FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	MEETING OF THE

	DERMATOLOGIC AND OPHTHALMIC DRUGS ADVISORY COMMITTEE

	8:30 a.m.

	Tuesday, September 19, 2000

	Holiday Inn
	2 Montgomery Village Avenue
	Gaithersburg, Maryland

	ATTENDEES

COMMITTEE MEMBERS:

WILMA BERGFELD, M.D., Acting Chair
Head of Clinical Research 
Department of Dermatology
Cleveland Clinic Foundation
9500 Euclid Avenue
Cleveland, Ohio  44195-5001

KIMBERLY TOPPER, Executive Secretary
Advisors & Consultants Staff, HFD-21
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland  20857

GLORIA ANDERSON, PH.D., Consumer Representative
Morris Brown College
Atlanta, Georgia  30314-4140

O. FRED MILLER, M.D.
Director, Department of Dermatology
Geisinger Medical Clinic, M.C. 1406
Danville, Pennsylvania  17822

VOTING CONSULTANTS:  

ELIZABETH A. ABEL, M.D.
Dermatology
2660 Grant Road, Suite D
Mountain View, California  94040

JENNIFER ANDERSON, PH.D.
CHQOER
Bedford Veterans Administration 
Medical Center (152)
200 Spring Road
Bedford, Massachusetts  01730

ROBERT A. BRANCH, M.D., F.R.C.P.
Director, Center for Clinical Pharmacology
University of Pittsburgh Medical Center
100 Lothrop Street, 623 Scaife Hall
Pittsburgh, Pennsylvania  15213-2582

	ATTENDEES (Continued)

VOTING CONSULTANTS:  (Continued)

JANET CRAGAN, M.D.
Division of Birth Defects & Pediatric Genetics
National Center for Environmental Health 
CDC MS F45 4770
Buford Highway NE
Building 101, Room 2158
Atlanta, Georgia  30341-3724

ROSELYN EPPS, M.D.
8630 Fenton Street, Suite 300
Silver Spring, Maryland  20910

MICHAEL GREENE, M.D.
Department of Obstetrics and Gynecology
Massachusetts General Hospital
Founders Room 430 
Boston, Massachusetts  02114
 
ERIC HOLMBOE, M.D.
FACP Yale University School of Medicine
1074 LMP
333 Cedar Street
New Haven, Connecticut  06510

LLOYD E. KING, JR., M.D., PH.D.
Professor of Medicine
Dermatology Division
Vanderbilt University
1301 22nd Avenue North
3900 The Vanderbilt Clinic
Nashville, Tennessee  37232-5227

ARTHUR LEVIN, M.P.H.
Center for Medical Consumers
130 Macougal Street
New York, New York  10012-5030

RICHARD MALONE, M.D.
MCP Hanneman University, School of Medicine
Philadelphia, Pennsylvania  19129

WILLIAM ROSENBERG, M.D.
956 Court Avenue, Room E-332
Memphis, Tennessee  38163

	ATTENDEES (Continued)

VOTING CONSULTANTS:  (Continued)

MING T. TAN, PH.D.
Associate Member of Biostatistics
Department of Biostatistics
St. Jude Children's Research Hospital
332 North Lauderdale Street
Memphis, Tennessee  38105

ANDREW WINOKUR, M.D., PH.D.
University of Connecticut Health Center
10 Talcott Notch Road
Farmington, Connecticut  06032

GUESTS:

JANE ADAMS, PH.D.
Department of Psychology
100 Morris Boulevard
University of Massachusetts
Boston, Massachusetts  02125

ALAN BYRNE, M.D.
18 Thorn Brook
Maas County
Kildare, Ireland

LAURENCE GREENHILL, M.D.
New York State Psychiatric Institute
1051 Riverside Drive
New York, New York  10032

KENNETH LYONS JONES, M.D.
UCSD Medical Center
200 West Arbor Drive, H8446
San Diego, California  92103-8446

ERIC KODISH, M.D.
RBC 340
11100 Euclid Avenue
Cleveland, Ohio  44106

ED LAMMER, M.D.
747 52nd Street
Oakland, California  94609-1809

	ATTENDEES (Continued)

GUESTS:  (Continued)

JAMES MILLS, M.D., M.S.
NICND, NIH
6100 Executive Boulevard, Room 7B03
Bethesda, Maryland  20892

