
	4	simple analysis of variance, is non-significant, and as you 
	5	can see, largely because the difference between the European 
	6	study and the North American study was, as you see in the

	7	placebo group in the European study, you have a change of 
	8	minus 0.31 per month.  In the North American study, that 
	9	change was plus 0.16 per month, with the treatment effect 
10	changes being about the same between the two studies. 
11		So I think this is an indication of the placebo
12	response in the European study. 
13		DR. LEBER:  Actually, you made the point that I 

14	was hoping you would make, that this is a not statistically 
15	significant, and when you take into account pre-slope, that 
16	is, prior to randomization how these patients were doing,
17	you find a difference. 
18		You offered an explanation for it which might be 
19	true, but we have no guarantee that it is, in fact, the true 
20	explanation.  In fact, we displayed very similar data.  If 
21	you will remember that when John Feeney was making his
22	presentation, he showed you the cumulative distribution of 
23	pre-slope minus post-slope or vice versa, but the 
24	difference, and you saw that those ogives -- that is what 
25	that sigmoidal curve is called -- is pretty much 

			144 1	superimposable, which is why this mean difference is so
	2	small. 
	3		DR. DOBBINS:  Not to belabor this point, but to 

	4	clarify, this is again the ordinary simple analysis.  The 
	5	method applied was to the post-slope analysis and it takes 
	6	into account all the total scores post-baseline.
	7		DR. GILMAN:  Dr. Hoberman, did you want to 
	8	continue? 
	9		DR. HOBERMAN:  I just have a minor appendix to 
10	what Dr. Leber said.  The real issue I think here is the 
11	difference in the visual display that Dr. Feeney showed

12	makes it quite clear that these are indistinguishable and 
13	that any variation he sees of noise. 
14		The problem with the way the sponsor has presented 
15	this, I think, is to present what in numbers, actually 

16	quantifying the noise and saying, gee, there is a trend
17	going on here, and when there is nothing even close to a 
18	statistical significance. 
19		The third thing is I think that, also as Dr. 
20	Feeney pointed out, it is very treacherous to compare the 
21	placebo groups in these two trials and say that something

22	happened in placebo group of one trial, it happened in this 
23	trial, and that is an explanation for why anything happened.  
24	I don't think there is any merit in there. 
25		DR. GILMAN:  Do you want to respond, Dr. Dobbins? 

					145 1		DR. DOBBINS:  Yes.  The figures shown this morning
	2	are not analyses.  The ogives, as it is called, is a 
	3	presentation of the raw data.  This was a designed 
	4	experiment.  In a designed experiment, you take into account 
	5	the effects of site and treatment, and when you do that, and 
	6	you look at the difference in terms of averages, what we are
	7	the difference in terms of averages, and we believe that 
	8	that represents a meaningful effect. 
	9		DR. GILMAN:  Dr. Gennings wanted to ask a 
10	question. 
11		DR. GENNINGS:  I just wanted a clarification about
12	the repeated measures analysis.  Are you actually fitting 
13	the linear relationship within patients? 
14		DR. DOBBINS:  The repeated measures fits the 
15	group.  It fits actually a slope for the treated group and a 
16	mean slope for the treated group, a mean slope for the
17	placebo group, and then compares on an average basis. 
18		DR. GENNINGS:  So your model is that it is linear, 
19	not just letting the means go. 
20		DR. DOBBINS:  I am sorry? 
21		DR. GENNINGS:  You are not just fitting means, you
22	are forcing a linear fit. 
23		DR. DOBBINS:  Yes, and it is very key point 
24	because, as we have seen earlier, this data is 
25	extraordinarily suited to this kind of method because within 

					146 1	a patient, how highly linear the Appel Scale is.  That is a

	2	fundamental point.  The data are very correlated within a 
	3	patient and very suited to capturing that kind of 
	4	correlation with this method. 
	5		DR. GILMAN:  Well, we have successfully ground 
	6	down to a halt again.

	7		Dr. Temple. 
	8		DR. TEMPLE:  I just wondered whether there was a 
	9	way of doing the repeated measures analysis that could take 
10	into account baseline slope.  It seems to be one of the 
11	critical points here.  I mean yours didn't, but it could be
12	done, couldn't it? 
13		DR. GILMAN:  Dr. Dobbins. 
14		DR. DOBBINS:  I think from a simple standpoint, 
15	the average difference in the pre-study slopes between 
16	treatments was not significant.

17		DR. TEMPLE:  I don't think that is a full answer.  
18	It could still be different enough to affect the analysis. 
19		DR. DOBBINS:  That would seem to be borne out in a 
20	noncomparability at baseline. 
21		DR. TEMPLE:  I am sorry, I didn't understand that.
22		DR. DOBBINS:  I think to the extent that that was 
23	true would be seen in the noncomparability of the pre-slopes 
24	at baseline in terms of their averages.  In other words, 

25	there would have to be a pretty large deviation on average 

				147 1	at baseline for it to be meaningful enough the influence the
	2	post-study slopes, and we did not see that. 
	3		DR. TEMPLE:  I don't think that is necessarily so, 
	4	but I don't want to get into that. 
	5		DR. GILMAN:  In the interests of moving on, let me 
	6	try to summarize this little point in the duel of the
	7	statisticians here. 
	8		I am taking away from this the following.  The 

	9	prospective analysis was nonsignificant in the European 
10	trial.  Post hoc analyses showed different results than the 
11	results of the prospective analysis, and we can take away,

12	each committee member, how we want to interpret that, but at 
13	least for me, this is not a robust finding. 
14		So I will simply state that and let's proceed. 
15		DR. GRANEY:  May I have the next slide, please. 
16		[Slide.]
17		The colors may not be optimal here, but in a look 
18	at the time to the occurrence of an event until a protocol- 
19	specified event in Europe, there is a separation although it 
20	is not statistically significant. 
21		A Cox proportional hazards analysis shows a 36
22	percent reduction although I would hasten to point out that 
23	the confidence intervals on that 36 percent does include one 
24	going along with the fact that the difference, although the 
25	magnitude was correct, was not statistically significantly 

					148 1	different.
	2		DR. ADAMS:  Mr. Chairman, can we go back to the 
	3	slide, the last one. 
	4		Now, this is proportion without termination. 
	5		DR. GRANEY:  Yes. 
	6		DR. ADAMS:  So the N below there, on months, would
	7	vary between active and treated patients because there is a 
	8	fair number of patients that prematurely terminate for death 
	9	or adverse experience or something.  These are only patients 
10	that are on active treatment? 
11		DR. GRANEY:  The patients are counted as they move
12	along, so all patients really count in this, because they 
13	either move to the portion of discontinued or they stay with 
14	the group that are in the population.  That is why it 
15	basically says that 100 percent of each group are included 
16	here, because we are basically just counting them one way or
17	the other as the analysis moves along. 
18		DR. ADAMS:  So what does the heading mean?  I 
19	thought this was the number of patients that reached either 
20	a score of 115 or an FVC under 39 percent. 
21		DR. GRANEY:  Yes, this is the patients who --
22	basically, the fraction we see here are the percent who have 
23	not terminated, one at the beginning, heading down to 
24	somewhere between 0.6 and 0.7 at the end. 
25		DR. ADAMS:  I am still confused.  This is the 

				149 1	number that reached one of those endpoints.
	2		DR. GRANEY:  It is the number of patients who have 
	3	not reached one of those endpoints.  It is the proportion 
	4	without termination, which basically means the patients who 
	5	are represented by the 60 percent or 70 percent figure here 
	6	are the patients who have not yet reached the total score of
	7	115 or an FVC of 39.  The proportion of patients represented 
	8	above the line are those who have had an event. 
	9		DR. GILMAN:  The label is misleading here. 

10		DR. LEBER:  Put another way, is this a smooth 
11	Kaplan-Meier plot?  In other words, instead of showing the
12	jumps, have you just smoothed out a Kaplan-Meier, is this 
13	just a survival function? 
14		DR. DOBBINS:  Yes. 
15		DR. GRANEY:  I think you have got a sense of the 
16	discussion that Dr. Feeney had relative to whether patients
17	who die should be included in here.  I think you heard from 
18	our earlier discussion where Dr. Gelinas and Dr. Appel 
19	commented.  It is our feeling, and the feeling of our 
20	consultants after we reviewed the data, that death occurs 
21	independent of the progress of the disease, and our feeling
22	on this was that the AALS total score of 115 and the FVC of 

23	39 represented events that were clearly tied to the progress 
24	of disease as measurable by the Appel, which was the overall 
25	goal of the study. 

			150 1		We did not include death because death occurs sort
	2	of independent of that progress, as you saw -- although I 

	3	can't give you the fraction of patients who have an event 
	4	based upon their score -- it does occur along all of the 

	5	scores.  That is the reason for which we have not included 
	6	death in this analysis either in this protocol or in the
	7	North American one. 
	8		There are differences of opinion on that. 
	9		DR. GILMAN:  First, Dr. Leber, Dr. Zivin, Dr. 
10	Temple. 
11		DR. LEBER:  The reason I asked about this being a
12	Kaplan-Meier plot is I was trying to clarify, I believe, Dr. 
13	Adams' point, and that is that you reach a given month.  How 
14	many patients are at risk at the beginning of that interval 
15	compared to earlier ones, because that probability of 
16	suffering the event, that is, either having a total score

17	exceed 115 or having a forced vital capacity go below 39 
18	percent, is a function of how many remained at risk for 
19	that. 

20		If you are having censoring or deaths going on in 
21	this time, the numbers at seven months are quite different,
22	are they not, than those at one month, because of the nature 
23	of the censoring process or death.  What are they actually 
24	would be the question. 
25		DR. GRANEY:  I will ask Dr. Dobbins to comment on 

					151 1	that.
	2		DR. DOBBINS:  Yes, that is essentially a correct 
	3	statement, but the month-to-month withdrawal in both studies 
	4	for all reasons was generally uniform. 
	5		DR. LEBER:  But the issue would be if you would 

	6	look at the conditional probability of having an event in
	7	any subsequent month, having reached that month without 

	8	having an endpoint, the confidence limits are going to blow 
	9	up because they are going to be fewer at risk.  The hazard 
10	may go up, but your confidence limits around that hazard 

11	differ, so there is great imprecision at the end of those
12	two months, the point in this plot that you are emphasizing. 
13	So I mean you have more error there. 
14		DR. GRANEY:  We are not necessarily emphasizing 
15	it, I would say. 
16		DR. LEBER:  Huh?
17		DR. GRANEY:  We are not necessarily emphasizing 
18	it. 
19		DR. LEBER:  I understand that. 
20		DR. GILMAN:  Dr. Zivin. 
21		DR. ZIVIN:  My question was answered.
22		DR. GILMAN:  Dr. Temple. 
23		DR. TEMPLE:  If people who leave because of death 
24	aren't included, how does it turn out that the groups are 

25	100 percent?  Those people aren't in that analysis anymore, 

				152 1	they must be censored, right?  Am I misunderstanding?
	2		DR. LEBER:  At the beginning of this analysis, 
	3	everybody is in it.  You start with 100 percent.  Everyone 
	4	is thrown into it, but all Kaplan-Meier product limit 
	5	survivals are based on the idea that either you have the 
	6	event or you are censored and then you reach the end, and
	7	everybody is right censored. 
	8		During the time, the way it is constructed, is you 
	9	reach a point in time -- it is almost like an actuarial life 
10	table -- and you say how many are still at risk, and you say 
11	in the successive interval how many will fail adjusting for
12	the losses over that interval, and you multiply these 
13	together to get the number surviving. 
14		DR. TEMPLE:  But in this case you die, so to 
15	speak, and have an event only if your AALS total score gets 
16	above 115 or your FVC goes below 39 percent.  Hang on.  You
17	don't die if you die.  That is not counted. 

18		DR. GILMAN:  You are dropped, yes. 
19		DR. TEMPLE:  I guess my question is -- you may or 
20	may no believe that progression is correlated with death, 
21	although as I have said before, it is difficult to believe
22	that there is no relationship -- do you have the same 

23	analysis for the other events that get you out of the study, 
24	as well, in addition to these two? 
25		DR. GRANEY:  I think we can give you a display of 

					153 1	the events.  I am not sure whether we have it over time.
	2		DR. DOBBINS:  Maybe we can have a short answer to 
	3	that.  An analysis was performed in both the North American 
	4	study and the European study including death, and the 
	5	results in the North American study are essentially the same 
	6	with a little less significance.
	7		The European study is nonsignificant, and the 
	8	results did not change with the inclusion of death. 
	9		DR. TEMPLE:  These results don't change with the 
10	inclusion of deaths? 
11		DR. DOBBINS:  Yes.
12		DR. TEMPLE:  The p doesn't get worse? 

13		DR. DOBBINS:  No.  I mean not worse than that, no.  
14	That p value is actually favoring treatment, so the p value 
15	goes up. 
16		DR. TEMPLE:  Yes, that is what I meant.
17		DR. DOBBINS:  Yes, in that sense it gets worse, 
18	yes. 
19		DR. TEMPLE:  I am not surprised. 

20		DR. GILMAN:  We resolved that one. 
21		Please continue.
22		DR. GRANEY:  Thank you.  May I have the next 
23	slide. 
24		[Slide.] 
25		We are looking here at the results of the Sickness 

			154 1	Impact Profile study in the European trial, and I think you
	2	will agree as we found there were no significant 
	3	differences.  There is very slight magnitude differences in 
	4	the overall end physical, but we would not make much of 
	5	those, and of course, it is reversed in the psychosocial. 

	6		I think we have to comment on this, that this was
	7	the first time that the SIP had been attempted in a multi- 
	8	language, multi-cultural environment, and I think, 
	9	prospectively, we did not pick up that there were likely to 
10	be problems in the interpretation and indeed in the 
11	application of the study.  But in any event, we did not
12	reach statistical significance in the SIP in Europe. 
13		[Slide.] 
14		I would like to turn now to the area that Dr. 
15	Feeney indicated we would be spending a fair amount of time 
16	on, which is the discussion of the patient by strata, and it
17	is a complex area.  Dr. Dobbins will actually discuss quite 
18	a number of the statistical and the fine points involved 
19	with why we believe strata is an appropriate way to look at 
20	the rapid progressing patients that Dr. Gelinas mentioned 
21	exist in this disease.
22		The sequence in which we turn to do this analysis 
23	is that after the initial analysis was done in the North 

24	American trial, and an effect was seen by strata, it was, as 
25	you will see, fairly marked and really we would have been 

			155 1	remiss had we not looked at the European trial where again
	2	the effect in strata is strong. 
	3		I think as we were looking at those data, we saw 
	4	that strata is not a perfect way to pick up the rate of 
	5	progress of patients, and Dr. Dobbins will talk about that 
	6	at some length.
	7		So I would ask you to just keep those caveats in 
	8	mind when I show you the data from our look at the strata, 
	9	and I will ask Dr. Katz' forbearance because we do call them 
10	rapid and moderate progressors, and I can't change the 
11	slides now.
12		[Slide.] 
13		The consistency between the trials in terms of the 
14	responses in these rapidly progressing patients is seen most 
15	clearly in the rapid progressors when we look at slopes and 
16	the change scores.
17		In the North American study, we found, if you 
18	recall the values that we had previously, that really the 
19	effect, both for slopes and change score were largely 
20	concentrated in the rapid progressors. 
21		In the European study, that was true, as well.  I
22	think a notable finding for this, two-thirds of patients now 
23	who are represented in this strata, is that across the two 
24	trials, the magnitudes are very, very close, and they are 

25	the same for the change score. 

			156 1		Granted that this was not a prespecified analysis. 
	2	The fact that it does represent two-thirds of the patients, 
	3	that fortuitously, the European trial had a distribution of 
	4	rapid and slow progressors across the treatment groups and 

	5	across the sites that was almost the same as the U.S. does 
	6	lend some weight to this along with the actual numbers.
	7		Now, there is another side to this, and we will 
	8	look at the moderate progressors next, and Dr. Feeney 
	9	pointed out one of the concerns for you in the European 
10	trial. 
11		[Slide.]
12		If we look at the North American trial, we 

13	basically find the effect is squeezed out of the North 
14	American trial when we look at the one-third of patients who 
15	are these moderate progressors, the lower strata, if you 
16	will, and a problem for us, as well as for the agency when
17	we are looking at this, is do we just have a seesaw effect, 
18	are we getting a positive effect in the high strata and we 
19	are getting positive values here, which I have told you are 
20	not favorable, and in fact, we have to keep in mind that we 
21	are looking at one-third of the patients, and especially in
22	the placebo group, where this comparison is made between the 
23	placebo and treatment, obviously, we are talking about 
24	relatively small numbers here. 
25		But there is another point that several of the 

				157 1	questioners, as well as the speakers, have brought up.  The
	2	initial stratification that we did, this cut by 40 to 60, 60 
	3	to 80, really is imperfect.  It is a snapshot in time.  What 
	4	Dr. Dobbins will show you when he presents his data is that 
	5	if we look a little further and do this analysis on the 
	6	basis of pre-slope, trying to sharpen our stratification, we
	7	find that this really resolves, and yet the effect is 
	8	maintained in the upper stratum. 
	9		Dr. Dobbins did that analysis and will present it 
10	for you.  Again, my comment is we freely admit these were 
11	not prespecified analyses.  Stratification in the first
12	trial really was done to balance patients, but the findings, 
13	especially in the high group and in both groups, when we 

14	look at the strata another way, really are compelling. 
15		DR. ADAMS:  A clarification.  For the North 

16	American studies, the N's reflect both the patients and the
17	active treatment, both the 0.15 and the 0.1 -- is that 
18	right? 
19		DR. GRANEY:  I am sorry.  The stratification study 
20	here is done for the	0.10 dose groups only in both trials.  
21	So the intermediate dose is not included.
22		DR. ADAMS:  Thank you. 
23		[Slide.] 
24		DR. GRANEY:  Again, we want to extend this look 

25	further, and if we take a look at the strata for the SIP, 

			158 1	what we find is again a prominence of the effect with the
	2	dose relatedness in the North American trial, sort of 
	3	localizing it into the rapid progressors, and we find in 

	4	Europe, although we don't get the significance, we do see 
	5	that the difference between them becomes more apparent. 

	6		So the effect carries over even into the SIP,
	7	which was administered by a different group of testers. 
	8		[Slide.] 
	9		To summarize the data that I have shown you, I 

10	think it is clear that the North American study demonstrates 
11	Myotrophin's effectiveness in ALS.
12		The European study is supportive.  You have heard 
13	the arguments back and forth as questioners and speakers 

14	have discussed it today, but I think we have to note that 
15	the values are in the correct direction. 
16		The therapeutic effect remarkably really is most
17	evident in the rapidly progressing patients in both trials, 
18	whether we are looking at the AALS or the SIP.  I think 

19	together the North American and European studies provide 
20	sufficient evidence of the efficacy to support the treatment 
21	use of Myotrophin in patients with ALS.
22		This has been a complex presentation, and you have 
23	heard the intensity and the length of discussions that have 
24	gone on.  I think there are a couple of points that we would 
25	like Dr. Dobbins to address specifically for you. 

			159 1		DR. GILMAN:  Thank you, Dr. Graney.
	2		Questions for him?  Dr. Zivin. 
	3		DR. ZIVIN:  I would like to get away a little bit 
	4	from the statistical complexities and ask a simpler 
	5	question, which is to the best of my information, this drug 
	6	does not get into the central nervous system, and the
	7	question is what is this drug doing about the upper motor 
	8	neuron disease. 
	9		DR. GRANEY:  I think we don't really have from 
10	this clinical trial, information that addresses itself to 
11	that, and we have to turn to the preclinical environment to
12	look at that, where there are a range of models. 
13		I will ask Dr. Jeffrey Vaught from Cephalon to 
14	address that issue of what is the relative effect likely to 
15	be on upper as opposed to lower motor neurons. 
16		DR. JEFFREY VAUGHT:  There is no data to suggest
17	that we have an effect on upper motor neuron preclinically.  
18	However, there is one report that IGF may cross the blood- 
19	brain barrier although in small amounts. 
20		However, I think it is important to point out that 
21	for the disease parameters that are being measured, and also
22	from the preclinical animal models, it is not necessary for 
23	IGF to cross the blood-brain barrier, and that signals to 
24	the central nervous system due to the peripheral projections 
25	of the lower motor neuron can be manifest by systemic 

				160 1	administration of IGF.
	2		So the simple answer is that for upper motor 
	3	neuron and cortical involvement, we have no data to support 
	4	or refute any effect there. 
	5		DR. GILMAN:  Another way of asking that question 

	6	is whether the substance will pass across the synaptic cleft
	7	going from the motor neuron to interneurons, and thereafter 
	8	to the terminals of cortical spinal track fibers. 
	9		Is there any evidence for that? 
10		DR. VAUGHT:  There is evidence that Myotrophin or 
11	recombinant human IGF-1 or IGF-1 can be retrogradely

12	transported by peripheral axons, and actually appear 
13	proximal in the motor neuron.  There is also evidence that 
14	in fact retrograde signal can signal to the motor neuron. 
15		Now, as far as crossing the synaptic cleft and 

16	actually going through a variety of events, there is no data
17	that would indicate that. 
18		DR. GILMAN:  Thank you.  Any other questions? 
19		Dr. Graney, thank you. 
20		Dr. Dobbins, before you begin, can I ask the 
21	length of your progressor approximately without questions?
22		DR. DOBBINS:  Less than 10 minutes. 
23		DR. GILMAN:  I suggest that we hear Dr. Dobbins.  
24	Please go ahead, and we hope to break for lunch by about 
25	1:00. 

			161 1		DR. THOMAS W. DOBBINS:  Thank you, Dr. Graney.
	2		[Slide.] 
	3		At this time we would like to address two key 

	4	points regarding the results presented by Dr. Graney and 
	5	respond to points addressed by the agency earlier.  We want 
	6	to briefly review patient withdrawal in the North American
	7	and European studies and stratification. 
	8		We will examine patient withdrawals in the North 
	9	American and European studies and show that patient 
10	withdrawal did not influence conclusions in either study. 
11		[Slide.]
12		This table shows the patient disposition in the 
13	North American study.  Terminations fall into two 

14	categories, protocol-specified termination, patient 
15	withdrawal including death, adverse experience, all other. 
16		Protocol-specified terminations are expected to be
17	imbalanced if the treatment is effective.  Also, ALS scores 
18	in these categories are reflective of late stage disease.  
19	Protocol-specified terminations were dose related, 17 
20	percent in the 0.1 mg/kg group, 26 percent in the 0.05 mg/kg 
21	group, 33 percent in the placebo group.
22		Patient withdrawals, on the other hand, should be 
23	unrelated to treatment effect and therefore are not expected 
24	to be imbalanced.  Patients withdrawals in the North 
25	American study were balanced between the Myotrophin groups 

			162 1	and the placebo group and total discontinuations were
	2	balanced among the Myotrophin groups and slightly higher in 
	3	the placebo group. 

	4		[Slide.] 
	5		The next table shows patient disposition in the 
	6	European study.  Again, protocol-specified terminations

	7	clearly demonstrate treatment effect, 20 percent in the 
	8	Myotrophin 0.1 group, 34 percent in the placebo group. 