CYNTHIA MOORE, M.D., PH.D.
CDC
4770 Buford Highway, F-45
Atlanta, Georgia  30341

FOOD AND DRUG ADMINISTRATION STAFF:

E. DENNIS BASHAW, PHARM.D.
JONCA BULL, M.D.
PETER K. HONIG, M.D., M.P.H.
DIANNE MURPHY, M.D.
KATHRYN O'CONNELL, M.D., PH.D.
NANCY OSTROVE, PH.D.
MARILYN R. PITTS, PHARM.D.
ERICK TURNER, M.D.
JONATHAN K. WILKIN, M.D.
JANET WOODCOCK, M.D.
DIANE K. WYSOWSKI, PH.D.

HOFFMANN-LaROCHE REPRESENTATIVES:

RUSSELL ELLISON, M.D.
DOUGLAS JACOBS, M.D.
JOHN McLANE, PH.D.
ROBERT C. NELSON, PH.D.
DAVID YOUNG, PHARM.D., PH.D.

ALSO PRESENT:

LIAM GRANT
MARGARET H. HAGER, M.D.
RICHARD JOSEPHSON, ESQ.
JAMES PALAZZOLO
KIMBERLY A. SMITH

	C O N T E N T S

AGENDA ITEM	PAGE

CONFLICT OF INTEREST STATEMENT
	by Ms. Kimberly Topper       	11

REPRISAL OF RISK MANAGEMENT OVERVIEW
	by Dr. Jonca Bull	13

MEDICATION GUIDES
	by Dr. Nancy Ostrove	15

	* * *

	ACCUTANE ASSOCIATED PSYCHIATRIC EVENTS

ROCHE PRESENTATION:
	Introduction - by Dr. Russell Ellison	30
	Clinical Definition - by Dr. Douglas Jacobs	32
	Pharmacoepidemiological Analysis -
	  by Dr. Robert Nelson	40
	Clinical Case Review - by Dr. Douglas Jacobs	59
	Additional Data and Conclusions -
	  by Dr. John McLane	63
	Risk Management - by Dr. Russell Ellison	74

FDA PRESENTATION:
	Isotretinoin and Depression - by Dr. Alan Byrne	82
	Drug-induced Depression - by Dr. Erick Turner	89
	Case Review - by Dr. Marilyn Pitts	104
	Postmarketing Experience Suicide and 
	  Depression - by Dr. Diane Wysowski	115
	Biological Plausibility and Risk Management 
	  Options - by Dr. Kathryn O'Connell	120
 
OPEN PUBLIC HEARING PRESENTATIONS:
	by Dr. Margaret Hager	136
	by Ms. Kimberly Smith	137
	by Mr. James Palazzolo	146
	by Mr. Liam Grant	147
	by Mr. Richard Josephson	161

QUESTIONS TO THE COMMITTEE 
	by Dr. Jonca Bull	192

COMMITTEE DISCUSSION AND VOTE	194

	C O N T E N T S (Continued)

AGENDA ITEM	PAGE

CONFLICT OF INTEREST STATEMENT
	by Ms. Kimberly Topper       	239

	* * *

	ACCUTANE NEW FORMULATION

ROCHE PRESENTATION:
	Safety and Efficacy - by Dr. John McLane	  241
	Pharmacokinetics - by Dr. David Young	248
	Risk Management - by Dr. John McLane	  255

FDA PERSPECTIVE:
	by Dr. Jonathan Wilkin	258
	by Dr. Dennis Bashaw	262
	by Dr. Kathryn O'Connell	268