	9		Total discontinuations were balanced among the 
10	treatment groups, 48 percent in the Myotrophin 0.1 group, 47 
11	percent in the placebo group.  However, an imbalance was
12	observed in the patient withdrawals. 
13		To determine if this imbalance influenced results, 
14	in particular with regard to the LOCF analysis that we 
15	discussed earlier, we performed an analysis of the 
16	robustness of that result focusing on the rapid progressors. 
17	We focused on rapid progression for two reasons.  First, the 
18	majority of withdrawals were in the rapid progressing 
19	patients, actually in both studies, but in particular in the 
20	European study were greater than 90 percent in the upper 
21	stratum.
22		As we have observed and the point we are making is 
23	that rapid progression is where the treatment effect was 

24	observed in the European study.  So to address this, we 
25	performed two simple analyses.  First, simply removing 

			163 1	deaths from the analysis, and secondly, removing all
	2	withdrawals, essentially, an analysis of terminations versus 
	3	completions.  If an imbalance is influencing results, we 
	4	would expect the results to be dependent on these analyses. 
	5		[Slide.] 
	6		This table shows the results of the analysis of
	7	the AALS total score change from baseline in rapid 
	8	progressors.  The analysis including all patients is the 
	9	analysis presented by Dr. Graney earlier.  The results 
10	showed a significant treatment difference favoring 
11	Myotrophin at minus point 7.8 points.
12		When analyses were performed first removing deaths 
13	and then removing all withdrawals, the results were 
14	essentially unchanged.  The analysis removing deaths, minus 
15	8.6 points, the analysis removing all withdrawals, minus 7.9 
16	points.  This indicated that the results were not dependent
17	on patient withdrawals. 
18		[Slide.] 
19		Therefore, we conclude that patient withdrawal did 
20	not influence the conclusions from either study. 
21		DR. DRACHMAN:  What score did you use in the all
22	patients for those who died? 
23		DR. DOBBINS:  Well, to address the question 
24	simply, we simply removed them from the analysis.  In the 

25	all patients analysis, it was the score at their last visit 

			164 1	prior to death.  The average score for the patients in the
	2	treated group was 92. 
	3		DR. GILMAN:  Dr. Katz. 
	4		DR. KATZ:  A couple points.  First of all, you 
	5	call these analyses Last Observation Carried Forward, which 
	6	ordinarily is usually used to apply for an intent-to-treat
	7	analysis, in other words, an analysis that takes into 
	8	account all patients. 
	9		These analyses do exactly the opposite, they 

10	remove patients.  So that is one thing.  It is sort of 
11	counterintuitive to what we ordinarily think of as an LOCF
12	analysis. 
13		Beyond that, these analyses don't correct for the 
14	bias that both Dr. Feeney and Dr Leber talked about earlier 
15	this morning, which is that in a degenerative disease, a 

16	monotonically, if you will, degenerative disease, early
17	dropouts will tend to bias -- the treatment with early 

18	dropouts will be positively biased, I think we actually even 
19	have an overhead of that, the point being that you are going 
20	to be carrying forward scores that are better than they 
21	would have been had they stayed in the trial.
22		So the analyses that you have done in which you 
23	dropped those patients actually doesn't get at the bias that 
24	we had mentioned earlier. 
25		DR. DOBBINS:  It simply assumes that it didn't 

				165 1	influence it.
	2		DR. GILMAN:  Well, but it may have. 
	3		DR. DOBBINS:  I think it makes that point pretty 
	4	clearly. 
	5		DR. LEBER:  Point taken. 
	6		DR. GILMAN:  Other questions?  Please.
	7		[Slide.] 
	8		DR. DOBBINS:  Next, we would like to review 
	9	stratification on baseline AALS score in the North American 
10	and European studies.  We would like to make the important 
11	point here.  We will show that stratification is related to
12	disease progression, and in particular, stratification based 
13	on AALS score at baseline did delineate rapid progressors. 
14		[Slide.] 
15		This figure illustrates the correlation between 
16	baseline AALS score and AALS pre-study slope among the
17	evaluable patient population in the North American and 
18	European studies. 
19		The vertical axis shows baseline AALS score, the 
20	horizontal axis shows AALS pre-slope in points per month.  
21	The horizontal line in the figure represents the
22	stratification based on baseline AALS score of 60. 
23		The figure illustrates several essential important 
24	points about these clinical trials. First, there is a clear 
25	correlation between the baseline AALS score and disease 

			166 1	progression as measured by the pre-study AALS slope.
	2		Secondly, rapid progressing patients based on the 
	3	AALS slope are overwhelmingly represented in the upper 
	4	stratum, as we see rapid progression based on AALS pre-study 
	5	slope in the range 6, 8, 10, 12 points in the month entirely 
	6	captured by the upper stratum in these studies.
	7		However, equally important, patients in the upper 
	8	stratum are not necessarily rapidly progressing as exhibited 
	9	by the group of patients in the upper stratum with low AALS 
10	pre-slope scores.  That is this group in particular here, 

11	and that group effectively represents the overlap noted by
12	Dr. Feeney earlier. 
13		Alternatively, the majority of lower stratum 
14	patients are moderate progressors by AALS slope, this group 
15	in here. 
16		Therefore, although not a perfect surrogate for
17	disease progression, stratification based on the AALS score 
18	at baseline was clearly capturing rapid progression.  Based 
19	on these observations, we considered stratification based 
20	directly on disease progression as measured by the AALS 
21	slope.
22		To determine an appropriate cut point, we 
23	consulted the literature. 
24		[Slide.] 
25		This figure, as you have seen earlier, is adapted 

			167 1	from the important paper by Havercamp and Appel, Brain 1995. 
	2	The figure shows a clear relationship between survival and 
	3	rate of disease progression based on a cut point of AALS 
	4	slope of	3.3 points per month using, as you see, the upper, 
	5	less than or equal to 3.3 points per month, greater than 3.3 
	6	points per month.
	7		As Dr. Gelinas pointed out, based on this cut 
	8	point, there was a greater than two year advantage in median 
	9	survival for moderate progressors. 
10		Therefore, using the cut point of 3.3 points per 
11	month to define strata, we performed an analysis of the AALs
12	slopes in the North American and European studies.  We will 
13	present the results of this analysis first for moderate 
14	progression, then for rapid progression. 
15		[Slide.] 
16		This table compares the results of the AALS slope
17	analysis for moderate progression defined by AALS pre-slope 
18	less than or equal to 3.3 points, an AALS score at baseline 
19	less than or equal to 60. 
20		As you can see on the right-hand side are the 
21	results for the lower stratum Dr. Graney presented earlier. 
22	On the left-hand side are the results for the AALS pre-slope 
23	stratification less than or equal to 3.3 points per month. 
24		The results were consistent whether patients were 
25	stratified by AALS pre-slope or baseline AALS score. 

			168 1		[Slide.]
	2		The next table compares the same results for the 
	3	AALS slopes analysis for moderate progression in the 
	4	European study.  Note the nonsignificant positive difference 
	5	observed for AALS score than or equal to 60 resolved when 

	6	patients were stratified directly by disease progression.
	7		Note also in this figure that the sample sizes 
	8	virtually remained unchanged in the two definitions of 
	9	moderate progression. 
10		[Slide.] 
11		Next, we consider rapid progression and we ask

12	ourselves the question did the change in the stratification 
13	based directly on disease progression change the results in 
14	the upper stratum in the rapid progressing patients. 
15		This table compares the results of the AALS slope 
16	for rapid progression for the North American study.  Again,
17	therapeutic effect is evident whether patients were 

18	stratified by pre-slope or the baseline AALS score. 
19		[Slide.] 
20		This next table compares the results for the 
21	European study.  Again, the therapeutic effect is evident

22	whether patients were stratified by pre-slope or baseline 
23	AALS score. 
24		[Slide.] 

25		So our conclusion then, and a very important point 

			169 1	that we want to make today, is that stratification based on
	2	the AALS score at baseline delineates rapid progressors in 
	3	these studies. 
	4		Thank you. 
	5		At this time, I would like to turn the 
	6	presentation back to Dr. Graney, who will present the safety
	7	of Myotrophin. 
	8		DR. GILMAN:  Dr. Leber. 
	9		DR. LEBER:  Actually, I think it would, if I can 
10	suggest, be important for the committee to understand why we 
11	don't necessarily agree that pre-slope in any way tells you
12	what it should, and believe it is confounded with the entry 
13	criteria and almost auto-correlates in the sense that you 

14	will have a more rapid progression if you have a higher 
15	baseline slope. 
16		We would like to explain it.  It comes about that
17	if you wanted to use -- well, I don't want to explain what 
18	Dave is going to do, but basically, it says this.  If you 

19	have two patients who have the same AALS score at pre-slope, 
20	say, at entry of this study, the patient with the higher 

21	slope is going to achieve a baseline score by the time they
22	are randomized. 
23		The one with the higher slope is going to be 
24	higher systematically than the one with the lower slope.  
25	This is on pre-slope.  So there will be sort of an auto- 

			170 1	correlation.  What you really want to know is given a
	2	baseline score, does it predict the post-slope after 
	3	randomization, and it has a little bit of predictive power, 
	4	but not very much. 
	5		So this whole thing is very complicated and not so 
	6	easy to understand, and I think it would be useful for you
	7	to understand the rebuttal to the arguments that have just 
	8	been presented before too much time goes by. 
	9		DR. DOBBINS:  I think that I would like to address 
10	that comment directly. 
11		DR. GILMAN:  Please.
12		DR. DOBBINS:  I think this is a fundamentally very 
13	simple analysis, and the pre-slope is completely predictive 
14	of the post-slope within a patient.  If this analysis were 
15	performed -- and it was directly on post-slope although we 
16	don't have that information here -- it would show exactly
17	the same results. 
18		It is simply not true that the pre-slope value 
19	within a patient does not predict that patient's post-slope 
20	progression.  These slope scores within a patient are highly 
21	linear.  The agency's own presentation this morning, in
22	which two patients were shown, the linearity, the 
23	progression made that quite evident. 
24		They were very illustrative of the type of 
25	patients that are in both of these studies.  Irrespective of 

			171 1	whether we consider pre-slope or post-slope, the implication
	2	of this analysis is that the stratification captured rapid 

	3	progression in these studies.  It wasn't perfect, but it 
	4	delineated rapid progression, and progression of this 

	5	disease, the optimal stratification for future studies 
	6	should be based directly on disease progression, as the

	7	Havercamp and Appel paper point out, I think very clearly 
	8	and very profoundly. 

	9		Thank you. 
10		DR. GILMAN:  Dr. Leber and then Dr. Drachman. 
11		DR. LEBER:  I think Dave should be given a chance
12	to respond.  I don't want to argue about this.  Actually, 
13	this morning, very early, I was able to take Studies 1200 
14	and 1202 using data provided by the firm and actually show 
15	the relationship between pre-slope as a predictor of post- 
16	slope, which does shown an r-square of somewhere around	0.4
17	or so.  It explains about 40 percent of the variance. 
18		But if you actually look at pre-slope predicting 
19	baseline and actually baseline predicting post-slope, you 
20	get correlations, r-squares that are very small, relatively 
21	small, around 10 percent, 20 percent of the variance, which
22	is not something you would normally say is a robust 
23	predictor. 

24		I don't have overheads of this.  I will pass these 
25	around as self-explanatory.  In the meantime, Dave can take 

			172 1	a look at them.  Again, I haven't had a chance to verify it. 
	2	We just got some of these arguments presented last night, 
	3	and I was doing this early in the morning.  They could be in 
	4	error, but I think, since I was using a cam stat program, 
	5	they are unlikely to be. 
	6		DR. GILMAN:  Go ahead.
	7		DR. HOBERMAN:  Again, Dr. Leber has done my work 
	8	for me.  Thank you. 
	9		I want to make a very simple point, and as I 
10	listened to the discussion, I get a little confused.  I hear 
11	about pre-slopes, I hear about baseline values, I hear about
12	strata.  I am here only to illustrate what Dr. Leber said 

13	about baseline values and slope, and respond to an analysis 
14	the sponsor did.  I just want to talk about something very 
15	simple. 
16		I want to reiterate what Dr. Leber said about a
17	primary flaw in the sponsor's analysis.  The sponsor may be 
18	correct.  All I am doing is I am saying that they did not 
19	choose the best way to make the argument, and if you use 

20	other data that I think is more appropriate, the argument 
21	becomes a little weaker.
22		Because of the entrance criteria, as Dr. Leber 
23	mentioned, there is a potential -- and we certainly didn't 
24	have time to investigate this tremendous detail -- that 
25	because a person in order to get into the trial because of 

			173 1	the selection criterion was likely to have a higher slope

	2	just to get into the trial, there is a possibility that 
	3	there was some selection bias, whereas, you get a self- 
	4	fulfilling prophecy. 

	5		The self-fulfilling prophecy is that you are not 
	6	going to be surprised if you wind up having higher baseline
	7	Appels associated with higher pre-slopes. 
	8		So what we did is simply look at the alternative 
	9	way of looking at the data, which is to look at the post- 
10	slopes. 
11		[Slide.]
12		Now, this is what the sponsor produced in their 
13	document showing the scatterplot of pre-slope and baseline 
14	score.  I like to think of it the other way around, but 
15	that's all right. 
16		[Slide.]
17		What we did very recently is simply produce a 
18	scatterplot in 1202 that has unfortunately baseline on the 
19	horizontal and post-slope on the vertical.  Now, this is 
20	only partial data and what I did was I took both placebo 
21	groups in Trials 1200 and 1202, and pooled them.
22		I asked a very simple question:  What is the 
23	relationship between baseline Appel score and the placebo 
24	slope on study? 
25		The answer to that was rather than getting a r- 

			174 1	square in this case which would be around 0.36 or 4, in
	2	other words, roughly 40 percent of the variation being 
	3	explained by the relationship between baseline and on-study 
	4	slope, it turned out to be about 10 percent. 
	5		Now, 10 percent variation, it is statistically 
	6	significant, but it is important to realize that there is a
	7	difference between something that is real and something that 
	8	has any predictive value. 
	9		So what we are merely doing is questioning the 

10	strength of evidence that baseline Appel really does relate 
11	to the slope on study, no more, no less.
12		DR. GILMAN:  Thank you. 
13		I think we should break for lunch.  It is now 
14	seven minutes of 1:00.  We will back here starting at seven 
15	minutes of 2:00. 
16		[Whereupon, at 12:53 p.m., the proceedings were
17	recessed, to be resumed at 1:53 p.m.] 

			175 1		           AFTERNOON SESSION
	2		                                       [2:00 p.m.] 
	3		DR. GILMAN:  Take your seats, please.  This 
	4	session is about to begin. 
	5		I thank the patients who are here for your 
	6	patience.  We do need to hear additional information from
	7	Dr. Graney and Dr. Miller.  Then, the committee will discuss 
	8	the information they have heard, and then we will hear from 
	9	you.  Appreciate your patience. 
10		Dr. Graney, would you please continue. 
11		DR. GRANEY:  Yes.  Thank you, Dr. Gilman.
12		[Slide.] 
13		We will open this afternoon with a brief 
14	discussion of the safety of Myotrophin.  Myotrophin was very 
15	well tolerated in both studies.  As you saw, there were few 
16	discontinuations for adverse experiences and drug-related
17	events, as you will see, are largely those anticipated from 
18	previous experience with IGF-1 or from the disease.  There 
19	was neither clinical nor laboratory evidence of hypoglycemia 
20	in our trials. 
21		[Slide.]
22		The pattern of adverse experiences was similar 

23	across both clinical trials and this slide, which may be 
24	difficult to read, so I will point some things out, shows 
25	the 10 most frequently reported adverse experiences across 

				176 1	both studies.  Also, the data on each study is included in
	2	the briefing book. 
	3		It shows that disease-related findings, such as 

	4	weakness and dyspnea and coordination abnormality were, as 
	5	we expected, common.  The most frequent drug-related event 
	6	was pain at the site of injection.  As you can see, it
	7	occurred quite frequently, and in fact, the overall total 
	8	for all injection site events was quite high and occurred 
	9	the most frequently in the placebo-treated group. 
10		Dr. Gilman, you had a question relative to the 
11	potential of this for unblinding, and if you would like, I
12	can show a transparency about it now or come back to it 

13	later. 
14		DR. GILMAN:  Did you say that correctly, did you 
15	say that injection site pain was most frequent? 
16		DR. GRANEY:  It was most frequent in the placebo. 
17	The percentage is given, yes. 
18		DR. GILMAN:  I see, yes. 
19		DR. GRANEY:  In any event, actually, the 

20	differences are not very large between the groups. 
21		DR. GILMAN:  The patients that received 0.05 had
22	even fewer in percentage anyway than placebo. 
23		DR. GRANEY:  Yes, that's right, and I would remind 
24	you that the placebo, as well as the drug, were all in the 
25	same vehicle with a pH of 4.0. 

				177 1		DR. GILMAN:  That is probably the reason for the
	2	pain, yes? 
	3		DR. GRANEY:  Yes, we believe so.  In any event, to 
	4	just basically tell you what we would show on the 
	5	transparency -- and we would be happy to -- when we looked 
	6	across all of the injection-related events and the number of
	7	patients who had events, they distribute at all of the sites 
	8	quite evenly in total across the various treatments. 
	9		That, in fact, ties in with the fact that many 

10	patients had not just an event that might be described as 
11	pain, but they also had bleeding, they had some redness. 
12	So, in fact, it was a fairly complex constellation that 

13	presented in the clinic of reactions at the injection site. 
14		DR. GILMAN:  Can we conclude from this that pain 
15	at the injection site would not be a way that patients could 
16	be unblinded?
17		DR. GRANEY:  That is correct.  That is our 
18	impression. 
19		DR. GILMAN:  Dr. Adams. 
20		DR. ADAMS:  I think I know the answer, but for the 
21	record, were there any adverse experiences attributed to the
22	study drug that were serious, that resulted in death, 
23	admission to the hospital, or some compensatory therapy? 
24		DR. GRANEY:  We actually had a very simple 
25	clinical profile.  I will ask Dr. Richard Civil about any 

				178 1	that may have, other than the disease related ones, that
	2	might have been translated or described as serious by the 
	3	regulations. 
	4		DR. RICHARD CIVIL:  Rich Civil, Cephalon. 
	5		In tabulations of serious adverse events by 
	6	regulatory requirements, one quickly finds that the
	7	tabulations encompass a litany of the most common and 
	8	expected adverse events encountered in progressive ALS. 
	9		For example, the most common serious adverse event 
10	-- and by this I mean adverse event requiring a 
11	hospitalization -- was percutaneous gastrostomy placement or
12	PEG.  This was the number one serious adverse event 
13	occurring in the trials. 
14		DR. GRANEY:  Perhaps I could just go further and 
15	say we did not see a pattern of serious adverse events that 
16	appeared to be related to IGF-1, unrelated to the disease.

17		DR. GILMAN:  Including the deaths in the European 
18	trial? 
19		DR. GRANEY:  I will talk about those at some 
20	length.  We believe that those were ALS-related. 
21		[Slide.]
22		Although the clinical program was not intended to 
23	examine survival, we obviously reviewed the mortality 
24	experience from the point of view of safety. 
25		In the North American study, this study displays 

			179 1	mortality experience.  ON the left we have the North
	2	American study with its three treatment groups; on the 
	3	right, the European study. 
	4		The first row of data displays the deaths of 

	5	patients during the double-blind treatment and because 
	6	patients had a variable length of time in the double-blind
	7	treatment, we also went out to 300 days, which is close to 
	8	the amount of experience that we would see if all of the 

	9	patients did continue through the full possible nine months. 
10		As we look at the North American trial, we find 

11	that in the placebo there were 7.8 percent of deaths, in the
12	0.5, 12.4 percent, and in the 0.10, 9.2 percent of deaths. 
13		We will go over to the European trial, and as 
14	regard to numbers, I will remind you again there was a 2 to 
15	1 ratio.  So we look and we find that the placebo-treated 
16	patients had 8.5 percent deaths and the high dose drug had

17	14.5 percent deaths, and this was the origin of some concern 
18	at which we wanted to look further. 
19		When we did go out to the 300 days, as I 
20	mentioned, which would be about the experience we would 
21	expect -- and we have to keep in mind that many patients
22	here had entered open-label, which was open to virtually all 
23	patients who ended or discontinued from the double-blind 

24	trial -- we find that the numbers really do smooth out. 
25		In the North American trial, the placebo has 24 

			180 1	percent, the low dose 22 percent, the 0.1, 19.5 percent. 
	2	Placebo here is 22 percent, and 29 percent in the European 
	3	trial. 
	4		It is important to note, as I believe was noted 
	5	this morning, the differences in the deaths between groups 
	6	nowhere in this presentation reached statistical
	7	significance. 
	8		We did want to look further, and there is always a 
	9	clinical interest in the nature of these deaths.  One of the 
10	items that drew our attention was the early death within the 
11	first 30 days of five patients in the 0.1 mg/kg.  These were
12	examined very carefully and were in fact typical ALS deaths 
13	with no apparent factors that separated them from the other 
14	ALS-related deaths within the study. 
15		[Slide.] 
16		We looked in a broader sense beyond looking just
17	at these particular patients, and we found that there were 
18	factors identifiable in our group, in our clinical program, 
19	also identified in the literature that are associated with a 
20	greater likelihood of death, and those are greater age, a 

21	lower vital capacity, and the greater rate of change of AALS
22	total score during screening. 
23		When we looked at these factors, we found that 

24	they were evenly distributed across the patient groups in 
25	the North American trials, but in the European trial there 

			181 1	was a predominance at baseline of these factors, suggesting
	2	that the randomization which succeeded in the U.S. in 
	3	distributing the risk factors for deaths through the 
	4	treatment groups, did not succeed in doing that in the 
	5	European trial. 
	6		Again, in light of the extensive discussions of
	7	analyses that went on this morning, we should point out that 
	8	this, like some of the others, was a post-hoc analysis, but 
	9	it is interesting that the three factors that we found had 
10	indeed been identified within the literature. 
11		[Slide.]
12		We then took a further step and again these are 

13	post-hoc analyses, but we did a Cox proportional hazards 
14	regression model, and I know this has only been completed 
15	within the past few days, and I apologize to the agency for 
16	that.
17		The analysis that we did when considering these 
18	factors basically shows that the experience of the two 

19	groups is very close all the way through the end of the 
20	trial.  I offer that analysis as one we believe has been 

21	done in good faith and one which is congruent with the other
22	things that we found with this group of patients. 
23		[Slide.] 
24		In summary, I think you saw other than what we 
25	believe are the well-explained mortality experiences in the 

			182 1	European trial, a fairly straightforward Myotrophin safety

	2	experience.  The drug was well tolerated and certainly has 
	3	an acceptable safety profile for the treatment of patients 
	4	in ALS. 
	5		DR. GILMAN:  I would just like one bit of 
	6	clarification.  You said that the patients in the European
	7	trial who died, died of typical ALS complications or words 
	8	to that effect. 
	9		Can you explain what you mean, what did they 
10	specifically die from? 
11		DR. GRANEY:  Yes, in fact, I was again ask Dr.

12	Civil to come to the microphone.  He was the safety officer 
13	who reviewed the data extensively in both the North American 
14	and European trial, really looked at all of these in great 
15	detail, compared them across studies, and I will ask Rich to 
16	talk about that.
17		DR. CIVIL:  Thank you.  In a review of all of the 
18	deaths, it was very clear that the vast majority of deaths 
19	that occurred in the course of both the North American and 
20	the European trial had directly contributing factors 
21	identified by the treating physician of two types:  one,
22	respiratory insufficiency either alone or respiratory 
23	insufficiency in combination with a pulmonary infection. 
24		That probably accounted for 90-plus percent of all 
25	deaths as attributed by the investigators, and based on 

			183 1	medical review it seemed to be very clear that that was the
	2	predominant cause.  These patients had clear evidence of 
	3	disease progression with declining respiratory function both 
	4	symptomatically and on forced vital capacity measurements, 
	5	as well as other clear indices of disease progression, 
	6	namely, increasing swallowing difficulties often leading to
	7	PEG placement. 
	8		So based on these clusters of progressive deficits 
	9	leading to both respiratory insufficiency and swallowing 

10	difficulties often associated with the requirement for PEG 
11	placement, investigators and I regarded these as really

12	being quite prototypic of the expected outcome in ALS 
13	patients. 
14		DR. GILMAN:  Again, I believe we heard that there 
15	were no autopsies performed on any of the patients who died.  
16	Is that accurate?
17		DR. CIVIL:  No, that is an inaccuracy.  I am aware 
18	of perhaps 10 to 12 autopsies. I had actually just been 
19	informed that, unknown to me previously, that the majority 

20	actually came from Dr. Appel's site, not surprisingly given 
21	the database being accumulated there and the interest in
22	obtaining autopsy results. 
23		In reviewing the autopsies personally, I found no 
24	patient who had an autopsy who did not have a diagnosis, an 
25	autopsy-confirmed diagnosis of amyotrophic lateral 

			184 1	sclerosis.
	2		Oftentimes the attendant ante mortem or agonal 
	3	associates of respiratory insufficiency and/or overwhelming 
	4	sepsis and pneumonia were present, as well, but in all 
	5	instances, patients with autopsies in our clinical trial 
	6	were pathologically confirmed amyotrophic lateral sclerosis.
	7		DR. GILMAN:  That is reassuring. 
	8		Dr. Leber wanted to comment and Dr. Hoberman. 
	9		DR. LEBER:  Again, we can probably unfortunately 
10	spend a lot of time since neither the agency and the firm 

11	have had a chance to join each other and look at the same
12	data and the same analyses because there has been iteration 
13	of arguments as the days pass, but I want to make a 
14	distinction between the issue of an analysis done in good 
15	faith and a valid analysis. 
16		We could easily challenge the validity of analysis
17	even if we think it were done in good faith.  I bring that 
18	up because I believe the method of correcting the deaths 

19	probably is flawed as to the extent we understand it, and 
20	therefore I just don't want it to stand unrebutted as though 
21	it is explained, and if we find it necessary, Dave can
22	explain why. 
23		I would also like to bring up the point that only 
24	on the unstudy period can you fairly compare the deaths as 
25	to causal attribution because of the mixture of treatments 

			185 1	assigned to patients after the end of the double-blind
	2	period, and even then the failure to detect statistical 

	3	significance is a bit bogus because the studies are not 
	4	powered to detect it. 
	5		What you have is a difference which is different 
	6	as much as anything else, but you can't determine whether it
	7	is due to chance or not.  You just can't say for certain 

	8	that it is not or that it is.  It is just not the kind of 
	9	study that was done. 
10		So we just leave these things out as they are 
11	without reaching a firm conclusion.  Nobody is saying the

12	drug kills anyone, but I want one last point to make.  Not 
13	too many months ago or time ago, this committee voted to 
14	approve a drug to prolong survival in which there was no 
15	clear basis for how that drug acted to do so. 