QUESTIONS TO THE COMMITTEE 
	by Dr. Jonca Bull	294

COMMITTEE DISCUSSION AND VOTE	295

	P R O C E E D I N G S
	(8:30 a.m.)
		DR. BERGFELD:  Thank you very much, and welcome to the second day of the Accutane advisory committee.  Yesterday you know that we met and we dealt with the issues of Accutane and the pregnancy prevention program.  Today we are moving on to other subjects regarding Accutane, namely, Accutane associated with psychiatric events for the morning and this afternoon Accutane's new formulation.
		At this time, because some of the audience was not here yesterday I suspect, I would like to go around again and re-introduce the panel members.  I would like to state, first of all, that we have voting and non-voting panel members.  Both will participate in the discussions, but only the voting members will address the questions and vote upon them. 
		I guess if we could start again with you, Dr. Dianne Murphy.
		DR. MURPHY:  Dr. Dianne Murphy, Associate Director for Pediatrics at the Center for Drug Evaluation and Research. 
		DR. WILKIN:  Jonathan Wilkin, Director of the Division of Dermatologic and Dental Drug Products, CDER.
		DR. BULL:  Dr. Jonca Bull, Deputy Office Director, Office of Drug Evaluation V.
		DR. O'CONNELL:  Kathryn O'Connell, medical reviewer, Division of Dermatologic and Dental Drug Products.
		DR. WINOKUR:  Andy Winokur from the Department of Psychiatry, University of Connecticut Health Center.
		DR. ROSENBERG:  Bill Rosenberg, dermatology at the University of Tennessee College of Medicine.
		DR. GREENE:  Mike Greene, maternal/fetal medicine, Massachusetts General Hospital, Harvard Medical School.
		DR. BERGFELD:  I'm Wilma Bergfeld, dermatologist and dermatopathologist at the Cleveland Clinic.
		DR. MILLER:  I'm Fred Miller, Director of Dermatology, Geisinger Clinic, Pennsylvania.
		DR. KING:  Lloyd King, Jr., dermatology at Vanderbilt University and Nashville VA Medical Center.
		DR. EPPS:  Roselyn Epps, pediatric dermatology, Children's National Medical Center, Washington, D.C.
		DR. MALONE:  Richard Malone, Department of Psychiatry, MCP Hanneman University.
		DR. BRANCH:  Bob Branch, clinical pharmacology, University of Pittsburgh.
		DR. HOLMBOE:  Eric Holmboe, general internal medicine, Yale University.
		MR. LEVIN:  Arthur Levin, Center for Medical Consumers in New York.
	 	DR. GLORIA ANDERSON:  Gloria Anderson, Callaway Professor of Chemistry, Morris Brown College in Atlanta.
		DR. JENNIFER ANDERSON:  Jennifer Anderson, biostatistician at Boston University Medical Center and Bedford VA in Massachusetts.
		DR. TAN:  Ming Tan, Associate Member of the Department of Biostatistics, St. Jude Children's Research Hospital.
		DR. JONES:  I'm Ken Jones, Department of Pediatrics at the University of California, San Diego.
		DR. MILLS:  I'm Jim Mills, Pediatric Epidemiology Section, the Child Health Institute at NIH.
		DR. LAMMER:  Ed Lammer, medical genetics, Children's Hospital, Oakland. 
		DR. KODISH:  Eric Kodish, pediatric ethics, Rainbow Babies' and Children's Hospital in Cleveland, Ohio.
		DR. BYRNE:  I'm Alan Byrne.  I'm an adult psychiatrist from Ireland.
		DR. MOORE:  Cynthia Moore, Centers of Disease Control and Prevention, the Birth Defects and Pediatric Genetics Branch.
		DR. ADAMS:  Jane Adams, Department of Psychology, University of Massachusetts, Boston.
		DR. BERGFELD:  Thank you very much.  As you can see, we have a very large group to discuss the issues at hand.  
		We're going to move forward then and go on to the meeting statement by the Executive Secretary, Kimberly Topper.
		MS. TOPPER:  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.  
		Based on the submitted agenda and information provided by the participants, the agency has determined that all reported interests in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting when evaluated against the agenda.  
		With respect to FDA's invited guests, Drs. Jane Adams, Alan Byrne, James Mills, and Edward Lammer have reported interests which we believe should be made public to allow the participants to objectively evaluate their comments.
		Dr. Adams would like to disclose that in the past she has participated in two research grants to study Accutane.  One was funded by Roche and the other was funded by NIH/NICHD. 
		Dr. Byrne would like to disclose that he has published articles on the subject of Roaccutane.  
		Dr. Mills would like to disclose that he is currently collaborating with Roche on an unrelated research project.  He has also written an article and attended a seminar which were unrelated to the particular matters at hand, but sponsored by Roche.  
		Dr. Lammer would like to disclose that in the past he has served as principal investigator on phase I and phase II longitudinal studies of infants exposed to isotretinoin in utero.  The studies, sponsored by Hoffmann-LaRoche, were designed to document the developmental toxicities of isotretinoin following inadvertent human use during pregnancies in North America.
		In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record.  
		With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon. 
		Thank you.
		DR. BERGFELD:  Thank you. 
		Our next item on the agenda is to have Dr. Jonca Bull present to us the FDA's position, reprisal of risk management overview.
		DR. BULL:  Good morning.  Once again, I would like to begin by extending thanks to the advisory committee and everyone here this morning for their presence, for their sharing of their intellect, their time, their talents in helping us better understand and develop options for the management of certain aspects of use of Accutane.