16		We took an empirical look at the distribution.  So
17	that the idea that you can explain the mechanism of death by 
18	examining cases and saying they are the same kind of deaths 
19	that patients had, had they had ALS and nothing else, 
20	doesn't really say that the drug could not have had a causal 
21	role.
22		I just throw that out as a logical argument, 
23	because it, in fact, could change slopes, it could change 
24	how you handle secretions, you would never know it.  The way 
25	we look at this is empirical, what are the rates, and I 

				186 1	think that would be our position.
	2		We don't know, but we don't say you can discard it 
	3	simply because you come up with an argument. 
	4		DR. GILMAN:  Dr. Dobbins, do you want to reply 
	5		DR. DOBBINS:  No. 
	6		DR. GILMAN:  Dr. Hoberman was next.  Dr. Hoberman,
	7	did you want to comment? 
	8		DR. HOBERMAN:  I would like to make this optional 
	9	for the committee.  The sponsor has stated that there was an 
10	imbalance at baseline in risk factors in 1202, suggesting 

11	that that is why there were an apparent excess of deaths.
12		I don't agree with that analysis.  I don't know 
13	whether the committee wants to hear my explanation of how 

14	they came to that conclusion because they didn't explain how 
15	they came to that conclusion, or else they are satisfied 
16	that mortality in these trials is not an issue, so that you
17	don't need to spend time on it. 
18		DR. GILMAN:  I think you should explain further to 
19	us what you have in mind. 
20		DR. HOBERMAN:  I will need the overhead projector. 
21		DR. GILMAN:  Please, go ahead.
22		Dr. Adams, in the meantime, do you want to 
23	comment? 
24		DR. ADAMS:  Maybe I am misunderstanding something 
25	again.  The slide that shows the overall data from the North 

					187 1	American and European studies had the number of deaths
	2	during double-blind treatment, when the patient was taking 
	3	study drug, is that right? 

	4		DR. GRANEY:  Yes. 
	5		DR. ADAMS:		And then there were a number to day 
	6	300, which is approximately 10 months, and the numbers
	7	obviously increase because of the nature of the illness.  
	8	Now, I think you said it, I think Dr. Leber said it, were 
	9	patients in this period -- there are a number of patients 
10	that drop out of the trial -- 
11		DR. GRANEY:  Tes,
12		DR. ADAMS:  And are they getting active drug 
13	during that time? 
14		DR. GRANEY:  Yes, that is correct. 
15		DR. ADAMS:  So they would meet at endpoint, for 
16	example, it would be 115 by that Appel Scale.
17		DR. GRANEY:  Yes. 
18		DR. ADAMS:  And then would be stopped as far as 
19	the study and be given active drug thereafter? 
20		DR. GRANEY:  That is correct. 
21		DR. ADAMS:  That is kind of on an individual
22	patient and investigator decision? 
23		DR. GRANEY:  That is correct, although the 
24	majority of patients, I believe the number approached 70 
25	percent in most of the groups, went on to open label after 

				188 1	either completing the nine months or reaching an endpoint.
	2		DR. GILMAN:  Dr. Leber and then Dr. Temple. 
	3		DR. LEBER:  This is just a technical 
	4	clarification.  The answer to your question is it depends 
	5	when in the time course of the trial, the real secular time, 
	6	whether or not someone could go on to open label treatment. 
	7	I believe there was a period of time when there wasn't 
	8	enough drug available to put everybody on, and then later on 
	9	there was. 
10		So not consistently did everyone immediately go 
11	from double-blind to drug.  Isn't that correct?
12		DR. GRANEY:  That is correct.  There was a period 
13	for some patients, that is correct. 

14		DR. GILMAN:  Dr. Temple. 
15		DR. TEMPLE:  If the period on study shows one 
16	thing and then people on the placebo group who were doing
17	slightly better, at least in one study, at least in 1202, 
18	while on placebo cross over, and the numbers get closer, 
19	what do you think that means? 
20		DR. GRANEY:  Well, I think I can come to a 
21	conclusion of what you are implying.  I think the concern,
22	as has been expressed other times, is the fact that the 
23	rates come together due to a possible adverse effect on 

24	Myotrophin when it is first administered to patients, and I 
25	think one of the important points to bring out is that we 

			189 1	did not see this in the North American trial where we
	2	started a very significant number of patients, and there was 
	3	no evidence of a sorting out or a significant increase in 
	4	the deaths there.  That is really all the data that we have 
	5	available. 
	6		DR. GILMAN:  Dr. Hoberman, would you please
	7	proceed. 
	8		DR. HOBERMAN:  First, I would like to acknowledge 
	9	an error that I made in one of my earliest remarks of the 
10	day.  Dr. Carl Yoshizawa of Chiron pointed out to me that in 
11	stepwise regression, the selection is based on the maximum F
12	statistic, and thereby implying that order would not be a 
13	factor in the selection of the covariates. 
14		I apologize to the committee for that error, and I 
15	thank Dr. Yoshizawa for the correction, but at any rate, I 
16	expect it is something that one UNC grad would do for
17	another anyway. 
18		Ultimately, as I said before, the conclusions are 
19	totally unaffected by that issue. 
20		Now, getting to the question of the baseline 

21	factors, the sponsor has submitted to the FDA a couple of
22	analyses regarding this issue, and I just want to explain 

23	why I think that the logic isn't -- it certainly isn't quite 
24	clear to me. 
25		What they, in fact, did was to go into the 

			190 1	database in 1202 and they looked at the subgroup of
	2	uncensored.  Uncensored people are people who die and 

	3	censored people who are alive at the end of the study. 
	4		Now, what they did in again as simple terms as 
	5	possible is construct for each patient their own personal 
	6	score that would predict death, so the higher the risk
	7	score, the higher probability of death on study. 

	8		Now once you have all of these risk scores, then, 
	9	you can ask the question what is the distribution of these 
10	risk scores at baseline between the two treatment groups.  
11	Now, when the sponsor first submitted this analysis, what
12	they did was they concluded that since among the people who 
13	died, there was a slightly higher mean risk score at 
14	baseline than the people -- I am sorry -- the mean of the 
15	risk scores in the treatment group, but only among people 
16	who died, was greater than the baseline risk average among
17	placebo patients, again among people who died. 
18		Now, at the time, they stated that this implied 
19	that there was a 27 percent higher risk of death just based 
20	on baseline factors alone.  I question this logic because 
21	the answer to the question -- and the question is very
22	important -- the question is:  Was there a maldistribution 
23	of risk of death at baseline in the entire randomized 
24	cohort? 
25		By going into and only looking at the people who 

			191 1	died, you are looking at a subgroup.
	2		[Slide.] 
	3		Now, if you look at the distribution of risk 

	4	scores at baseline, using -- we just got another later 
	5	version of the model -- first, it had a muscle function 
	6	score and all of a sudden it doesn't -- but I had to use

	7	this, and this does include a muscle function score in order 
	8	to predict death. 
	9		This is actually the representation of the answer 
10	to the question you are really interested in.  You don't 

11	have to go into a subgroup of people who died in order to
12	infer back to what was correct about the distributions of 
13	patients you were really interested in. 

14		So if you want to say, well, it is true that there 
15	was a slightly greater mean in the risk factors of the 
16	people who died on the study in the treatment group, that is
17	all well and fine, but you can't make any inference from 
18	that about the predisposition of people when the started the 
19	race and what would befall them during the trial. 
20		DR. GILMAN:  Dr. Leber. 
21		DR. LEBER:  David, I still have a couple of
22	questions about what you are actually displaying.  You 
23	didn't put the slide on the projector in a way that would 
24	show us what the key was.  What are you actually plotting in 
25	terms of is this combined across the groups and what are the 

				192 1	plots?
	2		DR. HOBERMAN:  No.  I am sorry. 
	3		DR. LEBER:  Okay.  Treatment group of pluses.  So 
	4	when this lies to the right, is that a benefit? 
	5		DR. HOBERMAN:  No.  The higher the risk, the 
	6	greater the number.  The pluses is the treatment group.  So

	7	if you want to make any case at all that there was any kind 
	8	of imbalance at baseline, you might as well point up there 
	9	and say, gee, aha, I see some pluses that happen to be to 
10	the right of the squares. 
11		But that is not the analysis that the sponsor did,

12	and I would say that if somebody really wants to answer this 
13	question, as to whether the patients who died or in some 
14	sense there was some collective excess of risk at baseline, 
15	it is going to take a considerable more analysis or at least 
16	if you want to try to explain why there was an excess of
17	deaths in the drug group, it is going to take considerably 
18	more work than the sponsor had yet done. 
19		DR. LEBER:  This one last clarifying question.  

20	The scores that you are actually plotting that go across on 
21	your ogive, they represent a function that is applied to

22	every patient or his covariates.  They get a score that 
23	supposedly predicts death, and you are just plotting that 
24	score from that function. 
25		DR. HOBERMAN:  Yes. 

			193 1		DR. LEBER:  Where does the function come from,
	2	Dave? 
	3		DR. HOBERMAN:  I was trying to avoid that.  The 
	4	function comes from using a logistic regression model where 
	5	you simply compute the coefficients that, when multiplied by 
	6	each person's covariate, each person's baseline
	7	characteristic, and you add all those up, B1X1 + B2X2 + 
	8	B3X3. 
	9		Then, you get coefficients from that model that 

10	you are going to apply to each individual patient.  Then, 
11	you take each individual patient's scores and you construct
12	a score for each individual patient. 
13		The scale on the horizontal axis is completely 
14	arbitrary.  It has no clinical meaning.  However, it is a 

15	perfectly valid scale to show the range of risk scores that 
16	you get and the fraction of people who get those risk scores
17	or less. 
18		So this is the background of what the sponsor did, 
19	but the difference between what they did and what I did is 
20	take scores.  They took scores and applied them to the 
21	subgroup of people who died, and I am maintaining that this
22	is an improper way to make a statistical inference back to 
23	the original baseline population. 
24		DR. GILMAN:  Any further questions? 
25		Dr. Graney. 

			194 1		DR. GRANEY:  No, we are fine, thanks.  What I
	2	would like to do, then, is just if I can have my last slide, 
	3	I will close the clinical data presentation. 
	4		[Slide.] 
	5		The North American trial demonstrates Myotrophin's 
	6	effectiveness as measured by the AALS total score and the
	7	sickness impact profile, and the results are statistically 
	8	significant. 
	9		This morning you heard a great deal of discussion 
10	about complex statistical arguments on the European trial, 
11	but we believe that at the end of it, the effect of

12	Myotrophin in this study in Europe, although not 
13	statistically significant, is directionally correct and is 
14	supportive of the North American study. 
15		A review of the findings in the two-thirds of 
16	patients who progress rapidly, whether selected by original
17	score or by pre-slope, demonstrates the mutually supportive 
18	findings of the two trials. 
19		In summary, the body of evidence indicates that 
20	Myotrophin is well tolerated and reduces disease 
21	progression.
22		In closing the presentation of the clinical trial 
23	results, it is necessary to take a moment to express 

24	appreciation to the consultants and investigators who 
25	participated in the design and implementation of the 

			195 1	clinical program and to the patients and their families.

	2		Their efforts made the clinical evaluation of 
	3	Myotrophin in ALS possible. 
	4		With that, I will now ask Dr. Miller to present a 
	5	clinical interpretation of the findings of the Myotrophin 
	6	program.
	7		        CLINICAL INTERPRETATION 
	8		DR. ROBERT G. MILLER:  Thank you. 
	9		Dr. Gilman, ladies and gentlemen, I am grateful 
10	for the opportunity to provide a clinician's perspective to 
11	the information that you have heard this morning, shifting
12	gears a little bit from such an intense discussion of so 

13	many methodological and statistical issues to look at this 
14	from the perspective of a clinician. 
15		I was not involved in this study, and yet I am 
16	very involved in the care of patients with this disease and
17	also in clinical research in ALS. 
18		[Slide.] 

19		So I want to remind you about the disease itself.  
20	This patient who has a tracheostomy and a feeding tube, 
21	feeding gastrostomy, is completely paralyzed in his arms and
22	in his legs.  He has a motorized wheelchair that can be 

23	driven by head movements and by a puff and sip mechanism. 
24		He has full time attendant care and still has 
25	considerable quality in his life, but he illustrates the 

			196 1	extraordinary burden that this disease ALS places upon
	2	persons who suffer from it. 
	3		[Slide.] 
	4		We really are still in the unfortunate position of 
	5	being able to treat only the symptoms of the disease, and we 
	6	have gotten better and better at helping to relieve some of
	7	the suffering of the symptoms of ALS. 
	8		We can control the spasticity to some degree, and 
	9	cramps, and excessive saliva, and the disturbed sleep that 
10	so many patients with ALS suffer from, and we have really 

11	developed a lot of methods to help with mobility and with
12	nutrition, and even with modern methods of helping with 
13	ventilation, and these symptomatic therapies are helpful, 

14	but we have nothing that stops or reverses the progress of 
15	ALS, and I want to provide you with a perspective on the 
16	past several decades in attempting to find a treatment for
17	this terrible disease. 
18		[Slide.] 
19		There is a large body of literature documenting 
20	scores of negative clinical trials in ALS including all 
21	manner of immunosuppressive drugs, calcium channel blocking
22	agents, branch chain amino acids, and even, more recently, 
23	some studies using other neurotrophic factors, and these 
24	studies have been uniformly negative.  There has been no 

25	drug until now where the progressive, relentless decline in 

			197 1	function and quality of life for ALS patients has been
	2	altered in a beneficial way. 
	3		[Slide.] 
	4		As a clinician, I would like to reiterate a few 
	5	points that have been made today, and I must say that this 
	6	is the first time I have heard a public peer review
	7	discussion of these data, and I am grateful to Dr. Leber and 
	8	his team, and to the penetrating questions of the committee, 
	9	because a lot of information has come out that is important 
10	about the methodological considerations in the trial and 

11	about the very complex statistical issues in the trial.
12		But having said all of that, I believe that the 
13	evidence from these studies does demonstrate that the 

14	progressive decline in function of patients with ALS is 
15	slowed with Myotrophin, and that in patients who are 
16	progressing rapidly, these effects are particularly clearly
17	seen. 
18		I am grateful also for these discussions about 
19	safety because we participated recently in a trial of CNTF 
20	where patients were made quite sick by this neurotrophic 

21	factor, and the increased death rate was very troubling, but
22	patients were made so sick and the adverse events were so 
23	obvious that it was easy to understand that there were 

24	safety concerns, and I personally feel satisfied on the 
25	basis of the discussions that we have heard today that there 

			198 1	do not appear, in my view, to be significant safety
	2	concerns. 
	3		[Slide.] 
	4		Now, I want to highlight an important point, and 

	5	that is that we have come a long way in the trial design of 
	6	attempting to find a treatment for this disease, and one of
	7	the things that I think we have learned is that it isn't 
	8	enough for clinicians to evaluate patients and indicate how 
	9	they are doing.  We have to ask the patients. 
10		In this trial, there was a parallel assessment 

11	using a Clinicians' Rating Scale and a Patients' Rating
12	Scale, quality of life measured by the Sickness Impact 

13	Profile, a well-standardized, widely-utilized instrument, 
14	patient perception. 
15		The results of these two instruments follow a 
16	congruent assessment in these studies.
17		[Slide.] 
18		Now, just a brief comparison.  This is not an 
19	attempt to establish anything about statistics.  It is only 
20	to show you and give you a flavor, in a side-by-side 
21	comparison, in the change from baseline to endpoint in each
22	of the various scales of the Baylor rating method. 
23		You can see that in the North American study there 
24	is a dose-response and a directional consistency favoring 
25	Myotrophin treatment and that the same directional 

				199 1	consistency is seen across each of the scales in the
	2	European trial. 
	3		The point that I would particularly like to 

	4	underscore as a clinician is that strength and upper 
	5	extremity function, these two categories which are so 

	6	critical in terms of a person's function as they attempt to
	7	manage this disease were beneficially effective and no other 
	8	drug had shown this kind of beneficial effect upon strength. 
	9		DR. GILMAN:  Excuse me.  Strength where?  Where is 
10	that measured? 
11		DR. MILLER:  This is manual muscle testing.
12		DR. GILMAN:  Arms or legs or both? 
13		DR. MILLER:  Both upper and lower extremities, a 
14	composite measure. 
15		DR. GILMAN:  Yet, there was no change in lower 
16	limb function.
17		DR. MILLER:  Yes.  Dr. Gelinas, do you want to 
18	comment about that? 
19		DR. GELINAS:  If I could address that.  Muscle 
20	strength was assessed with the manual muscle examination, 
21	and it did examine upper and lower extremities across
22	joints.  However, the lower extremity functional testing are 
23	time-to-test, so that they involve much more than just 
24	strength, but they involve also assessments of strength 
25	through the spine and the ability to right yourself when you 

			200 1	are about to fall, how quickly you can walk, your timing, so
	2	a lot more attention to upper motor neuron problems and 
	3	spasticity problems with regard to function. 
	4		[Slide.] 
	5		DR. MILLER:  Comparable data are shown here for 
	6	the roughly two-thirds of patients in each of the two
	7	studies, the North American and the European trials, who 
	8	were considered rapid progressors or upper strata patients. 
	9		I would just point out again the consistency 
10	across every measure of the Baylor Scale in the North 
11	American study, where the results are, I believe, robust, to
12	use a word that has already been used today, and in the 
13	European trial, where the directional consistency is 
14	observed in each of the scales and where there appears to be 
15	supportive evidence about drug effectiveness. 
16		[Slide.]
17		I would just make a comment about the European 
18	trial, and that is that the investigators figured 
19	prominently in the design of the European trial, and because 
20	the company worked closely with the investigators and 
21	respected their preferences, there were a number of issues

22	that made the European study different from the American 
23	study, and as you have heard, one of them was the 2 to 1 
24	assignment which changed the power of the trial. 
25		Another point is that when this study was 

			201 1	designed, a larger effect size was anticipated than was
	2	observed, and therefore, this study, the European trial, was 
	3	underpowered for the observed effect, something that we 
	4	recently experienced in a trial of gavapentin. 
	5		This is particularly true for patients who are 

	6	changing very slowly, where a much larger sample size is
	7	needed to observe an alteration in the slope. 
	8		[Slide.] 
	9		Quality of life for patients with ALS is a 

10	critical issue, and here you see the scales which were 
11	beneficially impacted by Myotrophin in the study where the
12	Sickness Impact Profile was used to measure quality of life 

13	related to such important issues as ambulation and mobility, 
14	social interaction, improved communication, management in 
15	the home, and finally, the ability to enjoy recreation again 
16	showing tendency toward both a dose-response and a favorable
17	drug effect upon the preservation of quality of life. 
18		[Slide.] 
19		Our group, separate from these studies, carried 
20	out an analysis of the Sickness Impact Profile in comparison 
21	with declining isometric muscle strength in a large group of
22	patients with ALS, and found a very high correlation between 
23	the changes that occur in muscular strength and the changes 
24	that occur in the Sickness Impact Profile as a measure of 

25	life, again underscoring the value of this measure in 

			202 1	declining quality of life in patients with ALS.
	2		[Slide.] 
	3		To sum up, then, this is a study that in many ways 
	4	has grown out of the neurobiology laboratory where 
	5	anticipated preclinical effects of this compound have now 

	6	come to fruition in a clinical trial and where I think we
	7	have seen evidence of efficacy using a valid and reliable 
	8	and disease-specific measure, the AALS Scale. 

	9		We have seen a robust effect in the North American 
10	trial and I believe we have seen a supportive effect in the 
11	European trial, and it is true that when patients are
12	rapidly changing, there is more likely to be an effect than 
13	in patients who are moderately changing, and that was 

14	observed in the patients who were rapidly progressing. 
15		I would make the point again that this is the 
16	first clinical trial in ALS demonstrating a slowing of a
17	decline in quality of life, that is, patient ratings of 

18	their own quality of life, a very important element in the 
19	trial. 
20		Finally, I would say that I believe that we are 
21	seeing here a drug that shows minimal risk.
22		[Slide.] 
23		I would just like to comment about the therapeutic 
24	effect.  In neurology, we don't have a lot of experience 
25	with therapeutic effects, particularly for neurodegenerative 

			203 1	diseases.
	2		I would just like to make the parallel with the 
	3	Guillain-Barre syndrome and the treatment plasmapheresis 
	4	where a large North American trial demonstrated a beneficial 
	5	impact on the slope of recovery for patients with Guillain- 
	6	Barre syndrome.  The size of the effect was about 25
	7	percent, that is, patients who were treated with 
	8	plasmapheresis improved with a slope that was about 25 
	9	percent faster than patients who did not receive the 
10	treatment. 
11		This was not an effect that patients could see, it
12	was not an effect that clinicians could see, but it was 
13	confirmed in a number of studies and quickly became adopted 
14	as the gold standard for therapy for patients with this 
15	disease. 
16		In Duchenne's muscular dystrophy, another
17	desperate progressive disease in children, prednisone has 

18	shown a very modest clinical effect, but it is sometimes 
19	apparent to both patients and physicians even though the 
20	improvement in strength is very modest. 

21		The drug riluzole, which is the only drug that has
22	been approved for ALS, has an impact on mortality, and the 
23	size of the improvement in mortality range between 4 and 18 
24	percent, and with Myotrophin we are talking about an impact 
25	in the slope that ranges between 20 and 25 percent.  It is 

			204 1	not clinically apparent.  It doesn't stabilize the disease. 
	2	It does not improve life for patients, but it slows the 

	3	decline in a fashion that compares favorably with these 
	4	other accepted therapies. 
	5		[Slide.] 
	6		So I believe that the one drug that is approved at
	7	the present time impacting on survival, but not function, 

	8	and now we have a drug that slows the loss of function and 
	9	delays the loss of quality of life, and I think we are in a 
10	position that in many ways is analogous to the early days of 
11	cancer therapy and the treatment of AIDS.
12		[Slide.] 
13		This is a drug that patients want and that 
14	clinicians want, and it is really the reason that we are all 
15	here today, because ALS is, after all, the Grim Reaper of 
16	neurologic disease, and people like Jane here struggle
17	courageously to cope with the disease, but the burden is too 
18	great for any patient, any family, and for the society. 
19		As a clinical investigator in ALS, I am convinced 
20	by the data.  Myotrophin has a beneficial impact on the 
21	disease both in terms of the loss of function and the
22	erosion of quality of life. 
23		As a clinician caring for patients with ALS, I 

24	urge you to approve this treatment IND for Myotrophin. 
25		Thank you. 

				205 1		DR. GILMAN:  Thank you, Dr. Miller.
	2		Dr. Copple, you had a question. 
	3		DR. COPPLE:  Yes.  On the slide that you showed on 
	4	the Sickness Impact Profile, there was substantial effect on 
	5	social interaction and recreation, and I wonder if you have 
	6	any thoughts as a clinician as to the mechanism of that or
	7	the rationale, since there was not that much improvement in 
	8	strength and muscle function.  There was certainly some, but 
	9	-- 
10		DR. MILLER:  The question is about Sickness Impact 
11	Profile and about the mechanism of improvement, and I should
12	be clear that -- I think probably everyone understood, but 
13	just to be doubly sure -- we are not talking about people 

14	improving, we are talking about slowing the decline in 
15	function and slowing the loss of these various important 
16	motilities of quality of life.
17		I think what you saw is that every functional 

18	scale on the AALS Scale showed a response, a dose-response, 
19	albeit not always statistically significant, and I think it 
20	is very hard to say why each one of these very important 

21	factors was preserved, if you will, for patients.  I don't
22	have a specific mechanism, but I think it correlates with 
23	the slowing of the loss of function. 

24		DR. GILMAN:  Dr. Gelinas, did you want to respond? 
25		DR. GELINAS:  I have been very interested in the 

			206 1	impact on the quality of life of Myotrophin, and in looking
	2	at the separate categories that are endorsed under 
	3	Recreation, they encompass such items as I am able to spend 
	4	much time with my family members, I am going out almost as 
	5	often as I did before my illness, and they really have 
	6	functions that have a lot to do with fatigue in life, and if
	7	you can combat the fatigue, then, you have the energy to do 
	8	those things on those outings.  I think that is really where 
	9	it hits in terms of fatigue. 
10		DR. COPPLE:  Thank you. 

11		DR. GILMAN:  Dr. Hoberman.
12		DR. HOBERMAN:  Dr. Miller, I have a copy of the 
13	paper that you referred to, and it is true that you found a 
14	p value of 10-4, but in your talk you stated there was a 

15	very high correlation.  That is not the same thing as a 
16	highly statistically significant result.
17		In one of the tables it states that the 
18	correlation between the TQNE and the change in overall SIP 
19	has an adjusted r-squared of 0.08.  Now, that is not a very 
20	high correlation.  That is almost of no predictive benefit. 
21		In one of the concluding paragraphs in the paper,
22	it states, "In its present form, the SIP is insufficiently 
23	sensitive for monitoring disease progression at the level of 
24	the individual ALS patient." 
25		Now, I don't see how those statements in your 

			207 1	paper hang together with simply stating that there is a --

	2	what you stated -- a high correlation between the TQNE and 
	3	the SIP. 
	4		The second thing I would like to say is that 
	5	stating that you didn't get an anticipated treatment effect 
	6	and therefore less power is sort of tautological and is the
	7	excuse of a lot of failed trials, in this case, it is 

	8	possible -- and we have produced and Dr. Feeney showed -- an 
	9	analysis of the difference in the progression post-baseline 
10	to pre-baseline, in which the issue of power doesn't even 
11	arise because the effect is null, the distribution is
12	superimposed.  There isn't a statistical method on earth 
13	that could pull those curves apart and set one to the left 
14	of the other. 
15		The last thing is you referred to a treatment 
16	effect.  This may seem like a technical point, but my
17	understanding is that we are not in a position to state that 
18	there is an actual documented treatment benefit that any 
19	patient can expect. 
20		That would probably take further study, and just 
21	because there was a number like 25 percent that did come out
22	in the North American study, it is not clear that people 
23	should walk away thinking that this in fact is an 
24	expectation that a patient should entertain. 
25		DR. GILMAN:  Dr. Miller. 

			208 1		DR. MILLER:  Well, with respect to the first --

	2	and those were all very good questions, Dr. Hoberman, in 
	3	fact, I had a dream that you would ask me that question -- 
	4	because the first question that you asked really reflects 
	5	the difference between the way a clinician looks at a 

	6	comparison of two different measures, the TQNE and the
	7	Sickness Impact Profile, and the way, with all due respect, 
	8	you would look at these data as a person who is much more 
	9	knowledgeable than I about the statistics. 
10		I felt satisfied, as did our group, that the 
11	decline of the Sickness Impact Profile measuring quality of
12	life, and the decline in muscular strength fall in parallel, 
13	and that the relationship between these two measures was 
14	highly significant, and if I overstated the correlation, I 
15	apologize about that. 
16		The point that you made that the Sickness Impact
17	Profile is not an adequate way to follow an individual 
18	patient is a good one.  We don't use it to follow individual 
19	patients, but we do think that it has great value to follow 
20	groups of patients and to make comparison about quality of 
21	life.
22		The truth is we do not have an excellent quality 
23	of life measuring instrument, but the Sickness Impact 
24	Profile is about as good as they get now in my view, and 

25	this is a start.  This is a first step, and we are now 

		209 1	measuring the best way we can quality of life, and we are
	2	seeing a change that appears positive and congruent with the 
	3	changes measured in the functional scale by clinicians. 
	4	          The issue about power is a very important one.  
	5	You quite rightly say that if there is no therapeutic 
	6	benefit, you can't talk about power, but I would say that
	7	since one-third of the patients were progressing at a very 
	8	slow rate, and two-thirds were progressing at a rapid rate, 
	9	and when you look at those patients who are progressing at a 
10	more rapid rate or are more serially affected, or both, you 
11	see changes that, to me, looked directionally consistent and
12	not as robust as the changes in the North American study, 
13	but all in the same direction.  To me, that is a therapeutic 
14	benefit, and if we had larger numbers, I believe that we 

15	would have had more of a statistically significant effect. 
16	          The final point about the treatment effect that
17	people can infer from the changes in slope is a very 

18	important one.  It is very hard for us to measure the impact 
19	of any treatment upon this disease.  We cannot quantitate 
20	what people really want to know, which is how much longer 
21	will I live, how much longer will I be able to do the things
22	that I want to be able to do, but we can quantitate the rate 
23	of decline of our best measure of quality of life and the 

24	rate of decline of function measured in a way that has been 
25	validated and where there is a lot of experience in ALS. 

				210 1		When we see a slowing of that rate of decline, and
	2	when the difference is about 20 or 25 percent, then, I think 
	3	we can explain it that way to patients, and for the reasons 
	4	that I explained here, I think that is meaningful. 
	5		DR. GILMAN:  Any further questions from the 
	6	committee for Dr. Miller, Dr. Graney?  Any further
	7	statements from the sponsor? 
	8		SPONSOR:  No, sir, that concludes our 
	9	presentation. 
10		DR. GILMAN:  Thank you. 
11		Any further comments from Dr. Leber, Dr. Temple?
12		All right.  Then, it is time for the committee to 
13	do its due deliberations. 
14		          COMMITTEE DISCUSSION 
15		DR. GILMAN:  Let me start by reminding all of us 
16	that the reason we are here today is to respond to the
17	question as to whether we agree that there are two seemingly 
18	adequate and well-controlled clinical investigations of the 
19	effects of Myotrophin in patients with ALS and whether we 
20	have sufficient data to support a treatment IND. 
21		That is all we are being asked to do, do we think
22	there is enough evidence to support a treatment IND. 
23		To initiate the discussion, I think I would prefer 
24	to be provocative at this point and just tell you what I 

25	think at this point having heard the material today and 

					211 1	having read the material that we were provided.
	2		Yes, Dr. Leber? 
	3		DR. LEBER:  One critical point and I hate to 
	4	interrupt you at this particular moment. 
	5		DR. GILMAN:  That's all right. 
	6		DR. LEBER:  We want to make certain that it is
	7	understood that the committee is not going to reach a final 
	8	view until it has had a chance to hear from the open session 
	9	testimony. 
10		DR. GILMAN:  That's right. 
11		DR. LEBER:  Right now I just want to emphasize
12	this again for people who wouldn't have understood, that we 
13	hope this would focus on the evidence adduced in the two 
14	trials, and the final question about how to use that 
15	evidence, and what purposes it may serve, will be addressed 
16	after.
17		Is that a clarification that helps a little? 
18		DR. GILMAN:  Absolutely right.  Yes, thank you for 
19	that. 
20		Yes, we are here at this moment to discuss our 
21	views of the information we have had presented before us, so
22	that we can share those views.  Then, we will hear from the 
23	patients and other advocates, and then will have further 
24	discussion prior to voting. 
25		So, to continue, it strikes me on having evaluated 

			212 1	the evidence, that we have convincing evidence from the
	2	North American trial, the 1200 trial, that there is 
	3	efficacy.  It was a prospectively designed and executed 
	4	study with the data showing improvement at least as compared 
	5	with placebo in the Myotrophin-treated group. 
	6		Personally, I was not convinced that there are
	7	sufficient data to be convincing, that the European study 
	8	had data that convinced me that there are sufficient reasons 
	9	to agree that it is an effective agent. 
10		I think I would like to hold the issue of safety 
11	for a moment and see what others say about efficacy at this
12	point. 
13		So, committee? 
14		DR. KAWAS:  Can I ask a more procedural question 
15	about the comment you started the discussion with? 
16		DR. GILMAN:  Yes.
17		DR. KAWAS:  Is the question we are trying to 
18	answer whether there are two studies, and is it two studies 
19	that are necessary for a treatment IND? 
20		DR. GILMAN:  No.  We are trying to determine 
21	whether there is sufficient evidence for us to recommend a
22	treatment IND.  The "sufficient" will be our judgment. In 
23	order to provoke the discussion, I thought it would be best 
24	to reflect my own thoughts, which are that there is one 
25	study that to me provides sufficient evidence, another study 

			213 1	that does not provide sufficient evidence.
	2		I think we need to talk about that first and then 
	3	we can determine whether the combination of the two studies, 
	4	with whatever you think about their results, provide you in 
	5	your mind with sufficient evidence to grant a treatment IND. 
	6		Dr. Zivin, Dr. Snead, and then Dr. Drachman.
	7		DR. ZIVIN:  I have a question that I would like to 
	8	ask first, which is, from both the FDA and from the sponsor, 
	9	what are the practical implications of either approval or 
10	disapproval? 
11		DR. GILMAN:  Dr. Temple, do you want to respond to
12	that? 
13		DR. TEMPLE:  Let me dance around it a little and 
14	just say a few things.  It relates to the question, I can 

15	assure you of that.  You will see it happen eventually. 
16		We have obviously spend some time thinking about

17	these data and discussing them with Cephalon, and are coming 
18	to you because we have to make a decision about a treatment 
19	IND request that seems somewhat complicated.  This was all 
20	laid out well by Paul, so I won't try to replicate it. 
21		There is one study, and you can tell we have few

22	reservations about the 1200 study.  We can argue about this 
23	and that, but on the whole, the primary endpoints were met 
24	and it all kind of leans the right way.  So we don't have 
25	reservations about that, and as you can obviously tell, we 

			214 1	have substantial reservations about 1202, and we wanted to
	2	be sure you knew what those were. 
	3		To state the obvious, those reservations certainly 
	4	don't mean that we think we know Myotrophin doesn't work, 
	5	but in the face of a study that looked pretty clean and 
	6	neat, one of the questions we wanted to ask was what are the
	7	implications of a study that is of very similar design, but 
	8	not supportive. 
	9		As you have heard, Cephalon clearly knows that 

10	that study is not a clear winner, but they have a lot of 
11	reasons and they have offered them to think that you
12	shouldn't be as discouraged as it might first seem, because 
13	there are reasonable explanations for why the study wasn't 
14	so robust. 
15		Now, at the back of all this is, while we are 

16	asking you about a treatment IND, a marketing application
17	based on those same studies would obviously have to make the 
18	same kinds of arguments.  This is not a secret, everybody 

19	knows that.  Cephalon has said that that is what they think 
20	the data are. 
21		Now, the criteria for a treatment IND that are

22	pertinent are two.  There are really only two that are 
23	relevant here, one of which we have asked you an explicit 
24	question about, and that is, that there needs to be 
25	sufficient evidence of safety and effectiveness to support a 

			215 1	treatment IND.
	2		Sufficient is not further defined in the law 
	3	except to say that it is clearly less than the substantial 

	4	evidence of effectiveness needed to market a drug.  So you 
	5	don't need the same level of evidence.  If you did, then, 
	6	you would market the drug, you wouldn't have a treatment
	7	IND. 
	8		So, even if you think that there is sufficient 
	9	evidence for a treatment IND after a full discussion here, 
10	you don't need to think that you are then telling us what 
11	the answer to the NDA application would be, because it is a

12	different standard and a different thing, and we would look 
13	at the data more, and so on, and there would be more 
14	discussions. 
15		There is a second requirement for granting a 

16	treatment IND, however, and that is that the company be
17	actively pursuing marketing approval with due diligence.  In 
18	the regulation, that means generally that the trials that 
19	might support a marketing application are completed or that 
20	they are ongoing. 
21		That question becomes at least potentially
22	slightly tricky here, because it is no secret that Cephalon 
23	thinks that the current data would support a submission, and 
24	we have told them -- this has been publicly announced, so I 
25	am not telling anybody anything they don't know -- that we 

			216 1	would file such an application for review, we wouldn't say
	2	it is clearly not acceptable, and incidently, that it would 
	3	get priority review.  We have said those two things, and 
	4	those are not secrets. 
	5		So you could say, well, the question is moot.  
	6	Obviously, that sort of means that there is due diligence
	7	going on.  But, in fact, you could tell us things that would 
	8	shed light on that question.  I am not offering them in any 
	9	particular order. 
10		If, for example, you felt really strongly, but 
11	admittedly before there has been a total review of the data,
12	that 1202 is just really weak, you might want to say that 
13	because it conceivably could affect Cephalon's view and our 
14	view about what ought to happen. 
15		I am not trying to predict exactly how it would do 
16	that, that is a complicated question, but you might in that
17	case urge the sponsor to look very closely at any other 
18	ongoing studies or at least think about initiating further 
19	study early, whatever we might choose to do with the NDA. 

20		On the other hand, if you found the kinds of 
21	arguments that have been made about 1202 reasonably
22	persuasive under the circumstances, you know, one strong 
23	study and one study with a good excuse for not being as 
24	strong, you might tell us that, and that might affect our 
25	decision eventually and Cephalon. 

			217 1		So some of what you might say as you look at these
	2	studies and as you contemplate what you have talked about, 
	3	could have implications.  I am dodging what the exact 
	4	implications are because we really haven't come to grips 
	5	with the studies in the way we would at the time of an NDA, 
	6	and it is too soon to be precise on this.  So I am just
	7	trying to give some flavor. 
	8		Does that remotely come to answer what you were 
	9	asking about? 
10		DR. ZIVIN:  Remote. 
11		DR. GILMAN:  Let me paraphrase.  If we do not
12	believe that there is sufficient evidence, then, the sponsor 
13	would have to initiate another study, I assume, or start 
14	again.  If we do find there is sufficient evidence, we will 
15	make that recommendation to the FDA, and they will make that 
16	on up the scale.  It is then up to the company as to whether
17	it will or will not pursue an NDA, a new drug application, 
18	with the current data or whether they will decide to 
19	initiate a new trial.  I think that is what Dr. Temple was 
20	saying. 
21		Dr. Leber.
22		DR. LEBER:  Bob, unfortunately, did not come early 
23	enough to hear what I said to you, which I think is a 
24	slightly different pitch on the same problem.  I said -- and 
25	I was asked this question before -- what is sufficient 

			218 1	evidence.  We all agree it is less than substantial by
	2	definition, but it is a term of art. 
	3		We don't know precisely what it means, but it 
	4	isn't just the evidence alone.  It is the context in which 
	5	the evidence is used.  You could say that we are 
	6	anticipating the submission of an NDA, and if you say that
	7	you expect that the evidence that will be forthcoming will 
	8	be enough to approve -- make a decision, definitive decision 
	9	on the NDA, then, certainly the conditions of a treatment 

10	IND historically would be met, because you would have the 
11	evidence you need, and you want to accelerate the pace at
12	which patients can gain access to the drug. 
13		You could also approve a treatment IND under 
14	conditions in which you say, look, we think there is 
15	sufficient evidence for treatment use, but we don't think 
16	the evidence is sufficient to support an application's

17	approval, and therefore we urge you at this point to 
18	consider the conduct of additional studies to decide the 
19	question in a definitive manner.  That is another outcome. 
20		Finally, of course, I won't preclude the 
21	possibility that you could look at this evidence and say I
22	don't care, that 1200 is positive, the treatment effect is 

23	not large enough or important for us to say treatment use is 
24	necessary.  So you have a full range. 
25		But it isn't just the evidence alone.  It is the 

			219 1	evidence and the path it leads to.  Treatment use is
	2	intended not to allow a limbo system in which you have this 
	3	unapproved new drug forever being circulated.  You want to 
	4	reach a final conclusion.  So you have to factor that in. 
	5		But as a suggestion right now for this discussion, 
	6	you really have two trials before you, and I would suggest
	7	the possibility, if the Chair agree, that you might want to 
	8	parse this out until deciding what you think these two 
	9	trials show.  That would be step one.  And from there, you 
10	can move forward. 
11		I don't know even know what the sense of the
12	committee about them is. 
13		DR. GILMAN:  I felt there was convincing evidence 
14	about efficacy in 1200, and not in 1202, to be concise. 
15		Did you want to comment?  Please identify 
16	yourself.
17		DR. MONROE KLEIN:  Monroe Klein, Cephalon.  I am 
18	going to make two comments, the first about the pursuit of 
19	marketing approval.  When you look at the intent of the 
20	regulation, as indicated in the preamble which was 
21	published, the intent was to not unduly prolong clinical

22	investigation, and clearly, neither Cephalon nor Chiron 
23	intend to unduly prolong clinical investigation.  In fact, 
24	we intend to submit a treatment IND this summer -- NDA -- 
25	NDA this summer, and as Dr. Temple said, that is an 

			220 1	application that would be fileable.
	2		Also germane to that, the purpose of this 
	3	requirement of actively pursuing marketing approval was 
	4	focused in on companies that were charging for a treatment 
	5	IND, for the drug in a treatment IND.  I wanted to clearly 
	6	state that that is not our intent.  We intend to provide the
	7	drug free of charge to patients if we are granted a 
	8	treatment IND. 
	9		I would like to now respond to considerations of 
10	whether another study should be done.  It is our opinion 
11	that the clinical studies conducted to date have established
12	that Myotrophin is safe and effective. 
13		We think there is additional work that should be 
14	done with Myotrophin, but we see that being done in a post- 
15	approval environment.  One must consider the ethics of doing 
16	another placebo-controlled trial at this time.
17		Based on the epidemiology of this disease, the 

18	sponsor cannot justify spending additional resources to 
19	conduct another study pre-approval.  We would like to do 

20	another study post-approval.  We are committed to doing that 
21	if given the opportunity.
22		We think the appropriate study to advance this 
23	field is a combination study to see whether a combination of 
24	riluzole and Myotrophin have more benefit to patients than 
25	either drug individually. 

			221 1		We have discussed study designs for such
	2	combination studies with the World Federation of Neurology.  
	3	We have submitted a proposal to the agency.  I just ask you 
	4	to bear in mind that for this serious disease, we think that 
	5	a post-approval study, a Phase IV study or a Phase IV 
	6	commitment might be something for your consideration.
	7		Thank you. 
	8		DR. GILMAN:  Dr. Snead, I think you were next. 
	9		DR. SNEAD:  I had the same question. 
10		DR. GILMAN:  Dr. Drachman. 
11		DR. DRACHMAN:  The issue that I see is that when
12	you do one study, that should give you all the clues or most 
13	of the clues you need to design another study that is going 
14	to be more positive.  Whatever you learn from the first one, 
15	you may apply. 
16		If there is a subgroup that you believe is going

17	to help more, if you believe there is a dose level, if you 
18	believe there is a duration, all of those may be used to 
19	give you a better second study. 
20		Here, we see sort of the reverse.  This is a 
21	little worrisome to me, that is, one study was carried out
22	and worked.  Based on the findings partly from that study, 
23	the dose of the treatment in the second study was the one 
24	that was believed to be more effective in the first. 

25		But lo and behold, given this, things did not work 

			222 1	out quite that way.  This is one of the issues that I regard
	2	as very troublesome.  Were there a third trial, what would 

	3	be done that would be different from the first two? 
	4		Well, it might be that only those with the most 
	5	rapid progression would be entered, but I have no definite 
	6	way of knowing, and I sort of wonder whether that would, in
	7	fact, alter the way the trial goes. 

	8		It seems to me -- and I am troubled by the excuses 
	9	that are raised regarding why the second trial failed to 

10	reach significance.  There were many of them, as you know.  
11	The control group really didn't match, there wasn't enough
12	power, too many of the patients received drug, and not 

13	enough were in the placebo group.  All of these were factors 
14	that should have been thought about and clearly would have 
15	been thought about in designing study number two. 
16		One of the things that always worries me is if
17	someone flips a coin 100 times and finds that tosses number 
18	53 to 62 had a preponderance of heads, then, to say this is 
19	a subgroup of tossing a fair coin that is really different, 
20	so I am going to do another study, another trial of coin 

21	tossing in which I will ignore all the tosses until that
22	point. 
23		The issue then is whether these are random events 
24	or random concatenation of events, such that you see a lot 
25	more heads than you would have, but it is, in fact, by 

				223 1	chance, and not the result of what actually happened during
	2	the coin toss. 
	3		These are some of the issues that I find 
	4	troubling, that is, that the redesigned study with the 
	5	insights from the first one was less efficacious. 
	6		DR. GILMAN:  Thank you.
	7		Dr. Temple. 
	8		DR. TEMPLE:  Just a factual matter.  It wasn't my 
	9	impression that the European study was actually designed to 
10	follow on the first.  They were ongoing more or less 
11	concomitantly.  You know, it is a fact of life that attempts
12	to replicate studies don't always work, and it is also a 
13	fact of life that every time you chase one subset, you find 
14	out you were probably wrong. 
15		So whether one can, in some way, by being smarter 
16	actually do better on those things is what we all dream
17	about, but rarely achieve. 
18		I just want to say that this is not a case where 
19	they tried to single out -- as far as we can tell -- single 
20	out particularly characteristics and then failed to get 
21	them.  It just seems like a case where the second study was
22	not nearly as robust, or not robust at all, if you like. 
23		DR. GILMAN:  I think Dr. Drachman was referring to 
24	the multiple post-hoc analyses in which they looked a whole 
25	bunch of factors, and by chance, one of those is likely to 

				224 1	be positive.
	2		DR. TEMPLE:  As you know, we are concerned about 
	3	that, too. 
	4		DR. GILMAN:  Dr. Leber. 
	5		DR. LEBER:  I think it is fair to say that both 
	6	studies more or less overlapped.  There was a slight offset,
	7	so that the European study started slightly later.  It is 

	8	conceivable that data from that study might -- and this is 
	9	what we have to ask the firm -- have influenced the late 
10	decision to change the outcome variable, but I can't tell 
11	that.  It may have occurred totally independently, but it
12	was not a leak of data from one study to the next, but 

13	rather a strategy for maximizing something. 
14		But it is true, this is not an iterative 
15	development program where you do one result, look at it.  It 
16	is typical of modern drug development.  People know you need
17	two studies.  They try to do them simultaneous virtually and 
18	you sometimes get conflicting results. 
19		One thing that Bob said, that you find a result 

20	and you try to confirm it.  That is why we were ready to go 
21	ahead with the treatment IND without question when all we
22	had in hand was 1200.  The problem is when you have two 
23	studies and no clear means to decide which one is a better 
24	estimate of the truth. 
25		Now, you have heard the firm's arguments of why a 

				225 1	treatment effect is, in fact, the way to interpret the two
	2	studies, and a lot of this has to do with personal judgments 
	3	about how you get there with evidence, and I guess we want 
	4	to hear yours.  How do you see the evidence in these trials? 
	5		DR. DRACHMAN:  The question that then would arise 
	6	is what is the stage of the Japanese study that is ongoing
	7	and when might one expect those results. 
	8		DR. GILMAN:  I would be glad to get an answer to 
	9	that, but is that relevant? 
10		DR. DRACHMAN:  In a way I think it is.  If we are 
11	sort of uncertain about what we would do, we might say we
12	need a third look, and knowing when that would be or whether 
13	that would be might be helpful in thinking about how we 
14	would decide. 
15		DR. GILMAN:  Well, it seems to me we are here 
16	being asked to evaluate the evidence that is at hand, is it
17	sufficient for us to recommend a treatment IND. 
18		Dr. Temple. 
19		DR. TEMPLE:  The reason I was dancing is that we 
20	don't want you to review the NDA now.  We don't have the NDA 
21	now.  So we are not asking you that.  I think we agreed

22	ahead of time that that was not really the question. 
23		At the same time, some of the things you think 
24	about these two studies could have implications for what 
25	everybody does, and we did think it was worthwhile to find 

			226 1	out how you thought about that.
	2		I would agree with Paul.  We would very much like 
	3	to hear what your assessments of the two studies are and 
	4	what they mean, and as I tried to say, your assessments have 
	5	something to do with what Cephalon is going to take back and 
	6	what we are going to take back, but we are not asking you to
	7	decide on the NDA.  We don't have it.  You don't have it.  
	8	It has not been submitted.  And that would not be fair or 
	9	right. 
10		DR. GILMAN:  I would like to focus us on the 
11	question about whether there is sufficient evidence at this
12	time from what we have seen -- again, I would very much like 
13	to hear from the committee their thoughts about 1200 and 
14	1202. 
15		Dr. Khachaturian. 
16		DR. KHACHATURIAN:  I am not quite clear about

17	procedurally what we should do.  I get the sense that we 
18	have been given quite a bit of lemons and being asked to 

19	make lemonade, and the question is I am not sure what is the 
20	best way to go about doing it. 
21		We are being told there are two studies, and the
22	question is whether an IND should be granted, and if an IND 
23	is granted, then, we also hear that they would be coming 
24	with an NDA, and if they come with the NDA, given the 
25	likelihood is it might not get approved.  So the question is 

			227 1	what is the best strategy that we could use to solve a major
	2	problem, health problem that people are facing, what is the 
	3	most expeditious way to proceed through where we could 
	4	fulfill the requirements of the law for the IND. 
	5		My understanding is that there needs to be just 

	6	sufficient evidence, and the question is do we have enough
	7	of that, at the same time, looking at the whole long-range 
	8	implication of what is the best approach to take, so that 
	9	this disease can be -- at least a treatment could come for 
10	this disease. 