		Accutane is a highly effective drug for the treatment of cystic nodular acne.  Yesterday we discussed its well-characterized risk profile as a teratogen.  Today we will be discussing its risk profile for its uncertain risk for psychiatric adverse events.  In 1998, the labeling for Accutane was revised to reflect this concern. 
		I would like, as you deliberate this morning, to revisit, as part of your frame of reference, the presentations yesterday by Dr. Victor Raczkowski and Dr. Peter Honig, first, Dr. Raczkowski's talk on risk management options and Dr. Honig's talk on lessons learned, particularly the issue of labeling changes, the effectiveness of Dear Doctor letters, the concept of labeling fatigue and that labeling and labeling changes do not necessarily equal knowledge, and that knowledge does not necessarily drive behavior.
		From a risk management standpoint, this morning we will be addressing risk management and the uncertain risk of psychiatric adverse events, specifically depression and suicide.  Is more needed to educate providers and patients and their families?  Is more study needed to better characterize and to minimize risk and ensure safe use?
		This afternoon, for the new formulation, is there sufficient information on its dosing profile for safe and effective use, as well as delineating its relationship to the currently marketed formulation?
		Once again, we welcome this opportunity for discussion as we learn from your experience, your knowledge and perspectives on these issues.  We have asked for and again need your help and advice. 
		Now for an overview of day 2.  In presentations this morning, our first FDA discussant will be Dr. Nancy Ostrove from the Division of Drug Marketing, Advertising, and Communication, who will address the topic of medication guides. 
		Following the Roche presentation, the FDA presentations will begin with Dr. Alan Byrne, addressing clinical psychiatric case experiences, followed by Dr. Eric Turner who will talk on drug-induced depression.  Dr. Marilyn Pitts will present a case review of dechallenge case reports, followed by Dr. Diane Wysowski who will speak on postmarketing experiences and suicide and depression.
		Finally, Dr. Kathy O'Connell, along with Dr. Jon Wilkin and Dennis Bashaw, will be discussing the new formulation.
		In closing, I want to acknowledge and recognize the effort and commitment by FDA's scientists in gathering and analyzing information.  This involves both our Division of Dermatology, our Division of Neuropharmacology, and the Office of Postmarketing Drug Risk Assessment.  They have done a tremendous job in addressing the complex and difficult issues involved in preparing for this meeting.
		Thank you. 
		DR. BERGFELD:  Thank you very much. 
		We're now going on to Dr. Ostrove's presentation on medication guides.
		DR. OSTROVE:  Good morning.  As I believe you all heard yesterday, one of the risk management tools that the agency has to facilitate communications with patients about their medicines, when they receive their medicines, is called medication guide.  What I'm here to do today is to give you a really brief introduction to medication guides.  However, I think it's important that in order to understand this particular tool, it's also critical to understand the universe of information that is made available to patients. 
		So, patients can get information about prescription drugs both before and after a product is prescribed and dispensed.  You're all aware of advertisements -- I believe there was a discussion about them yesterday --  which can run the gamut from being completely promotional for a particular drug to being so non-drug specific that we don't even consider them to be drug advertisements, and we don't even have jurisdiction over them.
		In addition, drug sponsors make available other promotional materials such as patient brochures or patient booklets.  These also can be quite varied in content.  They are supplied to health care professionals, often for distribution to patients. 
		Now, even though we regulate the content of these materials if they're, in fact, supplied by the manufacturers, we have no authority to regulate whether they are given to patients.  So, that's all voluntary.  Sponsors simply make them available either directly to the patients or through the patients' health care providers.
		Then there is information that's supplied to pharmacies by independent groups that are not affiliated with drug sponsors.  There's currently a large scale private sector program, in fact, that is driven by specific distribution and information quality goals that's designed to ensure that patients get useful written information about their prescription medicines at the time that they receive their medicines.  Now, these are the kinds of things that you generally will see stapled to the bags that people get their prescriptions in.  They are computer generated usually at the point of purchase, or at least at the point of dispensing.
		Now, there's recent research that we've done that indicates these are fairly widely distributed to patients.  So, many patients get this kind of information.  However, there's also recent research that suggests that the quality of the information varies considerably, especially in the area of risk disclosure.  
		Now, this kind of information is out there.  It's not required to be given out, but there is a private sector program that encourages that to be given out.