11		DR. TEMPLE:  We think your first job is to tell us
12	whether you think the evidence, those two studies looked at 
13	together, support, provide "sufficient" evidence -- 
14		DR. KHACHATURIAN:  Couldn't we say just one is 
15	enough, throw the other one out, or are we obligated to look 
16	at both?
17		DR. TEMPLE:  No, you don't have to reach the 
18	decision that way.  You can look at them both, you can make 
19	your decision primarily on the basis of 1200 and merely 

20	concluded that 1202 doesn't cause you to think it is not 
21	sufficient anymore.  You are completely flexible on that. 
22	There is very little track record, so you are very free. 
23		It was our thought, though, that what you said 

24	about the studies could have some importance to everybody.  
25	So focus first on is there enough evidence, is it reasonable 

					228 1	to have a treatment IND, which could mean very substantial
	2	distribution, and you have heard from Monroe that they don't 
	3	plan to charge.  We don't address that question or actually 
	4	care one way or the other. 
	5		Maybe think about that first, and then we will get 
	6	to the due diligence question, which is I think a very
	7	complicated question. 
	8		DR. GILMAN:  I would like to take it step by step 
	9	actually, so I would like to hear the committee's view of 
10	Study	1200.  Do you think that has provided good, clear 
11	evidence of an effect?
12		DR. KHACHATURIAN:  Yes. 
13		DR. GILMAN:  Dr. Khachaturian, yes. 
14		Dr. Kawas? 
15		DR. KAWAS:  Yes.  Can I go ahead and comment? 
16		DR. GILMAN:  Please go ahead.
17		DR. KAWAS:  To my mind, we have been told that 

18	substantial is two studies, and substantial is what is 
19	necessary for an IND which we are not -- 
20		DR. GILMAN:  NDA. 
21		DR. KAWAS:  -- NDA, which we are not discussing
22	today. 
23		DR. GILMAN:  Correct. 
24		DR. KAWAS:  So the question is, is one study 
25	sufficient, because I think I certainly feel that the OO 

			229 1	study is compelling information to suggest both efficacy and
	2	reasonable safety for this compound. 
	3		The second study, however, does not provide either 
	4	to my mind.  I am not convinced that there is efficacy in 
	5	the second study, nor am I convinced that there is a 

	6	difference in the mortality rates in the second study.
	7		So for me personally, the second study is more 
	8	non-informative rather than specifically negative. 
	9		So I feel that I personally have one study, and 
10	the only question I am not completely certain of in my mind 
11	is, is one study sufficient.  I think that is sort of what

12	we are going around here with, is one study sufficient for a 
13	treatment IND, and if we suggest that it is, to what extent 
14	will that decision continue over time is another question I 
15	have.  That is not our worry. 
16		DR. GILMAN:  Let me try to respond to a couple of
17	points you made.  First, the matter of what is sufficient.  
18	I would think that if we view Study 1200 as demonstrating 
19	efficacy that is convincing to us, that that is enough.  
20	Even if we have a second study that doesn't show it, I would 
21	think in my mind that would be enough to show that there is
22	sufficient evidence for an IND. 
23		With respect to an NDA, that is not a question 

24	before us today.  It is true that we have to think about 
25	what might happen in the future, nevertheless, we are not 

			230 1	being asked by the FDA to make any sort of statement about
	2	an NDA, only an IND today. 
	3		With respect to the issue of substantial equating 
	4	to two trials, that is, do you need two trials for 
	5	substantial evidence.  I think the answer to that is no.  I 
	6	have in my time seen one trial come here and be approved.
	7		Dr. Leber, you are not agreeing with that. 
	8		DR. LEBER:  We have several people here, one more 
	9	senior than I from the agency, but I think we usually say if 
10	you look at the law, under the current law, ordinarily more 
11	than one adequate and well-controlled is the standard.
12		There have been occasions, which Dr. Temple will 
13	be happy to review, but we have found the evidence from a 

14	single trial so overwhelmingly compelling, robust and 
15	consistent, that even though nominally a single trial, we 
16	have decided that it served the purpose of independent
17	corroboration and replication, which is a scientific basis, 
18	I can't say enough about the legal history to know that it 
19	was the basis in law for the requirement that we have 
20	interpreted as being more than one. 
21		As a general rule, under the FD&C Act.  Now, if

22	you are talking about a decision made under the Public 
23	Health Service Act that dealt with the biologic product, and 
24	I think you may be, betaseron? 
25		DR. GILMAN:  I am thinking of betaseron. 

					231 1		DR. LEBER:  That is even more complicated because

	2	that Act, which began four years before the original Food 
	3	and Drug law, has a slightly different set of wording and 

	4	standard, and although we are moving toward I think a common 
	5	standard, that was exceptional, and I wouldn't use betaseron 
	6	as a precedent.  It certainly happened, but -- and it was
	7	also an accelerated approval. 
	8		DR. TEMPLE:  Accelerated has nothing to do with 
	9	the number of studies. 
10		DR. LEBER:  No, but it was a factor in that 
11	decision.
12		DR. TEMPLE:  I think you are actually saying the 
13	same thing, and the usual way we say it is you need two 
14	studies, but sometimes you don't. 
15		DR. LEBER:  But the fairness is what is the most 
16	common --
17		DR. TEMPLE:  You are right, the usual reason is 
18	that the study is very powerful, has internal replication.  
19	There is some reason that makes you think you don't, and 
20	working on defining that is of some importance, but I think 
21	you are actually both saying the same thing.
22		DR. GILMAN:  I think we should get back to the IND 
23	and what is before us today. 
24		In the minds of the committee, is there sufficient 
25	evidence today?  Does anybody else want to comment?  Dr. 

			232 1	Coyle.
	2		DR. COYLE:  Well, as I have heard the evidence, I 
	3	would think that 1200 seems to be a positive study, and 1202 
	4	seems to be a negative study, and that is a little bit of a 
	5	problem for me with regard to potential NDA in the future, 
	6	and I would urge the company to consider another clinical
	7	study. 
	8		DR. GILMAN:  Dr. Zivin? 
	9		DR. ZIVIN:  We have been discussing the 1200 study 
10	as being positive, and by standard statistical methods I 

11	suppose it probably is, but, in fact, it is really a very
12	weak positive result. 
13		I believe that the reason that the 1202 study is 
14	negative or at least not positive is because just by random 
15	chance when you have only a marginal effect, that it is 

16	logical to expect that the next time around you may very
17	well miss just because of the weakness of the overall 
18	effect. 
19		I am a bit disturbed to hear that there isn't 

20	really a good plan for additional research in this field, 
21	because as far as I am concerned, that is the purpose of an
22	IND, and if the company has solid plans for doing that, 

23	then, I have less trouble with approving an IND, but if they 
24	don't, then, I don't know where we are going from here and 
25	maybe it's nowhere. 

				233 1		DR. GILMAN:  Dr. Copple.
	2		DR. COPPLE:  I would concur with what Dr. Zivin 
	3	said.  It is semantic somewhat.  I certainly agree there was 
	4	an effect demonstrated in 1200, but I regard it as weak, not 
	5	compelling or robust.  1202, I don't think there was any 
	6	effect demonstrated, and I too would like to see a third
	7	study, because the bulk of the evidence taken in aggregate 
	8	is negative with both studies. 
	9		DR. GILMAN:  Dr. Adams? 
10		DR. ADAMS:  I think the issue that bothers me in 
11	both studies is mortality, yet, I understand the primary
12	hypothesis is to halt progression.  In the safety analysis, 
13	we were told that most of the deaths were due to the effects 
14	of ALS. 
15		I am disappointed that we do not have an effect in 
16	a positive way in mortality, and in fact, in the European
17	study a higher mortality presumably from ALS, which to me is 
18	a sign of progression.  The patient died of the disease. 

19		I would like -- and maybe it could still be done 
20	in the afternoon -- is somehow to look at the endpoint of 
21	death being equal to at least 115, and the vital capacity as
22	evidence of an endpoint.  If these patients are truly dying 
23	of the disease which we are trying to treat, to me, this is 
24	a very important endpoint and would greatly influence how I 
25	respond to the decision. 

				234 1		DR. GILMAN:  Other comments about efficacy?
	2		DR. TEMPLE:  My understanding is we do know that 

	3	endpoint for both studies, and for 1200 it doesn't make too 
	4	much difference because the deaths are approximately evenly 
	5	distributed, so it doesn't make much difference, and that 

	6	for 1202, as we heard, the p value already not significant,
	7	gets higher because the deaths went slightly the wrong way. 
	8		I think we know.  1202 still doesn't look so good, 
	9	and it doesn't affect 1200. 
10		DR. GILMAN:  Exactly.  Any other comments about 
11	efficacy?
12		If not, let's move on to safety.  Dr. Temple? 
13		DR. TEMPLE:  I guess I hear some disparate views 
14	about how enthusiastic one should be about 1200.  I wonder 
15	if we could explore why people perceive it differently, just 
16	so we will understand it.
17		DR. GILMAN:  All right.  I saw it personally as 

18	convincing with respect to an effect in the measures used, 
19	which were the slope of decline and to me the effect was 
20	positive.  It did not reverse the disease.  It depends on 

21	what one means by a truly magnificent effect.  This is not a
22	magnificent effect.  This slowed the decline to some extent.  
23	That is how I would phrase it.  I wonder if other committee 
24	members want to comment. 
25		DR. ZIVIN:  One of the biggest problems that I had 

			235 1	with the design in both of these trials is the endpoint, and
	2	the reason I am comfortable with it is because I am not 
	3	convinced that this is a logical way to evaluate the 
	4	disease. 
	5		This type of rating scale is a conglomeration of a 
	6	variety of things, which wasn't necessarily logically
	7	constructed for testing drug effect.  It may have been quite 
	8	useful for testing natural history, but I think that it 
	9	complicates the interpretation of the data, because I think 
10	it increases, as a matter of fact, the variance by putting 
11	these various different things together.
12		This committee struggled quite a bit with the 
13	riluzole issue last year, and the reason that I believe it 
14	got approved at that time for an NDA was because it had a 

15	hard endpoint, which this one doesn't. 
16		I am not trying to compare the relative merits of
17	the two drugs.  All I am trying to do is compare the 
18	relative merits of the trial design, and I believe that the 
19	riluzole trial design was superior. 
20		DR. TEMPLE:  If you can get a mortality endpoint, 
21	then, you get a mortality endpoint, but you don't always
22	have to have a mortality endpoint, and if you don't expect 
23	one, what should you do?  How should you measure it? 

24		DR. ZIVIN:  I wasn't expecting a mortality 
25	endpoint.  I think that time-to-criterion endpoint is a more 

			236 1	logical way to approach this type of a problem.
	2		DR. TEMPLE:  Actually, that was successful, wasn't 
	3	it? 
	4		DR. LEBER:  I would like to ask Dr. Adams 
	5	something.  This is actually an issue that came up a long 
	6	time ago.  You obviously can get continuous measures on
	7	individuals, and therefore you can have everybody 
	8	contributing to the data set. 
	9		If you look at events, time-to-events, only a 
10	fraction of the individuals randomized will contribute 

11	information that counts.  So, generally, to do a time-to-
12	event, where the event is fairly uncommon over the time of 
13	the trial, requires a much larger trial to generate enough 
14	events. 
15		So generally a trial that is powered to look at a 
16	continuous measure, as this one was, will be underpowered
17	with respect to the ultimate goal here, which is delaying 
18	death and delaying -- another thing might be in keeping you 
19	in a stage of the illness which is relatively mild and non- 
20	compromising if you are not changing death, and making the 
21	period of time you traverse the very bad portion of the

22	disease very rapid, but keeping you as long as possible 
23	doing well. 
24		Now, those would be reasonable things to do.  
25	Unfortunately, or fortunately, this sponsor has a right, and 

			237 1	as I told you earlier, to propose a treatment that is not
	2	for everything.  Remember, we approve drugs for the claim 
	3	made for the sponsor.  So that is legitimate. 
	4		You have a right to say that is not an appropriate 
	5	way -- that is what we struggled with dementia -- to 
	6	evaluate a drug for this use, but as has been put, many
	7	experts in the field thought it was, and they did it. 
	8		I certain take your point, Dr. Zivin.  It would be 
	9	much nicer if trials were longer, so we could really know 
10	their ultimate effect in controlled trials on mortality and 
11	the staging of disease you were in, but as somebody pointed
12	out earlier from the sponsor, that requires that patients be 
13	assigned in a randomized way to a treatment they don't want 
14	to be on for a long period of time.  So there is no easy way 
15	out of this box. 
16		We need to know what you think of this study as
17	designed, and I think if you are going to say you don't 
18	believe that any trial that doesn't look at mortality should 
19	be relied upon -- is that your point, Dr. Zivin, or are you 
20	willing to settle for less? 
21		DR. ZIVIN:  Oh, I was willing to settle for less. 
22	I wasn't talking about mortality.  They had a variety of 

23	reasons for censoring the patients, and they might be able 
24	to collect them together. 
25		DR. GILMAN:  Other comments? 

				238 1		DR. TEMPLE:  Have we pinned down satisfactorily

	2	the nature of the difference?  I hear some people saying, 
	3	well, I am reasonably impressed with 1200, and other voices 
	4	that say not so. 
	5		In addition to the slope score, which was the 

	6	primary analysis, there was an endpoint score, and it was
	7	favorable, right?  Am I remembering that correctly?  
	8	Endpoints of score over 115 plus -- 
	9		DR. LEBER:  The first trial used a slope analysis, 
10	and the second trial changed at -- 
11		DR. TEMPLE:  I know, but if you just look at
12	people who drop out because they have reached an endpoint, a 
13	pulmonary endpoint, a 115 endpoint or death. 
14		DR. LEBER:  Those are, in a sense, not clinical 
15	trial endpoints.  Those were safety reasons for withdrawing 
16	people because they couldn't measure them.  They couldn't
17	get them back to clinic. 
18		I think if you look at the protocols, that is not 
19	what they said they were.  It is in retrospect. 
20		DR. GILMAN:  Dr. Gennings. 
21		DR. GENNINGS:  I was just going to say I think it
22	is important for us to realize and to remember that the 1200 
23	trial did play the game correctly.  I mean they had 
24	prospective endpoints, and they showed that -- whether or 

25	not you agreed with the choice of the endpoint -- they were 

			239 1	able to show significance on that endpoint.
	2		Now, I think all of us would have liked to have 
	3	seen bigger differences  or more effects, but nevertheless, 
	4	it was significant.  1202, unfortunately, was not that 
	5	clear, and I think all the -- I will use the word "games" -- 
	6	that were played to show a difference just sort of muddied
	7	the water.  I think that 1202 is not very compelling at all, 
	8	and I am weighing what I would think about efficacy on 1200 
	9	only. 
10		DR. GILMAN:  Dr. Snead. 
11		DR. SNEAD:  I would just like to reiterate the

12	latter part of Justin's comment, because I know it is a 
13	major concern of mine, and that is I think that 1200 showed 
14	efficacy, I think that 1202 did not show efficacy, but the 
15	problem that I have is that the sponsor doesn't appear to 
16	have a plan for another trial, which in my mind is needed.
17		So if there is a treatment IND, is there going to 
18	be another trial or not? 
19		DR. GILMAN:  I am not sure that we need to know 
20	yes or no with respect to another trial if we believe the 
21	evidence before us suggests there is sufficient evidence for
22	an IND. 
23		DR. SNEAD:  I had the impression from Dr. Leber 

24	that -- I guess the question I am asking is can we make that 
25	a caveat of our vote? 

				240 1		DR. LEBER:  You are free to do anything you want.
	2		DR. GILMAN:  I believe the sponsor is here and is 
	3	listening intently. 
	4		DR. SNEAD:  Because I think that is a lot of our 
	5	major concern at this table, quite frankly. 
	6		DR. GILMAN:  Yes.  Dr. Temple.
	7		DR. TEMPLE:  Just one point.  As Monroe Klein 
	8	said, you could argue that the fact that an NDA is coming in 
	9	represents one version of due diligence.  I don't want to 
10	try to settle that issue, but I wouldn't dismiss that 
11	argument.
12		So it may just be that the sponsor is entitled to 
13	do that -- I mean the sponsor is entitled to submit an NDA, 
14	and it may be that we would reach the conclusion that is due 
15	diligence for this purpose, but I, nonetheless, believe it 
16	is very helpful to hear what your view of the total data is
17	and that that will prove helpful to all of us.  So I think 
18	you are doing fine as far as this goes, and I don't think 
19	you have to worry too much about some of these things. 
20		You are saying what you think, and I think that is 
21	fine.
22		DR. GILMAN:  I have not heard anybody in the 
23	committee say that they think 1202 is a study that shows 
24	convincing benefit, and I guess what we doing now is trying 
25	to hear what people think about the quality or the extent of 

			241 1	the benefit in 1200.  That is what Dr. Temple was asking us
	2	to express here.  Can we continue?  Anybody else want 
	3	comment?  Dr. Kawas. 
	4		DR. KAWAS:  I will just answer Dr. Temple's 
	5	question.  The reasons why I think 1200 is a reasonably 
	6	compelling study have to do with, first of all, the fact
	7	that the measures were defined ahead of time, and the study 
	8	was carried forth according to the rules. 
	9		The endpoints, while I agree with Dr. Zivin, there 
10	is not a harder endpoint than point, but the fact of the 
11	matter is that many studies like this require clinical
12	endpoints, and in fact, the study used multiple measures, 
13	most of which supported the fact that those patients in the 
14	1200 trial did improve. 
15		So the 1200 study is I think a positive study, but 
16	like most people here, I don't find the other study
17	satisfactory for compelling evidence. 
18		DR. GILMAN:  Dr. Khachaturian. 
19		DR. KHACHATURIAN:  I agree with most things that 
20	were said about the 1200.  My additional comment is that I 
21	look at the weakness of the effect attributed to perhaps the
22	heterogeneity of the disease, that there are subsets perhaps 
23	that are far more beneficial than to others, and there is 
24	that phenomenon that we need to keep in mind.  For that 
25	reason I would like to give the benefit of the doubt to 1200 

				242 1	and make sure that there is another trial done to prove it.

	2		DR. GILMAN:  Dr. Temple, have you heard enough? 
	3		DR. TEMPLE:  Yes. 
	4		DR. GILMAN:  Let's deal with the issue of safety 
	5	then.  In my own mind, there were no compelling reasons to 

	6	believe that this is an unsafe drug, as we have heard today. 
	7	We heard that there were many deaths.  That is the expected 
	8	in the course of this terrible disorder.  I didn't hear any 
	9	concern except for the mild side effects, and they were 
10	portrayed as a whole list of various abnormalities, 
11	symptoms, and some signs, but they are common in the course
12	of amyotrophic lateral sclerosis. 
13		So I didn't have particular safety concerns.  Let 
14	me hear what the committee thought. 
15		[No response.] 
16		DR. GILMAN:  Does silence mean approval or silent
17	disapproval? 
18		DR. ZIVIN:  It means approval for me. 
19		DR. GILMAN:  I think at this point, unless anybody 
20	wants to hear more or speak more about this, we should then 
21	turn to the people who wish to speak.
22		          OPEN PUBLIC HEARING 
23		DR. GILMAN:  The open public hearing is now in 
24	progress.  Seventeen individuals have notified Mr. Bernstein 
25	ahead of time and requested time to comment in the open 

			243 1	public hearing.
	2		When your name is called, please come forward to 
	3	the microphone.  We will use the microphone next to Dr. 
	4	Temple.  Identify yourself and your affiliation and begin 
	5	your statement.  Please limit your comments to five minutes 
	6	or less.
	7		Lynn Klein will read the statement for James 
	8	Rather and Cary Green. 
	9		MS. LYNN KLEIN:  Dr. Gilman, Dr. Leber, and 
10	members of the committee.  My name is Lynn Klein and I am 

11	the Executive Vice President of the National Organization
12	for Rare Disorders, most commonly known as NORD. 
13		I am also a nurse and have been involved with ALS 
14	patients for over 16 years including nine years as Vice 

15	President of Patient Services for the ALS Association. 
16		It is my honor and privilege to appear before you
17	today on behalf of James Rather and Cary Green, two patients 
18	who were unable to make the trip down here, but very much 
19	wanted to testify. 
20		I will start with Jim Rather.  Before I read Jim's 
21	prepared testimony, I would like to take a minute to tell
22	you a little bit about this inspiring man.  James B. Rather 
23	is the husband of Amelia, father of Jim, Ebgenia, and John.  
24	He is a Vietnam veteran, an attorney, and a founding partner 
25	of a major law firm in New York, the latter after he was 

			244 1	diagnosed with ALS.
	2		He has handled a wide range of cases including 

	3	commercial, environmental, product liability, employment, 
	4	and discrimination litigation.  Jim told me his favorite 
	5	work was when he was Assistant United States Attorney for 
	6	the Southern District of New York, where he tried numerous

	7	cases including organized crime, corruption, fraud, and RICO 
	8	prosecutions. 
	9		Among his prosecutions was the conviction of a 
10	major organized crime boss and 10 of his associates for 
11	violations of the Racketeering Influenced and Corrupt
12	Organizations Act, RICO. 
13		Jim has faced the violations and indignities of 
14	ALS with the same strength and confidence and courage he 
15	faced organized crime.  Jim is still working as an attorney, 
16	often spending all day in court.
17		I almost forgot to mention Jim is on life support, 
18	has a feeding tube, and speaks via a computer with a voice 
19	synthesizer.  He is also the recipient of the Muscular 
20	Dystrophy Association's Personal Achievement Award among 
21	many others.
22		Now for Jim's testimony. 
23		My name is Jim Rather.  I have been afflicted with 
24	ALS since spring 1990.  I regret that I am unable to speak 
25	to you in person, but am thankful for the opportunity to 

			245 1	address you through Lynn Klein.
	2		In my youth I saw the excellent movie Pride of the 
	3	Yankees about the great Lou Gehrig who was brought down by 
	4	ALS in the year of my birth 1939.  A scene that made a 
	5	lasting impression on me then, and has come back to haunt me 
	6	since, was of the kindly, sympathetic doctor telling a
	7	gracious and stoic Lou Gehrig that there was no cure for his 
	8	disease.  No cure. 
	9		At the time it seemed impossible to me, and it 
10	still does, although I have been witness to several hundred 
11	courageous lives cut tragically short by this most
12	mysterious and most dreaded of diseases. 
13		I never heard those draconian words from my kindly 
14	and sympathetic doctor, Louis Rowlin, head of the 
15	Neurological Institute at Columbia Presbyterian, but I well 
16	remember the day I first understood my sentence.  I
17	literally saw stars and my mind seemed to explode within my 
18	head. 
19		ALS has a way of sneaking up on people.  It enters 
20	the body innocently and imperceptibly and seems no cause for 
21	alarm.  In my case, it struck in my left foot and I was just
22	aware of less spring in that foot.  If I had not been a 
23	long-distance runner, I might not have noticed that. 
24		I had little concern and expected it to improve 

25	with some chiropractic adjustments.  I lived on in sublime 

			246 1	innocence.  But of course there was no improvement.
	2		A year later it had extended up my left leg and to 
	3	my right foot and leg.  I had run my last marathon and 
	4	wondered why I had been so slow and out of breath.  Initial 
	5	tests were negative for anything. 
	6		When I had my first EMG, the doctor could not
	7	conceal his concerned expression.  He suggested more tests.  
	8	His report stated the possibility of "motor neuron disease."  
	9	I began to read some medical texts and gradually eliminated 
10	less serious conditions. 
11		One day -- and it was one day -- it all came

12	together and I knew I had Lou Gehrig's disease.  What I 
13	could not believe was the description contained in every 
14	neurological textbook, no cure, and three to five years to 
15	live. 
16		I read and read looking for a way out.  I thought
17	there had to be a solution.  I had always found a solution 
18	to serious events.  As a combat airborne infantry platoon 
19	leader, I had always found a solution and survived to tell 
20	about it.  As a federal criminal prosecutor, I had always 
21	found the solution necessary to put the felons away.  There
22	had to be a solution, I thought, there is something for 
23	every disease even cancer.  But there was nothing for ALS. 

24		I decided to keep the diagnosis to myself, I just 
25	could not tell my wife.  I wanted life for her and our three 

			247 1	children to remain normal for as long as possible.  Nor did
	2	I want my four new law partners to be concerned about me 
	3	during the precarious start of our fledgling law firm. 
	4		I told everyone it was some kind of neuropathy and 
	5	it would soon stop bothering me.  As ALS progressed, it 
	6	became clear to me no cure and the unvarying sentence death
	7	in three to five years.  These words haunted me every night 
	8	at every moment.  I felt happiness whenever my children 
	9	spoke of their futures.  It seemed impossible, but the ALS 
10	relentlessly progressed. 
11		There was one glimmer of hope during that period. 
12	It was called Eldepryl, and I was in the clinical trial of 
13	the Eleanor and Lou Gehrig Clinic at Columbia Presbyterian.  
14	What a difference that small pill made.  I believed it was 
15	helping, and to this day I believe it may have helped slow 
16	progression.  It was my lifesaver because I felt it was
17	doing something that might help. 
18		When I finally faced that indescribably terrible 
19	day of telling my family, I was able to couch it with the 
20	possibility of hope.  When I learned of the IGF-1 Myotrophin 
21	clinical trial, I believed it was even more excitingly
22	hopeful than Eldepryl.  I certainly was prepared to accept 
23	any risk, any risk, where there was hope to possibly retard 
24	or reverse this disease that was devastating my body at an 
25	ever-increasing pace, but I did not qualify due to my low 

			248 1	vital capacity.
	2		Death did come for me, on schedule, in December 

	3	1994, however, my departure was deferred by my choice to 
	4	remain alive with a feeding tube and a ventilator.  It was 
	5	not an easy decision and many do not choose to live this 

	6	way, but I still have a strong desire to stay here with my
	7	family and try to help in an effort to find a cure.  Yet, 
	8	ALS is relentlessly continuing to destroy my remaining 
	9	functions. 
10		I have lost the ability to breathe, to eat, to 
11	speak, and to hug.  Even my smile is fading.  I have been
12	through every state of this devastating disease, yet 
13	continue to hope that my condition may be ameliorated. 
14		A great hope for me now, for all of us with ALS 
15	and our families and loved ones, is the potential of 

16	Myotrophin.  I am in almost daily contact with the ALS
17	community throughout the country by computer and know the 
18	great hope engendered by the potential of Myotrophin. 
19		We see to you let us have our hope.  It does not 
20	have to be with risk.  We measure our lives in days, weeks, 
21	or months.  We ask for you to help us give hope for one more
22	day without delay. 
23		We deeply appreciate the care and concern of this 
24	committee.  We know you will carefully consider all the 

25	factors.  We urge you to recommend early access for this 

					249 1	most hopeful of drugs, Myotrophin.
	2		Respectfully submitted, James Rather. 
	3		DR. GILMAN:  Thank you, Ms. Klein. 
	4		MS. KLEIN:  I had the second one that I was to 
	5	read. 
	6		DR. GILMAN:  You have one minute left.
	7		MS. KLEIN:  Cary Green. 
	8		DR. GILMAN:  Please. 
	9		MS. KLEIN:  I don't know Cary personally, but I 
10	have spoken with him.  He has been forced into retirement 
11	and he now spends his days watching his brother do his
12	favorite hobby, and that is fishing. 
13		My name is Cary Green.  I am 42 years old and was 
14	diagnosed with ALS in June of 1993 at the age of 39.  I have 
15	developed symptoms beginning with my right hand about a year 
16	prior to being diagnosed.
17		I have three children, ages 17, 15, and 13, who 
18	live with my wife in East Hampton, Connecticut.  Although I 
19	have limited use of my hands and arms, I can still walk with 
20	some difficulty.  I still live independently with the help 
21	of family, friends, and a home health aide.  My speech has

22	most recently become affected.  I am well aware that the 
23	progression of my disease has been slower than most. For 
24	that I am grateful, for it gives me precious time to spend 
25	with my children. 

			250 1		I can without question attribute this slow
	2	progression in large part to the drug Myotrophin produced by 
	3	Cephalon.  I am in the singular position of having more 
	4	experience with Myotrophin as a patient than almost anyone 
	5	else in the world. 
	6		I was the first participant in the Myotrophin drug
	7	study at the University of Connecticut Health Center in 
	8	August 1993.  When the study ended and the results were 
	9	announced in June of '95, I learned I had been on full doses 
10	of the drug for the entire 18 months of the study. 
11		Subsequent to February '95, when I was no longer
12	receiving Myotrophin, my deterioration became increasingly 
13	rapid and frightening.  The pace at which I was losing hand, 
14	arm, and leg function was readily apparent to all who knew 
15	me.  Each week I could measure my loss of strength and 
16	energy.
17		I was forced to retire from my work as CFO of a 

18	large company in October '95.  By January '96, I was no 
19	longer able to dress or feed myself.  It was obvious to me 
20	that Myotrophin dramatically slowed the pace of my 
21	deterioration and I was naturally anxious to get back on the
22	drug. 
23		I lobbied extensively with University of 
24	Connecticut, Cephalon, and the FDA to restart the program 
25	and release the drug for compassionate use.  Although my 

			251 1	friends and family couldn't understand the delay, I soon
	2	learned and accepted the complexities inherent in the 
	3	process.  Finally, after much frustration with misleading 

	4	information, the restart program was approved and I once 
	5	again start receiving the drug in February '96. 
	6		I was told that had I not made the efforts I did,
	7	the program, at least at the University of Connecticut, 
	8	would not have been revived. 
	9		After being on the drug again for four months, I 
10	have noticed my deterioration has once again slowed.  
11	Although it is in no way getting easier to live with ALS, I
12	am able to do things now that I never thought I would be 
13	able to do given the pace at which I had been previously 
14	deteriorating. 
15		It has given my friends, family, and myself 

16	renewed hope in an otherwise hopeless situation.  It is
17	extremely important to note that after taking Myotrophin for 
18	almost two years, I have had no adverse side effects.  
19	Concern with side effects with a disease as insidious as ALS 
20	should, in my opinion, have reduced focus anyway. 
21		Realistically, all one can hope for is a few extra
22	days of quality life.  If, by releasing this drug on a 
23	compassionate use basis, the FDA has the opportunity to 
24	offer this gift to other ALS sufferers, it would be inhumane 
25	not to do so. 

			252 1		Respectfully submitted, Cary Green.
	2		Thank you. 
	3		DR. GILMAN:  Thank you. 
	4		Janice Dorfman, please. 
	5		MS. JANICE DORFMAN:  My name is Janice Dorfman.  I 
	6	am very grateful for the opportunity to be here today
	7	speaking for myself and 30,000 known Americans suffering 
	8	from ALS. 
	9		Each of us has a story to tell, the story of how 
10	our lives and the lives of those who love us were forever 
11	changed.  The details are different, but the story tells of
12	a past that held a promise of a future.  For me it was the 
13	invitation of my beloved husband, grow old with me, the best 
14	is yet to be. 
15		But it was not to be.  ALS, like a thief, robbed 
16	me of a future, made the past too painful to revisit and the
17	present a day to day existence on which I am dependent on a 
18	caregiver to provide all physical needs, such as bathing, 

19	toileting, dressing, and feeding.  My young adult son 
20	toilets me, my elderly parents feed me 50 years after we 
21	began that way.
22		My husband maintains a full time job out of the 
23	home and manages all household responsibilities in addition 
24	to caring for me.  My ALS friends and I have no illusion 

25	about our future.  Without intervention, early death is 

			253 1	certain.
	2		When Myotrophin was first considered for approval, 
	3	I was able to stand, to walk, and to speak without 
	4	impairment.  Anything that slows the daily loss of function 
	5	by this dread demon of disease must be made accessible to 

	6	patients on a fast track regardless of the risk involved.
	7		Dr. Kessler himself has said that the greater the 
	8	risk, the greater the benefit.  The light of hope provided 
	9	by Myotrophin gives us back the future, the promise of a 
10	future.  For those in the early stages of disease, it means 
11	being able to maintain independence longer, being able to
12	use arms to hug the kids a while longer. 
13		For me, I know I won't be able to walk down the 
14	aisle at my son's wedding, but I want to be there.  I won't 

15	be able to find my daughter's first child, but I want to see 
16	my beautiful grandchildren.  I want to say to my beloved,

17	grow a little older with me.  Having this time is a gift. 
18		Please, give us the gift of time.  Give us the 
19	promise of a future.  Give us the light of hope.  Give us 
20	early access to Myotrophin. 
21		Thank you.
22		DR. GILMAN:  Thank you. 

23		Next is Mary Beth Parks. 
24		MS. MARY BETH PARKS:  Good afternoon.  My name is 
25	Mary Beth Parks.  By profession I am a nurse and I am the 

			254 1	owner of Gulf Coast Medical Personnel in Houston, Texas.

	2		Gulf Coast Medical Personnel is a home health 
	3	agency that specializes in the care of ALS patients.  Since 
	4	1983, I have had day to day contact with ALS patients. 
	5		ALS is a family disease.  It may only affect one 
	6	person physically, but it affects the entire family
	7	including the extended family of friends and colleagues. 
	8		It is a disease that leaves us all with a feeling 
	9	of powerlessness since the cause and cure remain unknown.  
10	The treatment has been aimed at managing the symptoms, 
11	assisting the patient to remain as independent as possible
12	for as long as possible with dignity and quality of life. 
13		ALS is commonly known as Lou Gehrig's disease or, 
14	what some people say, Stephen Hawkins has.  I know ALS as 

15	Jim Martin disease.  After a five-year battle with ALS, Jim, 
16	age 36, lived just short of two weeks after holding his
17	first child. 
18		Or William Gray, an Exxon executive, who 
19	discovered his ALS while training for his third triathlon.  
20	ALS has also claimed my lovely Lydia, who was a county clerk 
21	in Brezoria, Texas for 33 years, suffered the initial
22	symptoms of tremors in her hands, and eventually was locked 
23	in entirely except for the slight eye blink. 
24		There is one thing that ALS cannot take away from 
25	these patients, and that is hope, hope that medical science 

			255 1	will find the answers in their lifetime, hope that drug
	2	companies will take the risk and join the fight, and achieve 
	3	success in developing a treatment that will have some effect 
	4	in altering the course of ALS. 
	5		This is not about analyzing data, this is about 
	6	patients living longer and having a better quality of life,
	7	and so, members of the committee, today you have the 
	8	opportunity to recommend early access to Myotrophin for the 
	9	treatment of this hideous disease. 
10		In the words of Atouchette Dish, "I implore you, I 
11	shall pass through this world but once.  If therefore there
12	be any good I can do, let me do it now.  Do not defer it, do 
13	not neglect it, for I shall pass this way but once." 
14		This your chance.  Thank you. 
15		DR. GILMAN:  Thank you. 
16		Next is Linda McKnight.
17		MS. LINDA McKNIGHT:  Good afternoon, ladies and 
18	gentlemen.  Please allow me to introduce myself.  I am Linda 
19	McKnight from Seattle, Washington area. 
20		I lost a wonderful sister to this monstrous 

21	disease.  Since that time, almost four years ago, I have
22	worked extensively with ALS patients across the United 

23	States, Canada, and Europe.  I am here to speak on behalf of 
24	thousands of Americans, the ALS afflicted, their families 
25	and their loved ones. 

			256 1		It is not my role nor do I have the expertise to

	2	address safety and efficacy, but if I could, there is one 
	3	more thing I would include in there, and that would be the 

	4	need for this drug.  I think that is equally as important as 
	5	the two other items, and I think Myotrophin is the drug that 
	6	we all believe could help many people with ALS to fight for
	7	a longer and better life. 
	8		When I first heard of this disease, I was only 
	9	told half-truths.  I was told it was a disease that 
10	paralyzes the muscles of the body, and I am sure that you 

11	are familiar with this.  But that wasn't the whole story I
12	found out later.  It also paralyzes emotions, futures, and 
13	dreams of all of its victims.  It paralyzes what we call 
14	life. 

15		As I look at you, each of you around this table, I 
16	see the same needs that an ALS person has or any human

17	beings have.  I see you want to see your family grow to 
18	adulthood, to share the joys, the triumphs, and even the 
19	disappointments of their lives. 
20		It doesn't matter what age ALS strikes.  To each 
21	age we have our own private dreams and reasons to continue

22	our lives.  To be able to share these moments is what it is 
23	all about. 
24		It is not just the people you see around me here 
25	today.  It is the thousands of ALS patients spread all 

			257 1	across America.  They are so immobile or without speech that
	2	they could not be before you today to express what they 
	3	wanted you to hear.  They wanted so bad to be heard. 
	4		I had calls from all over America from the people 
	5	that knew I was going to be at this meeting today, pleading 
	6	with you that you would hear the message that is sent to you
	7	today. 
	8		I promised each one of them, yes, they are going 

	9	to be heard today, because I packed every one of them in my 
10	heart and I promised each one of them that, that I would 

11	speak to you, but it is your voices that they are hearing
12	today.  Each one of them stand before you. 
13		It is my heartfelt hope that you would take the 
14	great consideration, the right of ALS patients to make 
15	choices.  That has been so denied ALS patients for over a 
16	century.  All they want is the right of choice.  Their
17	physical sense may be in array, but they and their 
18	physicians are 100 percent capable of making these informed 
19	choices that so affect their future and control of their own 
20	bodies within this life struggle. 
21		Ladies and gentlemen, because ALS is a smaller
22	population disease, it is overlooked by so many of the drug 
23	companies.  I so respect and applaud every step that 
24	Cephalon has put forth for all ALS patients to bring this 
25	drug before you today. 

			258 1		I fully realize what these trials entail and
	2	without them we would be lost forever to this devastating 
	3	disease.  I thank you, Cephalon, from all the patients 
	4	across America.  Thank you. 
	5		One thing that I didn't have, that I was going to 
	6	say to you, and it happened to me last night.  We had a

	7	dinner and at the dinner a patient walked up to me and 
	8	handed me a picture of his two little children.  Somehow 
	9	with my travels in the ALS community I guess I kind of lost 
10	track of the fact I was so involved that it was a patient 
11	and give help to the patient, that somehow I had forgotten
12	the children of all these patients. 
13		So this meeting isn't just about the patient, it 
14	is about the children.  Give them a choice also to have 

15	their parents be with them and to do things with them, 
16	because it is about the children of these patients, too.
17		Also, I talked at length, about an hour and a 
18	half, just before I caught the airplane, which was real 
19	early a patient called that had been on the Myotrophin 

20	trial.  He has been on the trial since the beginning of it, 
21	and he mentioned to me, he said, Linda, he said you have got
22	to do something, you have got to let these people know that 
23	if it wasn't for the Myotrophin, I wouldn't be talking to 
24	you right now, and I feel in my heart that is the only 

25	reason why I am talking to you is because of Myotrophin. 

			259 1		So if you find that this drug in any way may in
	2	any little way may be effective, these people want so much 
	3	this option of choice. 
	4		Yes, I realize that there are many variances in 
	5	any drugs, but I carry the belief along with patients within 
	6	my heart today that many are willing to take a greater step
	7	for a drug if a potential of even just a touch of benefit is 
	8	there. 
	9		Ladies and gentlemen, we look towards this panel 
10	to give the ALS community the availability of that choice. 
11		Thank you from all of us for your time and
12	patience. 
13		DR. GILMAN:  Thank you. 
14		Don Altier. 
15		MR. DON ALTIER:  I was asking Linda if you had all 
16	gotten a picture like the one I showed Linda last night of
17	me and my sons. 
18		My name is Don Altier.  I am 36 years old and I 

19	have ALS.  I have traveled across the country to ask for 
20	your help in my battle to live each day God gives me as 

21	fully as possible.  I was diagnosed with ALS on October 13,
22	1992, one day after my wife Carrie and I found out that we 
23	were expecting twins. 
24		My wife and I had long looked forward to being 
25	parents.  From the time I was a young boy I had always 

			260 1	wanted to be a daddy.  We were both thrilled to find out she
	2	was going to have twins.  Only 24 hours later, we were 
	3	devastated by the prospect of my impending paralysis and 
	4	ultimate death as predicted by the diagnosis of Lou Gehrig's 
	5	disease. 
	6		We were both only 32 years old and had just found
	7	out our dream of being parents had come true and now we were 
	8	being faced with the nightmare of my having a terminal 
	9	illness with no known cause of available treatment. 

10		I sought out hope even though the situation 
11	appeared to be hopeless.  Our unborn twins cried out to be
12	from my wife's womb don't give up on us, daddy, don't give 
13	up. 
14		One doctor advised us that this was no time to be 
15	having a baby.  I advised him that we were going to have 

16	twins and that furthermore I was going to find a way to win
17	my battle with ALS. 
18		My research led me to late Dr. Forbes Norris, a 
19	renowned ALS specialist who was involved with a clinical 
20	trial of IGF-1.  There was hope.  Due to the fact that my 

21	disease progression was slow, however, I did not qualify for
22	the Myotrophin study. 
23		I was able to participate in another clinical 
24	trial for CNTF.  Unfortunately, I got placebo for a nine 
25	month double-blind period.  After one year on open label, I 

			261 1	was told that CNTF had not shown efficacy.  I take Eldepryl,
	2	neurontin, lots of vitamins, practice yoga, and pray for the 
	3	strength and wisdom to make it through another day smiling 
	4	despite the muscle and joint pain that is constantly trying 
	5	to get me to give up.  Every day is a victory. 
	6		Being able to see my sons' birth and to hold them
	7	and give them their first bottles was a miracle I will never 
	8	forget.  On May 13th, we celebrated Trevor and Brian's third 
	9	birthday.  We have been constant companions since the moment 
10	they were born. 
11		My wife works full time and I stay home and take

12	care of them, and I hope that I will be able to do that for 
13	a long time.  They have filled our lives with their joy, 
14	their innocence, and their endless love of live.  They have 
15	given me the inspiration to fight, to live and love life 
16	with an energy that I did not know I ever possessed.
17		Sometimes I am overwhelmed by how hard simple 
18	tasks become as ALS progresses, and I say to my wife I have 
19	had enough, I give up.  She replies look your sons in the 
20	eye and say that, and I immediately realize that giving up 
21	is not an option for me.
22		Today, when you cast your vote, look at the 
23	picture of me and my sons' smiling faces, and I believe you 
24	will decide you cannot give up on us.  Remember, there are 
25	thousands of families like ours waiting for anything that 

				262 1	will help ALS victims stronger and more independent.
	2		I will accommodate this disease, but I will never 
	3	surrender to it. 
	4		ALS patients have had patience enough.  It is time 
	5	to take the next step towards defeating ALS and approve a 
	6	drug shown to be safe and effective in slowing down the
	7	muscle weakness that plagues those affected by Lou Gehrig's 
	8	disease. 
	9		Many people have said to me since my diagnosis 

10	that they wish there was something they could do to help.  
11	Today, you have the opportunity to do something.  By helping
12	to reduce the rate of progression, Myotrophin can help us 
13	battling ALS, to hug a loved one for longer, to be able to 
14	play with our children, to enjoy the simple pleasures that 
15	most take for granted, eating, talking, and breathing for a 
16	bit longer is all we are asking for.
17		All we are saying is give us a chance.  Let's put 

18	Dr. Kevorkian on terminal hold by giving people with ALS and 
19	their families hope.  Suicide is not the solution to ALS.  
20	Access to effective drugs is the key part of keeping us 
21	alive and full of hope to await the next breakthrough in
22	ALS. 
23		We are fighting this disease with all our will and 
24	spirit.  We are counting on you to fight for us, too. 
25		In the words of Dr. David Kessler, Commissioner of 

			263 1	the FDA, as quoted in Newsday, March 1st, 1994, "When people
	2	are suffering and dying from a devastating disease, we 
	3	cannot wait for all the evidence to come in, for all the i's 
	4	to be dotted and all the t's crossed.  We must be prepared 
	5	to accept greater risk from a drug when greater benefits are 
	6	possible.
	7		 I am here today to cross a t for my son Trevor, 
	8	give you a B for my son Brian, and a C for my wife Carrie, 
	9	and lastly, to dot an i for all the eyes focused on the hope 
10	that today the next step towards a cure for ALS will be 
11	taken.
12		On behalf of all the ALS families fighting for 

13	hope, I thank you for your compassionate consideration of 
14	our situation. 
15		DR. GILMAN:  Thank you. 
16		Ben Gill, please.
17		MR. BENJAMIN GILL:  Ladies and gentlemen, my name 
18	is Benjamin Gill.  My speech is slow and tortured.  I will 
19	focus on two issues, time and hope. 
20		I was diagnosed with ALS two and half years ago.  
21	ALS patients understand the relentless, progressive nature
22	of this disease.  We know well that in the next several 

23	years or less, several of us here today will not be here. 
24		Will there be time, will medicine provide the 

25	answer to ALS in our lifetimes?  We do not have the answers 

			264 1	to such questions, but all of us have hope.  Hope is the
	2	most precious possession of an ALS patient.  That is why we 
	3	are here today, hope. 
	4		Last summer, the FDA approved access to riluzole.  
	5	I was a lucky one out of the lottery to receive this drug 
	6	while the approval process continued.
	7		I started Rilutek in October and continue it 
	8	today.  Rilutek has been of modest benefit for ALS patients 
	9	and we know that your decision was a close one.  I submit 

10	modest is a relative term, particularly to an ALS patient 
11	who can find hope in many small things including a drug that
12	might retard progression of the disease, a drug which 
13	researchers may find even more definitive benefits, and a 
14	drug that with other drugs may be the combination that 
15	actually arrests progression.  That, I submit is real hope. 
16		It also buys time.  Even if Myotrophin only has

17	mild benefits, has only several months, those extra months 
18	of modest treatment may allow parents to share a little bit 
19	mortality of a child's life, may enable an individual to 
20	enjoy a few more good days on this earth.  You can't measure 
21	that.
22		Quite frankly, unless you know today that 
23	Myotrophin is a fraud or is unsafe, the decision on early 

24	access should be made.  The manufacturers are willing to 
25	make it available, and it has demonstrated some positive 

			265 1	characteristics in dealing with ALS.  It provides hope and
	2	may well provide additional time to ALS patients.  There is 
	3	no doubts on it. 
	4		But you may say the FDA does not want to raise 
	5	false hopes among ALS patients and that you wish to protect 
	6	us.  I submit that we are experts in the category of
	7	realistic hope.  We know Myotrophin is not a magic bullet.  
	8	We know it may end up providing only modest benefits or non- 
	9	robust benefits. 
10		We accept that as a risk, are more than willing to 
11	take those risks for giving a potential reward involved.
12		[Portion not understandable.] 
13		That is not a false hope, but rather a rational 
14	request for immediate action.  I would be remiss if I didn't 
15	take this opportunity to also request the FDA to immediately 
16	adopt new criteria that will allow for expedited approval.
17		Thank you for your attention. 
18		DR. GILMAN:  Thank you, Mr. Gill. 
19		Christopher Pendergast. 
20		MR. CHRISTOPHER PENDERGAST:  My name is Chris 
21	Pendergast and I have come here to address this
22	distinguished panel, to present the perspectives of a 32- 
23	month combatant of the war on amyotrophic lateral sclerosis. 
24		I am in the front lines, down in the trenches, and 
25	fighting like hell for my life.  Though perhaps I might be 

			266 1	already mortally wounded, I have refused to yield.
	2		I, as well as 30,000 fellow Americans, have been 
	3	called to do battle with this horrific, seemingly invincible 
	4	and damnable foe and battle we will.  We will challenge it 
	5	on every front.  Some of those challenges will be poignantly 
	6	personal as we come to terms with living with ALS, and some

	7	of those challenges will be very public, as is this forum 
	8	today. 
	9		The battle is intense and the time is bitterly 
10	short, but before I succumb to this monster, I will do 

11	everything in my power to see it defeated.  I will not go
12	lightly and I will not go quietly. 
13		So I stand here before you today because by the 
14	grace of God I can still stand.  I can plant my two feet 
15	firmly in front of you and I can stand up and I can ask to 
16	be counted.  I am talking to you today because by that same
17	grace, I have a voice that can still be heard. 
18		I have not yet been silenced and therefore I can 

19	be a clarion and cry loudly and clearly our unified appeal.  
20	You realize, of course, that I am a lucky one.  I know not 
21	why, but I am.  There were four patients who began this
22	struggle with me two and a half years ago.  We were a group 
23	knotted in hope and in fear into a support session.  They 

24	are all dead. 
25		Their names I shall forever remember:  John 

			267 1	McPartland, Ronald Lichtenberg, Pat Stevens, and just last
	2	month, the last member of our group, Paula Shefrigo. 