		The second type of information that patients receive when they're dispensed certain prescription drugs is mandated by specific regulations for FDA approved patient labeling.  These are also known as patient package inserts, or PPIs.  Now, the regulations are out there only for certain products, for instance, for oral contraceptives and for estrogen replacement therapy.  In this case, the sponsor drafts the information.  The FDA approves the information.  Because the regulations are different, there's different format involved, there's different content involved.  These, on the other hand, are required to be distributed to patients.  
		However, there are questions that remain about whether in fact that distribution requirement is being achieved.  For instance, some early research that was done with oral contraceptives and whether they were being received by patients, indicated that over 90 percent of patients were getting the information.  These are packaged in unit-dose packaging.  I'll explain that in a minute.  Whereas, another study showed that for estrogen replacement therapy, which is not packaged in unit-of-use, only about two-fifths of the patients were getting that information. 
		Now, when I say unit of use, what I'm talking about basically is where the product comes kind of automatically packaged in the amount that the patient is generally prescribed.  You'll see many topicals and many inhaled medications coming in this kind of packaging so that the pharmacist doesn't have to repackage it.  It doesn't go into little amber bottles.  They just slap a label on it and give it to the patient.  This is basically something that is required in Europe but is not required in the United States. 
		Now, a second type of FDA approved patient labeling is labeling that is essentially a case where the FDA and the manufacturer agree that patient labeling for the particular product is appropriate.  Again, the sponsor drafts it.  The FDA approves it.  There is absolutely no uniformity in either the format or the content of what goes into the labeling.  It really depends on the sponsor and the review division that is reviewing it.  Basically it's all over the board.  So, there's no consistency, especially in having a uniform format where the patients would be able to find the information specifically that they're looking for.
		There is also no clear agreement as to whether this information is required to be distributed, unlike where you have a regulation that says, yes, this is required to be distributed.  We certainly have anecdotal evidence that indicates that the actual distribution is spotty, again especially when the information is not packaged in unit-of-use packaging along with the product.
		Now, the third type of information that's the focus here is what are called medication guides.  Medication guides came into being relatively recently with a rule that we finalized in 1998 and became effective in June of 1999.  This is unlike the products that are covered by specific regulations for patient labeling.  This rule was designed to identify products for which patient labeling is critical for safe and effective use.  Again, the sponsors draft this information.  FDA approves it.  It was designed mostly for outpatient products that pose a serious and significant public health concern that the agency believes that the information, as I said, is necessary for safe and effective use.  
		On average, the agency expected that between 5 and 10 products annually would need this kind of information.  
		Again, to address the issue of distribution, the rule actually requires that the information be distributed to patients, similar to the oral contraceptive and the estrogen replacement therapy regulations.
		When would you need a medication guide?  The rule basically specifies three circumstances under which a medication guide would be appropriate for a product.  One of the circumstances, the first one, would be where basically the information could help prevent serious adverse effects.  This is, for instance, where you have warning signs of particular side effects that can be recognized and, if acted upon promptly, can then be averted or the serious consequences can be minimized. 
		For instance, say you have a product that causes constipation that can lead to very serious complications of the constipation.  An action can be taken to minimize these complications by, for instance, the patient stopping taking the drug immediately and talking to their doctor.  So, this would be one instance where a medication guide would be appropriate. 
		The second type of trigger circumstance would be when the patient needs to know of serious risks that are relative to the benefits of the product that might affect the patient's decision to use the product or to continue to use the product.  So, you have a situation here where, for instance, a drug may cause serious outcomes of some sort or even life-threatening outcomes, but the drug itself is used to treat a condition that in itself is not life-threatening.  So, the patient needs to know where they fall in terms of determining whether they want to continue to take this product.  So, it's kind of along the lines of an informed consent purpose. 
		The third triggering circumstance is where the drug is important to health and patient adherence to directions is extremely critical to its effectiveness.  So, for example, the drug doesn't work unless it's taken in a certain way, say, on an empty stomach, and then no further ingestion for another 2 hours, and it's critical to the patient's health, and you don't necessarily even know that it's not working until something drastic happens. 