	3		Since my diagnosis on Columbus Day in 1993, 
	4	perhaps 15,000 others have died.  Going all the way back to 
	5	Lou Gehrig himself, felled in less than two years in the 
	6	prime of his life, at 37, perhaps 300,000 have died.
	7		Who have lamented their passing except our own 
	8	tiny band?  Who marshaled energy in support for them?  
	9	Nobody.  How can I let these fallen friends be forgotten?  
10	They had no voice, they had no mass protests, they had no 
11	media focus.  They had no stamps.  Instead, they had
12	obscurity and benign neglect. 
13		What have we done to deserve this disease or what 
14	have we done to develop it?  We relentlessly recall each 

15	detail of our own lives searching for answers.  Did we 
16	innocently expose ourselves to toxins, are we victimized by
17	pesticides or attacked by a slow-acting virus? 
18		Is it genetically coded?  Do we have faulty immune 
19	systems?  Ah, like so many other top killers, heart disease, 
20	lung cancer, and AIDS, mostly they result from lifestyle 

21	choices, and they could be nearly eradicated with a change
22	in those choices.  Oh, if we only had that choice.  But no, 
23	our sufferers slip into their graves hushed in silence and 
24	despair, and their numbers are only medical enigmas. 
25		But no more, never again.  I am here for them.  I 

				268 1	am also here for the person who is going to die in the next
	2	90 minutes as we deliberate, and that person who will die 90 
	3	minutes thereafter, day in and day out. 
	4		I am here, too, for the 6,000 who will be 
	5	diagnosed this year.  But be clear, I am not here as a 
	6	statistic, I am a vital human being.  I am your neighbor.  I
	7	am your child's teacher.  I am a volunteer naturalist.  I am 
	8	the gentleman at the end of the two at church. 
	9		I want you of the panel to look at my face and to 
10	see me.  I am real.  When this disease kills, it doesn't 
11	kill a number, it kills me.  We are not just case numbers or
12	a data point on a statistical curve.  We have faces, we have 
13	names, and we have families who love us, and we have jobs 

14	left unfinished, gardens that wasted hands can no longer 
15	till, children to lift but arms too weak, paths to journey 
16	but legs unable to bear, voices to sing, songs to sing, but
17	voices too frail. 
18		We have breaths to breathe and lungs and chests 
19	too weak to draw.  Look at my face and see us all.  We have 
20	suffered and we have died tormented.  No cures, not even 

21	potent treatment, absolutely nothing.  How much longer we
22	ask. 
23		Well, you might say this has been an unparalleled 
24	period of research and pharmacological activity.  Research, 
25	regulatory agencies, medical communities are working hard to 

			269 1	conquer ALS, and this may be so.  But who here would deny me
	2	if I held up that glass with water at the midpoint, and I 
	3	claimed it to be half empty even though we both knew it was 
	4	also half full. 
	5		And similarly, who can deny me that we have done 
	6	too little too late?  It is too late for my friends back at
	7	the support group, it is too late for that person dying this 
	8	90 minute, and it may well be too late for me. 
	9		Yet, before you again is a compound that holds 

10	promise in intervening in this disease process.  You have 
11	the statistics, and the scientific studies, black and white
12	tables, plots of curves are there in front of you on that 
13	paper. 

14		But let me ask you, is my picture there with them?  
15	Do you see my 11-year-old son held tightly in my arms after 
16	he has won a hockey game?  Do you see my 19-year-old
17	daughter and I walking proudly arm and arm as she graduates 
18	college next year? 
19		I am those numbers, those charts, those 
20	statistically significant data, that is my life.  Don't we 

21	have a right to ask then, are we too impertinent to want? 
22	Can't we be so bold as to wish? 
23		You have the most difficult task.  You are a 

24	regulator, and you must assess and protect.  A better 
25	medication for an ingrown toenail, a quicker removal of 

			270 1	warts, or something Americans have been waiting for, a cure
	2	to baldness. 
	3		Well, then yes, regulate us, assess us, do strict 
	4	objective, hard science, but, panelists, this, this is a 

	5	medication for ALS.  Where will the balance lie and how 
	6	tightly are you willing to walk that rope?
	7		Let us be part of this solution.  Let us continue 
	8	to have use of the medication.  Give us access to a 
	9	promising compound.  If there is reasonable belief in its 
10	efficacy, don't hold it back in bureaucratic limbo while we 
11	endure a living hell.
12		What else is there for ALS sufferers, pages of 
13	regulations and justifications? 

14		I said earlier we will fight.  Put a weapon in our 
15	hands.  Access hope and promise. 
16		I want to conclude with a brief metaphor using
17	baseball.  Just as Lou Gehrig did for over 2,000 games, each 
18	one of us is in our own batter's box, and the count is 3 to 
19	2, 3 balls and 2 strikes.  It is the last inning, the last 
20	game, it is the end of our career.  And, distinguished 
21	panelists, you are our umpires at home plate.
22		We have one pitch left.  It all comes down to 
23	this.  Let me swing at that last ball.  Please don't call me 
24	out on a questionable strike.  Don't make me stand there at 
25	home plate with my bat slung idly over my shoulders.  Don't 

			271 1	end up as I have to passively watch that ball zoom by.
	2		Let me home run.  Let me strike out.  If I must go 
	3	down, then, I will, but in heaven's name, please, let me go 
	4	down swinging. 
	5		I want to thank you in advance of your decision. 

	6		DR. GILMAN:  Thank you.  I believe we have an hour
	7	for the open hearing, so please limit your comments to five 
	8	minutes. 
	9		Dee Holden Norris. 
10		MRS. DEE HOLDEN NORRIS:  After such eloquence, it 
11	may be hard to follow.
12		I am Dee Holden Norris. I am an R.N. and the 

13	Executive Director of the ALS Research Foundation in San 
14	Francisco, a nonprofit medical research foundation which I 
15	co-founded with my late husband, Dr. Forbes Norris, a 

16	neurologist some of you on this panel may have known.
17		I was involved with my husband for over 20 years 
18	and remain actively involved with literally every aspect of 
19	ALS, the scientific research, the clinical management, the 
20	health care, the educational and patient services program 
21	which continue at the Forbes Norris, M.D.A. ALS Research

22	Center. 
23		Some of you who may have known of my husband knew 
24	of his long-time efforts and diligence in pioneering some of 
25	the early scientific research in this disease, but most 

			272 1	especially in the later years of his advocacy for aggressive
	2	clinical management and intervention to alleviate the major 
	3	degrading symptoms associated with increasing paralysis and 
	4	muscle wasting, the hallmark of this disease. 
	5		I am pleased to say that this philosophy of active 
	6	symptomatic management has come to be more and more accepted
	7	and advocated by the ALS medical community and will probably 
	8	be my husband's legacy. 
	9		He resorted to these efforts out of a compassion 
10	and desperation because there was nothing else to offer 
11	until now.  Patients were, and are, given this diagnosis as
12	an automatic death sentence.  They were old that there was 
13	nothing that could be done, so go home, take care of 
14	yourself, and, by the way, you had better stop off at your 
15	lawyer's office and write your will because you are going to 
16	be dead in three to five years.  But before that happens,
17	you are going to progressively become paralyzed, wind up in 
18	a wheelchair, unable to move your arms or legs, hold up your 
19	head, or scratch your nose, gradually losing your ability to 
20	speak or chew or swallow, and you will start choking on your 
21	own saliva and lose your ability to cough or even to take a
22	deep breath. 
23		All the while you will remain perfectly alert and 
24	aware of yourself, your body, and everyone around you. 
25	cognizant of your increasing entrapment and impending death, 

			273 1	cognizant that you have become a major financial and
	2	laborious burden to your family, cognizant that your 
	3	physician, not wanting to deal with the daily horrible 
	4	dilemmas and the mundane problems, knowing full well that he 
	5	or she has nothing else to offer, generally doesn't. 
	6		To a healthy man or woman who has never been sick
	7	a day in their lives, who is active, successful, and leading 
	8	a healthful, family-oriented life, this is an all 
	9	unacceptable, unbelievable, immeasurably horrible, and the 
10	ultimate demeaning indignity. 
11		For the physician, the nurse, the caretaker who
12	must hold these people's hands and watch helplessly as this 
13	inexorable process occurs, this is the ultimate nightmare. 
14		Thank God, at last we are entering a new era when 
15	this all too frequent, dismal scenario of utter helplessness 
16	and hopelessness is changing.  With your insistence on an
17	approval today for a treatment IND for Myotrophin, the first 
18	we hope of several possibly helpful drugs to stem the 
19	mercilessly relentless, downhill course of this scourge, we 
20	can for the first time look these patients in the eye and 

21	say that even though we don't have a cure, we can offer
22	something that gives a glimmer of hope for living with ALS 
23	until we can find the cause and most importantly the cure 
24	for this disease. 
25		We who have working for so long and so hard in 

			274 1	what my husband called the dark hole of ALS, and most
	2	importantly, these desperate people who live and are dying 
	3	in that dark hole, who have never had anything to offer them 
	4	hope before, need this drug.  They deserve this drug, and 
	5	they demand this drug. 
	6		I ask on their and our behalf that you give
	7	immediate approval to this IND for Myotrophin. 
	8		Thank you. 
	9		DR. GILMAN:  Thank you. 
10		David Coleman. 
11		MS. SUSAN GRAHN:  My name is Susan Grahn, and I am
12	speaking for David as he can no longer speak. 
13		Dear Members of the Committee:  On February of 
14	1995, I began to have speaking problems.  I went to my 
15	family doctor who sent me to a neurologist.  After several 
16	tests that included an MRI of the brain and a spinal tap for
17	Lyme disease, and other related diseases, and after 
18	everything else was eliminated, it was determined that I had 
19	amyotrophic lateral sclerosis or ALS. 
20		It was in May of 1995 that I was informed that I 
21	was diagnosed with ALS.  Since that time, my life as I knew
22	it has changed in many ways.  I can no longer dress myself, 
23	walk freely, swallow solid foods, drink liquids, or speak.  
24	I own my own business, which is a construction company, 
25	which took many years to build, and I can no longer run that 

				275 1	either.
	2		In December of 1995, I entered the hospital for a 
	3	period of time to have a tracheostomy and a feeding tube put 
	4	in.  I could not clear my throat any longer and the phlegm 

	5	was blocking off the airway.  The feeding tube was to get 
	6	the nutrients into my system that I so desperately needed.
	7		I have the bulbar form of ALS which affects the 
	8	muscles of the throat first and very slowly spreads to the 

	9	rest of the body.  I have been told that I have two to five 
10	years to live from last May.  I think with that kind of 
11	fatality rate, someone has to come up with a cure.
12		I have personally known three people that have 

13	died from ALS.  While I have participated in the Rilutek 
14	drug study and continue to take the drug today, the life 
15	expectancy, as I understand it, is an additional three 

16	months.  This is very little compared to a lifetime of hope
17	and dreams. 
18		I would just like to say that I have been dating 
19	David for two years now, the second year dealing with 

20	disease.  He was a very strong man one year ago, but he 
21	still remains strong inside.  That strength keeps me going.
22		A lot of people say to me you have to look out for 
23	yourself, Susan, you have to think about yourself, and I 

24	just think when do we think about others.  I think we need 
25	to think about others and help them fight for their life. 

			276 1		If you have something that can help, I hope you
	2	will give it to them. 
	3		David has typed out one sentence.  Well, he was 
	4	going to type out "Please help us." 
	5		Thank you. 
	6		DR. GILMAN:  Thank you.
	7		Steven Stricter. 
	8		MR. STEVEN STRICTER:  Boy, it is going to tough to 
	9	follow all the eloquence and sincerity that I have heard 
10	this afternoon. 
11		My name is Steve Stricter.  I am from near
12	Trenton, New Jersey.  I would like to say that I am very 

13	impressed with the level of expertise that I have heard in 
14	the discussions today in the fields of medicine, 
15	pharmacology, philosophy, statistics, and I am also very 
16	impressed with the dedication of the developers of this

17	medication, and I am very impressed with the families and 
18	fellow patients, and I have to applaud everything that I 
19	have heard so far. 
20		[Applause.] 
21		As for myself, now I have got to get to the

22	written form.  I am 53 years old and I live near Trenton.  I 
23	have a lovely wife Judy in the audience and two kids, six 
24	adorable grandkids.  I was the part owner of a small 
25	business, a very skilled worker in my time in my line of 

			277 1	work.
	2		My wife and I have traveled extensively throughout 
	3	the U.S., Canada, Mexico.  We have been to the Holy Land, to 
	4	Europe, Australia, many other fun spots and sun spots.  I 
	5	have enjoyed and been satisfied with all of the above, and I 
	6	certainly am not ready and willing to give it all up.
	7		But something entered my life recently which has 

	8	started to turn my life upside-down and screwy, and that is 
	9	something is ALS.  I was first diagnosed with this 
10	impediment to my happiness in July of 1993. 
11		It started with a weakness in my hands and arms,
12	kind of clumsiness that I had never experienced before.  

13	From all the information I could gather three years ago, the 
14	disease might lead to the ultimate unhappiness, my death, in 
15	about five years, the average life left after the initial 
16	diagnosis.
17		The progression of the disease in my case has been 
18	fairly slow and still concentrated in my upper limbs.  I 
19	have had to quit working at this point and travel is not the 
20	easy fun that it was when I was younger, but I sure don't 
21	want to give up the good times with my wife, the kids, the
22	grandchildren, and family members and friends. 
23		I was hoping that maybe I could pop a pill and my 
24	symptoms would just go away, but it is not that easy.  
25	Thanks to the research and development efforts over the last 

			278 1	few years, there are a few drugs which may show some promise
	2	in slowing the progression of the disease, and I am 
	3	presently taking one of these drugs, Rilutek, which became 
	4	available to me under an early access program. 
	5		I am hoping that that drug is effective in slowing 
	6	the advance of the disease.  I urge that the same early and
	7	expanded access availability be afforded to patients that my 
	8	be helped by taking Myotrophin.  When precious little time 

	9	is left in one's life, it is a matter of great urgency to 
10	have access to whatever tools may become available to treat 
11	the disease and that as many people have access to the drugs
12	as soon as the research deems that it is safe to take these 
13	drugs. 
14		I dread facing the inevitability of what lies in 
15	store for me and not being able to enjoy the good things 

16	that life has to offer.  My hope is that the drugs that may
17	offer increased efficacy will soon be developed and that 
18	they will be made available to patients like myself. 

19		I thank you very much for the opportunity. 
20		DR. GILMAN:  Thank you, Mr. Stricter. 
21		Joseph Polizzi.
22		MR. JOSEPH POLIZZI:  Hello.  My name is Joe 
23	Polizzi.  I am from Philadelphia.  I was diagnosed three and 
24	a half years ago, and my doctor told me the same thing he 
25	told everybody else, three to five. 

			279 1		Well, he also told me something about Myotrophin,
	2	and he put a little bit of wind in my sails.  I have been on 
	3	Myotrophin exactly three years, and truthfully, I think it 

	4	helped.  Otherwise -- I have been in this chariot for three 
	5	months.  It is no fun. 
	6		I am going to be short, but try not to take the
	7	wind out of my sails.  Okay? 
	8		Thank you. 
	9		DR. GILMAN:  Thank you, sir. 
10		Karen and Fred Micale, Jr. 
11		MR. FRANK MICALE:  Good afternoon.  My name is

12	Frank Micale and I am here today with my wife Karen.  I 
13	would personally like to thank Cephalon and the Greater 
14	Philadelphia ALS Chapter for extending to me this 
15	opportunity to speak to you today. 
16		I was diagnosed with limb onset ALS on July 12,

17	1995.  Since then, Karen and I have struggled immensely in 
18	dealing with this disease while at the same time trying to 
19	keep our family's daily routine as normal as possible. 
20		At the time, our daughter Lauren was 9 and our son 
21	Christopher was 3.  One of the hardest things we had to do

22	was to go home and finally explain to our daughter what was 
23	wrong with me.  After Karen told Lauren in very simplistic 
24	terms what ALS was, she responded in a positive youthful 

25	manner and said, "But dad can just take medicine from the 

			280 1	doctors to help him get better," to which Karen had to
	2	respond, at the time, "But there isn't any medicine dad can 
	3	take to make him better." 
	4		Receiving the diagnosis of ALS with all its 
	5	implications is very devastating.  To further be told that 
	6	there is no treatment at the time was even worse.  Since
	7	then, as most of you know, we have seen the approval of 
	8	riluzole.  Even so it is hard to accept that in this age of 
	9	advanced science and technology, there is only one drug for 
10	the treatment of a disease that was first identified 127 
11	years ago.
12		In our lifetime alone, we have seen the rewards of 
13	pharmaceutical intervention.  Karen has been a registered 
14	nurse for 17 years.  She experiences first-hand in the 

15	hospital setting the benefits of dedicated research and 
16	development as newer and safer drugs are introduced and

17	older drugs are improved upon or replaced for the treatment 
18	of chronic diseases and life-threatening illnesses including 
19	cancer and AIDS. 
20		For most ALS patients and families, it is a truly 
21	helpless and frustrating experience to wait patiently for
22	the treatment.  How has my life changed in the last year?  I 
23	consider myself fortunate that I can stand here before you 
24	today.  I am still able to work because I have a desk job 

25	and my company has been supportive.  I would like to 

			281 1	continue to contribute to society and work as long as
	2	possible. 
	3		The most difficult changes have been those at 
	4	home.  Karen elected 10 years ago, and I concurred, to give 
	5	up her full time job and stay at home with the children.  
	6	She continue to keep her nursing skills intact by working
	7	weekends.  We have always worked together as a team in 
	8	raising our children and I consider it the most important 
	9	thing I do.  However, it is becoming harder every day for me 
10	to participate in the daily routine with the children, 
11	something I have always enjoyed doing since the day they
12	were both born. 
13		Lauren is a bright, outgoing, athletic, 10-year- 
14	old child.  Up until recently I have been able to physically 
15	participate with her in all her school and extracurricular 
16	activities.  Sadly, she now understands that I am not able

17	to do as much as I would like to do with her as my muscles 
18	continue to deteriorate and my fatigue increases. 
19		Christopher is a typical rambunctious 4-year-old 
20	boy who has no idea why he is stronger and more coordinated 
21	than his own dad.  One good butthead is enough to knock me
22	to the ground, and he wins every time we wrestle. 
23		I cannot kick a ball to him or have a catch with 
24	him.  His idea of playing with his dad means sitting at a 
25	computer.  As he gains his independence in dressing himself 

			282 1	and learning to tie his shoes, I am losing mine.
	2		I used to take Lauren and Christopher to the parks 
	3	for hiking while Karen worked on the weekends.  I can no 

	4	longer do that.  We have always been an active family who 
	5	have enjoyed the outdoors.  My family has been my greatest 
	6	source of joy.  I know that if this disease is allowed to

	7	follow its course, I will be left totally paralyzed yet 
	8	mentally intact. 
	9		I want to be there for my family both physically 
10	and mentally.  Today I am here on behalf of all ALS patients 
11	that have gone before us and all present and future ALS

12	patients.  We understand the necessity of the formal FDA 
13	approval process for all drugs, however, given the 
14	aggressive and unpredictable nature of this disease, we do 
15	not have the time to wait. 
16		If Myotrophin is found to be statistically safe
17	and effective, we ask that you approve the early access 

18	program.  Faced with the terminality of this disease, we are 
19	left with no other recourse and are willing to risk the side 
20	effects in order to slow its relentless path. 
21		Irreparable damage occurs with each passing day. 
22	127 years is a long time to wait.  Rilutek was the first 

23	step.  Let your actions today be the second step.  I would 
24	like to go home today and tell my son and daughter and 
25	fellow ALS patients that yes, there is another drug 

			283 1	available.
	2		You have the power to approve this program and 

	3	renew our hope as we move one step closer to the eventual 
	4	cure of ALS. 
	5		Thank you. 
	6		DR. GILMAN:  Thank you.
	7		Fred Kanzler. 
	8		MR. CARL MAYLE:  Ladies and gentlemen, my name is 
	9	Carl Mayle.  I am a 28-year friend of Fred, and I am here 
10	with him today.  He has asked me to read his statement with 
11	your permission.

12		My name is Fred Kanzler.  I live in Mt. Holly, New 
13	Jersey, and I am 69 years old.  My wife Ann and I were 
14	married on June 27, 1959.  We have one son who is married 

15	and are blessed with two granddaughters.  On April 30th, 
16	1993, I retired an environmental manager from a plant with
17	about 160 employees manufacturing polyvinyl chloride. 

18		In that capacity I was responsible for the plant's 
19	industrial hygiene and environmental programs.  I was 
20	diagnosed by Dr. David Lee of Mt. Holly on June 25th, 1991, 
21	with sporadic ALS.  His diagnosis was confirmed by Dr.
22	Shartland of HUP in Philadelphia. 
23		Under the guidance of my physical therapist, who 
24	is trying to improve my gait, I started working out at a gym 
25	in September 1991.  My wife was determined to find something 

			284 1	which, in her mind, would give us hope.  Her efforts
	2	culminated with the discovery of the ALS Association, the 
	3	Greater Philadelphia Chapter. 
	4		Among others she spoke to, the ALS Chapter nurses 
	5	suggested that I get in touch with Dr. Howard Netter at the 
	6	Hahneman Hospital ALS Clinic.  Dr. Netter asked me if I
	7	would have an interest to participate in a drug study.  My 
	8	screening trips to Hahneman started in the summer of	1992. 
	9		The results of the tests seemed to show a rather 
10	rapid loss of strength in the legs and, to a lesser degree, 
11	in the arms.  Around February or March of 1993, I started
12	using a cane.  Based on my rapid rate of deterioration I was 
13	accepted on April 8th, 1993, to participate in the double- 
14	blind study for IGF-1. 
15		With the exception of the first four or five weeks 
16	where the thigh inject sites showed a reddening the size of
17	silver dollar, I experienced no other side effects.  The 

18	blush of the thigh inject site would abate after about 8 
19	hours.  The abdominal inject sites remain normal. 
20		About three to four months after the start of the 
21	study, Dr. Netter mentioned that the results of my Appel

22	test indicated a return of strength.  My own observation 
23	showed a marked reduction of fasciculations.  At the end of 
24	the 9-month study period, I noticed the muscle definitions 
25	in my shoulder muscles had returned and the circumference of 

			285 1	my calves had increased by 1.5 complication.
	2		After the completion of the 9-month double-blind 
	3	study period and the subsequent 9 months extension, which 
	4	ended October 6, 1994, I had to wait for two months to 
	5	continue with the IGF-1 treatment.  It was during this 2- 
	6	month period that I noticed atrophy returning associated
	7	with an increase in muscle weakness and fasciculations in 
	8	all limbs.  In fact, I had to reduce the weights for my 
	9	lifting exercises at the gym and the distance traveled in 25 
10	minutes on the stationary bike dropped by one mile, which 
11	represented nearly a 20 percent reduction.
12		No longer was I able to walk with a cane.  Rather 
13	than using a walker, I taught myself to walk with Canadian 
14	crutches.  During the same time, I also noted symptoms of a 
15	bulbar onset.  It is my understanding that my extrapolated 
16	Appel curve indicated I would have expired in June 1994,
17	therefore, I am thankful.  If it was to be, I was stricken 
18	with ALS at the right time and in the right place. 
19		Had I not had the IGF-1 treatment, I would have 

20	missed two dance recitals of my older granddaughter, and I 
21	would never have known my younger granddaughter, missed the
22	wedding of my son's best friend to the sister of my 
23	daughter-in-law, and all the wonderful days I was able to 
24	spend with my family, not to forget all the friends I made 
25	at the ALS Association and the gym and the visits with 

			286 1	friends from Canada and Germany.
	2		It is to me rather sad that despite the 
	3	demonstrated efficacy, the access of Myotrophin is denied to 
	4	wives or husbands, to mothers or fathers of young children, 
	5	and to older children of parents my age.  I have seen young 
	6	men at the age of my son, with children the same age as my

	7	grandchildren, wither away, despite the fact that there is 
	8	something out there that would buy them a longer life, more 
	9	time with the people they love. 
10		Not to speak of the countless who have already 

11	gone because of the denial of access to, in my opinion, an
12	effective treatment.  I am almost ashamed to tell anyone 

13	afflicted with ALS about my good fortune and my success.  Do 
14	we really want to continue to play God based on statistics? 
15		Based on my own successful experience with 
16	Myotrophin, isn't it time to have some compassion with all

17	the ALS patients out there who wait for a miracle to happen 
18	right here in this room right now. 
19		Thank you for the opportunity to appear. 
20		DR. GILMAN:  Thank you, Mr. Kanzler. 
21		Dr. Gerald van der Vlugt.
22		DR. GERALD van der VLUGT:  Good afternoon.  My 
23	name is Gerald van der Vlugt.  I am 57 years old and I come 
24	from a medical family.  My mother and father were both 

25	physicians.  My father died at the age of 55 from heart 

			287 1	disease and smoking, and my mother received the Outstanding
	2	Alumnus Award from the University of Oregon in 1994. 
	3		My wife just retired two years ago as medical 
	4	director of the United States Peace Corps for eight years, 
	5	and my daughter is a third-year medical student in the top 
	6	of her class at Stanford.
	7		I graduated from medical school in 1963 and 
	8	retired in 1989 from the Senior Foreign Service.  During 
	9	that time, I had the distinct pleasure of dealing with the 
10	FDA on getting approval of such things as depo provera, and 
11	I understand the politics of the FDA, as well as ivermectin,
12	and other drugs in my capacity as a senior executive service 
13	officer. 
14		When I retired in 1989, I took my RV and my 
15	motorcycle and I traveled to all of the 49 states that are 
16	accessible by RV, and had a wonderful five years of
17	retirement before I had the onset of ALS. 
18		In June -- June is my anniversary month -- in June 
19	1994, developed a right footdrop.  I was very physically 
20	active and physically fit, and like I say, I serve on 
21	several public service committees, which I continue to serve
22	on.  I am on the executive board of the Public Employers 
23	Roundtable, on the executive board of the Federal Physicians 
24	Association, so I am active in those things even today.  But 
25	I always used to arrive on my motorcycle.  Now I arrive in 

				288 1	my wheelchair with my wife pushing me, which is not quite
	2	the same, but I still am able to serve. 
	3		My right footdrop began in	1994.  I had a workup 
	4	and a diagnosis was made in March 1995.  I was begun in 
	5	September 1995 on BDNF trials, double-blind, and I began on 
	6	the Rilutek shortly after it was approved by the FDA.  I am

	7	on high doses of vitamins because my medical family would 
	8	want me to be that way. 
	9		When I was given the opportunity to come here 
10	originally, my firm intent was to think of my background in 
11	dealing with the FDA and its timidity in approving drugs,

12	and encouraging you to move forward with a great vigor and 
13	approve this drug. 
14		However, as I have researched the drug more -- and 
15	IGF-1 has been around for many years -- I am very thankful 
16	that the FDA has no vested interest in either the patients'
17	view or in the company's view, but is looking for safe and 
18	effectiveness, and does not want to put something on the 

19	market that would be a cruel hoax, raise hopes that would 
20	not be true. 
21		So as a patient, I would encourage you to go
22	forward with Myotrophin and approve it.  As a physician, I 
23	think there are serious concerns that I trust you all have 
24	more information than any of us, and will make a wise 
25	decision. 

			289 1		I note that when I began my BDNF trials that they

	2	also placed me on neurontin, 2400 mg/day, and I will leave 
	3	you with this experience.  I began in September taking 
	4	neurontin.  In the middle of December I suffered the rapid 
	5	onset of bilateral visual field loss, went blind to the 

	6	point where I could not see TV or my computer monitors.
	7		Luckily, when I stopped taking the neurontin, my 
	8	vision came back.  So I am very happy to be able to see and 
	9	talk and get around this way.  But I think that we have to 
10	be careful, and I trust again the FDA will make the right 
11	decision with your technical information and your
12	background. 
13		I certainly want to stay active as long as I can 

14	and appreciate the new drugs that are coming down  the pike, 
15	and I hope the drug companies keep up their good work to 

16	work on making more drugs available and help us as we go
17	forward. 
18		Thank you. 
19		DR. GILMAN:  Thank you. 
20		Dr. Theodore Munsat. 
21		DR. THEODORE MUNSAT:  Mr. Chairman, members of the
22	panel, thank you for allowing me to speak briefly.  It has 
23	been a long day and I shall my remarks very brief. 
24		I am Professor of Neurology and Pharmacology at 
25	Tufts University and Director of the Neuromuscular Research 

			290 1	Unit at New York Hospital.
	2		I have spent most of my professional life involved 
	3	in experimental therapeutics of ALS and I am pleased to be 
	4	here today and take part in this meeting. 
	5		I have heard these data presented many times at 

	6	scientific meetings in the United States and elsewhere, and
	7	I have heard them presented again today.  I would like to 

	8	join those of you on the panel and FDA in giving my support 
	9	for acceptance of the 1200 study, which I think is 
10	scientifically sound, it is statistically robust, and the 
11	drug is safe.
12		Let me make a few remarks about another issue that 
13	was touched upon and that has to do with further trials.  I 
14	have the pleasure of serving as Chairman of a World 
15	Federation of Neurology Committee that has been involved 

16	with therapeutic trials for several years.  Our mission is
17	to try to maximize resources for ALS trials and to bring 

18	together the skills and expertise of the private sector and 
19	the academic community, so that when further trials, future 
20	trials are presented to this committee, they won't pose as 
21	many problems with methodology and statistical analysis, and
22	so on. 
23		We have indeed had preliminary discussions with 
24	the sponsor of this drug, and are very willing to continue 

25	on discussing with them, as well as with other companies and 

			291 1	with FDA, trials that will be scientifically sound,
	2	statistically robust, and trials that will be economically 
	3	and time efficient. 
	4		As a matter of fact, we have a preliminary draft 
	5	of the study already.  Let me just make one additional 
	6	remark about the thinking of those of us who are involved

	7	with ALS trials.  We do believe we are in a very new and 
	8	promising era. 
	9		I think most of us believe that no single drug is 
10	going to provide the kind of major functional improvement 
11	that we all want, but we believe we are beginning to see

12	drugs that have modest effects and that we must move very 
13	quickly into combination trials. 
14		I think approval of the IND of Myotrophin will 
15	allow this momentum to continue.  It will be a bad time to 
16	interrupt the momentum of drug development at this point. 
17	So I hope you will vote in favor of this.  Thank you. 
18		DR. GILMAN:  Thank you, Dr. Munsat. 
19		Dr. Robert Brown. 
20		DR. ROBERT BROWN:  Thank you. I am a neurologist 
21	from Boston where I see a large number of patients with Lou
22	Gehrig's disease and conduct a research program 
23	investigating genetic factors that are predisposed to this 
24	illness. 
25		I had the pleasure of collaborating with 

			292 1	scientists at Cephalon, but I want to mention that I have
	2	absolutely no financial interest in that company, nor do I 

	3	stand to have any change in my financial status as a result 
	4	of your deliberations today. 
	5		I want to say simply that I too have had an 
	6	opportunity to review the results of Study 1200 and I would
	7	agree that it is well designed and that it shows clear 
	8	statistically significant benefit and a benefit which is 
	9	probably also clinically significant.  It may be of only a 
10	modest benefit, but it is nonetheless real. 
11		I think it is quite extraordinary sitting in the
12	back of the room this morning to hear FDA's own experts 

13	review the study and agree that it showed clinical efficacy.  
14	I would share your view that Study 1302 is at best 
15	equivocal.  That said, I would urge two things.  Like Dr. 
16	Munsat before me and many others, I would urge that
17	Myotrophin be approved. 
18		I would equally urgently urge that you invoke some 
19	mechanism to insist that a third study be done, so that once 
20	for all we can settle with finality the question of 
21	efficacy, because I think it is unconscionable to provide

22	this to our patients, presumably who have considerable 
23	expense, without knowing once and for all whether indeed it 
24	is helpful. 
25		Thank you. 

			293 1		DR. GILMAN:  Thank you, Dr. Brown.
	2		Has anyone else any comments or statements to be 

	3	made during the open portion of the meeting?  Dr. Brooks. 
	4		DR. BENJAMIN BROOKS:  Thank you.  I faxed 
	5	yesterday a request to speak. 
	6		I am Benjamin Brooks, Professor of Neurology and
	7	Director of the ALS Clinic at the University of Wisconsin 
	8	Hospital and Clinics in Madison, Wisconsin.  This is a 
	9	region of the USA that has a high rate of ALS. 

10		Our patients don't view their disease across their 
11	latest version of SAS.  They view it from their wheelchair

12	or behind by that machine.  There are four points I want to 
13	make. 
14		First, we needed an open public discussion of a 
15	separate independent review of all this data.  It was 

16	absolutely necessary.  At day's end, within the caveats
17	given by Drs. Leber and Katz, there are no safety issues, 
18	and 1200 seems to have made the day. 
19		The second issue, Dr. Zivin's issue, is, is this a 
20	significant clinical effect, and we see it primarily in the 
21	upper extremity function, in cutting, feeding oneself, these
22	are clinically significant, and I would opine that they 

23	probably explain the fact that an independent quality of 
24	life measure was somehow positive in 1200. 
25		The third point I want to make addresses some of 

			294 1	Dr. Munsat's issues.  There is symptomatic, palliative, and
	2	restorative therapies that may be available to these 
	3	neurodegenerative diseases.  At the present time we only 
	4	have one palliative therapy, and no restorative therapy.  We 
	5	need this added to your armamentarium. 
	6		The fourth and final point I want to make relates
	7	to the issue of the calculus of clinical trials and the 
	8	issues of how analysis can affect bias of outcome. 
	9		There are three types of analysis:  primary 
10	endpoint analysis, secondary endpoint analysis, and 
11	exploratory endpoint analysis.  The primary and secondary
12	endpoint analysis are usually in the clinical protocol.  We 
13	know from today's discussion that 1200 made that.  I would 
14	say that this provides substantial evidence for efficacy of 
15	this drug. 
16		The issue before the committee that I see is
17	whether exploratory analyses is supportive or negative, and 
18	I would opine and recommend that the committee look upon 
19	them as supportive. 

20		Thank you. 
21		DR. GILMAN:  Thank you.  Any other commentary? 
22	Dr. Jubelt. 
23		DR. BURT JUBELT:  I am Burt Jubelt and Professor 
24	of Neurology at SUNY-Syracuse and run an ALS clinic and see 
25	ALS patients on a weekly basis. 

			295 1		I wanted to comment just briefly from the
	2	scientific standpoint that, as all of you have heard, and I 
	3	want to make it very brief, that from my standpoint, the 
	4	1200 study, the North American study is clearly efficacious 
	5	and we have a second study that is either negative or 
	6	supportive depending on your point of view, and the drug has
	7	minimal side effects. 
	8		From the personal standpoint, I want to mention 
	9	that in the last year, I have had a family member that I had 
10	to care for as the physician, who had ALS, and seeing ALS 

11	patients dying every week, month.  From the patient advocate
12	standpoint, I think it is important to keep in mind that 
13	here you have a disease in which everybody dies.  From that 
14	standpoint, and they die in three to four years.  So it is 
15	worse than AIDS, it is worse than most cancers in this day 
16	and age, and here is a drug that if I had ALS tomorrow, I

17	would want to try this drug, because it appears from my 
18	standpoint that it is efficacious and has little side 
19	effects. 
20		Thank you. 
21		DR. GILMAN:  Thank you.
22		Yes. 
23		MS. ABBIE MYERS:  My name is Abbie Myers, 
24	President of NORD.  I had requested time on the program 

25	about three weeks ago, and I guess I never heard from you.  

			296 1	So I would like to just give you this written comment, but I
	2	would also want to say that the last time I was here at a 
	3	committee meeting, I remember the chairman of the committee, 
	4	Dr. Fahn at the time, in voting about Rilutek, said I cannot 
	5	vote for approval of Rilutek because the North American 
	6	study shows it doesn't work in North America, it only works
	7	in Europe. 
	8		So here we have got exactly the opposite.  This 
	9	drug seems to work in North America. 
10		DR. GILMAN:  Is there any other commentary from 
11	the floor?  Yes.
12		DR. BARRY FESTOFF:  My name is Barry Festoff, 
13	Professor of Neurology at the University of Kansas Medical 
14	Center and the VA Hospital in Kansas City, and I have been 
15	involved with ALS patients for more than 20 years in 
16	clinical trials and bench research and have been actively

17	investigating IGF-1 for the past 10 years beginning with 
18	studies with a predecessor hormone, Human Growth Hormone. 
19		You have heard a little about the Human Growth 

20	Hormone study, which was negative, but in fact, showed that 
21	the axis for IGF-1 in growth hormone was intact in ALS
22	patients and suggested that there was a window of treatment 
23	opportunity there for IGF-1. 
24		I have been involved in Phase I and Phase II 

25	studies with Cephalon, and we currently have now four 

			297 1	patients out of the initial seven that entered the study. 
	2	It was a double-blind study, and these patients have 
	3	received over 980 doses of 0.05 mg twice a day almost two 

	4	years on open label and extension, and the blind is still 
	5	coded, so we don't know the blind, whether or not these 
	6	patients in the nine months prior to that also received IGF-
	7	1. 
	8		These patients have essentially stopped in terms 
	9	of their maximum progression rate on the Appel Scale.  All 
10	of them fit the criteria for the large 1200 study in terms 
11	of entry, and although one patient is bedridden, still is
12	able to feed himself with assistance. 
13		The other three patients are ambulatory.  Just to 
14	give you that sort of notion that long term IGF-1 
15	administration seems not to have any significant side 
16	effects.
17		DR. GILMAN:  Thank you, Dr. Festoff. 
18		Thank you all very much.  We thank the patients 
19	who have testified before us.  We certainly appreciate the 
20	desperateness of this disease and we want to do all that we 
21	can to help make progress in this area.
22		    COMMITTEE DISCUSSION (CONTINUED) 
23		DR. GILMAN:  Now, I think it is time for the 

24	committee to continue its discussions and deliberations. 
25		Let me try and precipitate, again by being 

			298 1	provocative, in my own mind, Study 1200 has shown that
	2	Myotrophin is effective, that is, it shows a benefit over 
	3	placebo in altering the slope of the clinical scale that was 
	4	used, the Appel Scale. 
	5		The study was done utilizing the statistics that 

	6	were designed prospectively.  Safety is not an issue, and so
	7	I would conclude that the 1200 study did show effectiveness.  
	8	The 1202 study still in my mind did not show effectiveness.  
	9	So I wind up looking at one study that showed effectiveness 
10	and the other one that did not. 
11		On this basis, I am inclined towards approval in

12	that these two studies, taken together, have shown one that 
13	clearly shows effectiveness, and the other one I think we 
14	need to put aside for now because we do have a positive 
15	study.  Moreover, we are looking towards the request for 
16	approval of an IND, not an NDA.
17		That being the case, then, I would be in favor of 
18	approval at this point. 
19		I would like to hear from the other committee 

20	members.  I am stating my own personal opinion only, not 
21	that of the committee.
22		[No response.] 
23		DR. GILMAN:  You either all disagree or all agree. 
24		DR. KAWAS:  I would just say I think I agree with 
25	you, Dr. Gilman.  I think that the agency has told me that 

				299 1	two studies is substantial and that what we needed to decide
	2	was whether or not there was sufficient, and since one is 
	3	less than two, I think the criteria has been met. 
	4		DR. GILMAN:  Thank you. 
	5		Dr. Khachaturian. 
	6		DR. KHACHATURIAN:  I was expecting you to be
	7	provocative, but you weren't.  I think I agree with you. 
	8		DR. GILMAN:  All right.  Other commentary from the 
	9	committee? 
10		MS. PHILLIPS:  I think as a consumer 
11	representative, it is obvious that the consumers, the
12	patients made their case that they want the drug, and as a 
13	representative, I would concur with you also that the Study 
14	1200 showed effectiveness. 
15		Based on that, it would be very, very difficult, 
16	if not unconscionable, to not continue to proceed with the

17	IND. I think also for me personally, hearing other doctors, 
18	Dr. Brown, Dr. Munsat, who are eminently respected in the 
19	community, come forward with their statements would certain 
20	help me to approve. 
21		DR. GILMAN:  Well, I want to emphasize here that

22	when I speak for myself alone, I am speaking on the basis of 
23	the data that I have heard today.  I appreciate what a 
24	difficult, disastrous disease ALS is, and I want to do 
25	whatever I can to help patients with this disorder, but also 

			300 1	I want to base my own personal decision upon the evidence,

	2	and I hope that is what the rest of the committee will do 
	3	today. 
	4		Dr. Coyle. 
	5		DR. COYLE:  Can the panel also make a 
	6	recommendation that a third study be done?
	7		DR. GILMAN:  We can certainly discuss that.  We 
	8	have been asked whether evidence is sufficient to have us 

	9	support a treatment IND.  The tenor of the discussion today 
10	certainly does suggest that the company might consider a 
11	third trial because I, for one, do not see adequate evidence
12	to have me, at this point in time, favor an NDA.  If that 
13	were the question before us, I would say no, I don't think 
14	we have substantial evidence.  We have evidence, it is not 
15	substantial in my own mind. 
16		That is not the question before us, though, but I
17	believe the company has heard that multiple times today. 

18		Other commentary?  Dr. Adams. 
19		DR. ADAMS:  I would encourage the neurological 
20	community, who does this research, Dr. Munsat, and the other 
21	experts who have addressed us, to seriously talk to Cephalon
22	about doing a third trial that is amply sized to test the 

23	effect of this drug, not only on progression, but on 
24	mortality, and because there is some concern about the 

25	tremendous heterogeneity of the disease, that they consider 

				301 1	a trial with some prestratification by rapidity of
	2	progression, so that there is strong evidence that there may 
	3	be some people with ALS who may benefit more or less, and it 
	4	may very well be that those people that are rapidly 
	5	progressing are the individuals that are most likely to 
	6	benefit, and I think that is very important knowledge for me
	7	and probably for any other physician who deals with this 
	8	illness. 
	9		DR. GILMAN:  Thank you. 
10		Other commentary?  Dr.  Gennings. 
11		DR. GENNINGS:  I think it might have been Dr.
12	Dobbins earlier today  was saying that at the time, if he 
13	could have chosen a repeated measures analysis when the 1202 
14	was designed, he would have done that, and I think that now, 
15	maybe if we are talking about a third study, those kinds of 
16	thoughts in terms of statistics could also be placed in
17	there, which should be very helpful. 

18		DR. GILMAN:  Other comments? 
19		All right.  That being the case, let me ask the 
20	committee whether there is any other evidence you wish to 
21	hear or anything else any of you wish to say?
22		Let me ask the sponsor if there is anything.  Yes 
23	Dr. Snead. 
24		DR. SNEAD:  I have one question of the sponsor.  
25	There is talk about a combination study in the offing.  Do 

				302 1	you have drug-drug interaction data on these two compounds?
	2		DR. GILMAN:  Did you hear the question?  The 
	3	question is, if you are considering a two-drug trial next, 
	4	are you concerned about drug-drug interactions? 
	5		DR. GRANEY:  I think we are at the point where we 
	6	are just considering it.  We are aware that some toxicology

	7	would be needed.  We don't have the anticipation, but we 
	8	have not discussed the specifics of the preclinical studies 
	9	with the agency yet. 
10		DR. GELINAS:  If I could speak.  Some of the 
11	patients who were in the original Myotrophin study are still
12	living, and are taking Rilutek at my center, and are 
13	tolerating it without difficulty. 
14		DR. GILMAN:  Dr. Drachman. 
15		DR. DRACHMAN:  If there were not another trial, 
16	and you note the subjunctive for the condition, contrary to
17	the fact.  If there were not another trial, what would then 

18	happen, what would the duration of the treatment IND be?  We 
19	were carefully warned that this is a temporary or transitory 
20	phase. 
21		DR. LEBER:  That is a very good question, and you
22	may get more than one answer because I don't know.  If the 
23	NDA was submitted, and the NDA were approved on the basis of 
24	this evidence -- and I am not clear how that would go, we 

25	might come back to the committee, we might do a number of 

					303 1	things -- then, clearly you don't need the treatment IND.
	2		The problem comes up if the NDA were disapproved 
	3	on the basis of the evidence in the hand, and I -- Bob, do 
	4	you know what is anticipated?  Would we suspend the 
	5	treatment IND at that point? 
	6		DR. TEMPLE:  I would say that is relatively
	7	unlikely, but we would stamp our feet a lot in the hope that 
	8	further studies would get done. 
	9		DR. LEBER:  I don't recall the regs participating 
10	in this. 
11		DR. TEMPLE:  The regulations don't say that.  What
12	they say is that there is a responsibility to move forward 
13	in developing the data needed for approval, but at that 
14	point you would have a different set of information, and you 
15	would have to then decide what to do with it. 
16		DR. DRACHMAN:  What if they did nothing at all,
17	how long would it go on? 
18		DR. TEMPLE:  What do you mean nothing at all? 

19		DR. DRACHMAN:  I mean if they did not submit 
20	another study. 
21		DR. TEMPLE:  Well, as we have been saying, that is
22	not the only question.  They plainly are committed to 
23	submitting a new drug application. 
24		DR. DRACHMAN:  Right, but there are, in fact, 
25	three choices.  One is simply delay it, and how long would 

				304 1	that work?  What I would worry about is that we would be
	2	holding out a false hope that the drug would available, and 
	3	it would be available for a long period of time without the 
	4	final decision regarding it. 
	5		DR. TEMPLE:  We haven't had cause to worry about 
	6	the possibility that no application would be submitted, so
	7	we haven't worried about that, because we have been told to 
	8	expect one.  If they change their mind and did no further 
	9	work, and just let it sit, that would be a problem.  That is 
10	really not what the regs contemplate, but there is a lot of 
11	contingencies in there.
12		DR. GILMAN:  Are there other questions or comments 
13	from the committee now? 
14		Anything further from the sponsor?  Anything you 
15	would like to tell us that has not been said before? 
16		DR. GRANEY:  No, there is nothing else.
17		DR. GILMAN:  Anything from the Pharmacology 
18	Division, Dr. Katz, Dr. Leber anything further you want to 
19	tell us? 
20		DR. LEBER:  We have had our say. 
21		DR. GILMAN:  Dr. Temple?
22		DR. TEMPLE:  Only one thing actually, and it was 
23	Mr. Gill's comments that make me want to say this.  I will 
24	be very brief. 
25		Despite a perception that only drugs for AIDS and 

			305 1	cancer get any attention, I want to make it very clear that
	2	that is not so.  The last drug we had for a bad neurological 
	3	disease Rilutek was approved in less than six months.  Drugs 
	4	of that class are regularly treated as priority reviewed 
	5	drugs, which means we intend to respond to them in less than 
	6	six months.
	7		Treatment INDs of the kind we are considering are 
	8	most common for AIDS and cancer, and the third most common 
	9	use is one or another neurologic disease.  We are prepared 
10	to accept both survival and symptomatic improvement as bases 
11	for approval.  If anybody could think of a good surrogate,
12	we would certainly consider ti. 
13		I just want to make sure everybody knows that we 
14	are very concerned about these diseases for the reasons that 
15	we just heard for an hour, they are terrible diseases.  They 
16	are as bad as anything in the community.  So there is no
17	lack of will, interest, or the personnel to do it. 
18		DR. GILMAN:  Thank you.  Dr. Leber. 
19		DR. LEBER:  Speaking about things you can learn 
20	from what patients tell you, one of the individuals 
21	testifying mentioned that because of the hiatus of
22	availability that he had to come off the drug, and he 
23	reports measurable changes in the status of his disease from 
24	fasciculations, competence of his cath, and the like, which 
25	brings to mind the possibility within subject designs. 

				306 1		I just want to mention that because, you know, we
	2	are locked into this few in may ways parallel studies, 

	3	although I realize there are alternatives, but another 
	4	compelling design provided it is done the right way is 

	5	within subject change, that is, replicable and not occurring 
	6	under the circumstances the blind is penetrated.
	7		So people have done them, and that is another 
	8	source of evidence that we might consider looking at, that 
	9	doesn't expose large numbers of patients to no treatment at 
10	all. 
11		        RECOMMENDATION AND VOTE
12		DR. GILMAN:  If the committee is ready, then, 
13	there are 11 voting members of us. 
14		Let me see a show of hands.  All those who favor a 
15	treatment use of the product under an IND treatment 
16	protocol, please raise your hands.
17		[Show of hands.] 
18		DR. GILMAN:  I believe it is unanimous. 
19		[Applause.] 
20		DR. GILMAN:  Any opposed? 
21		[No response.]
22		DR. GILMAN:  It is unanimous. 

23		            CLOSING REMARKS 
24		DR. GILMAN:  Dr. Leber, Dr. Temple, any further 
25	questions for the committee? 

			307 1		DR. LEBER:  I have a very important announcement.
	2		DR. GILMAN:  Dr. Leber. 
	3		DR. LEBER:  I wouldn't want this day to end -- and 
	4	I understand there is a lot of joy and happiness in the room 
	5	about the decision -- I want to talk about something else 
	6	totally unrelated to ALS, but something that is not so a
	7	moment of happiness on our part. 
	8		I don't know how many of you on the committee know 
	9	that, Mr. Bernstein, this is his last time as our Executive 
10	Secretary.  He has decided after many years of government 

11	service to give up the ghost, to leave Washington to head
12	home toward Texas. 
13		So we will not see him again in this capacity, I 
14	hope we will see him as a friend, but I want to say this, 
15	that over the years that I have been here, there have been 
16	few executive secretaries or colleagues that have done such
17	a good job for so many times, so well. 
18		I thank you. 

19		[Applause.] 
20		[Whereupon, at 5:30 p.m., the proceedings were 
21	adjourned.]