		So, those are the three circumstances under which a medication guide might be required.  In many cases, you end up with a lot of overlap, that you have both 1 and 2, for instance.
		Now, getting down to the requirements.  If you've required that a medication guide be distributed for a particular product, what's in that medication guide?  Well, the regulation specifies that it must be written in nontechnical, understandable language.  So, we're saying it has to be understandable to consumers.  It can't be promotional in tone or content.  It must be scientifically accurate.  It has to be consistent with labeling. 
		Even though it needs to be consistent with labeling, the language does not need to be identical to what's in the professional labeling.  In fact, if you think about it, if it was identical to what was in the professional labeling, you'd automatically be going against the fact that it should be written in nontechnical, understandable language for the patients. 
		Also, the information needs to be specific and comprehensive.  This is not information that is kind of vague directions for use without explanations because basically if you don't give people a reason for what they're doing, they generally don't do it.  A warning is not effective without having the rational behind it.  So, it needs to be specific and it needs to be comprehensive.
		It needs to be at least in 10 point minimum type because we have concerns about especially older patients who are taking a lot of drugs who don't necessarily have the best eyesight, and I have to be able to attest to that because I'm not even that old, and my eyesight is definitely failing.
		Legible and clearly presented.  We're talking about appropriate use of highlighting techniques.  You can use bolding.  You can use italics.  You can use underlining, anything that makes the important information stand out to the patient. 
		Basically this is the kind of information that needs to be in the medication guide, and it's under headings that are actually specified in the rule.  I haven't given you the headings here because of what I'll tell you in a couple of minutes. 
		The first information that the patient gets is what is the public health concern that created the need for the medication guide.  This is basically in a little section that says, what's the most important information I should know?  So, if they read nothing else, that is the information that they get. 
		They will get also the benefits of treating the disease and some information about the disease. 
		They will get the information about contraindications and what they should do if any of those apply.
		What will be included after that is instructions for proper use. 
		Following that is specific instructions, things for instance to avoid while you're taking the drug.  For instance, if the drug causes photosensitivity, there will be a very, very clear direction there to avoid being out in the sunlight and the reason for it.  Also, if the drug interacts with other products, that will be included.  The risks to mothers and fetuses, to children, to older patients would be included in this particular section.
		Finally, the side effects would be included.  Now, not every single side effect from the professional labeling, but the side effects that the patients need to know about will be included.
		The thing to keep in mind about medication guides is that distribution is required.  The manufacturer is responsible for ensuring distribution of medication guides.  There are a couple of ways that it can be done.  Either they can provide sufficient numbers of medication guides to the dispensers so that every patient will be able to be given one or they can provide dispensers with the means to produce enough.  That could be, for instance, through computerization.
		The distributors are also responsible for passing on medication guides.  This is also in the rule.  And there needs to be a notation on the container label that there is a medication guide -- this is a notation to the dispenser -- and that this medication guide needs to be given out to the patient.  
		Then finally, as part of the regulation, the authorized dispenser is required to give these out.
		Now, we do allow some flexibility.  We have built in some flexibility to the regulation.  For instance, the FDA can exempt a sponsor from any of the requirements of a medication guide that are in the regulation except for two, one being consistency with the labeling and the other being the title, specifically "medication guide."  
		Also, if the prescriber believes there is information in a medication guide that would be deleterious to the patient, then the prescriber can direct the dispenser to withhold the medication guide.  However, if the patient says, I would like to have the information on this drug, then the dispenser is required to give it out.  So, the patient can override a physician's withholding request.
		So, in conclusion, medication guides are for products that pose a serious and significant public health concern for which patient labeling, patient information that is approved by FDA is necessary for safe and effective use.  They provide a uniform format and content to facilitate patients being able to find the information that they need to use the drug safely and effectively, and they are required to be distributed to patients. 
		Thank you. 
		DR. BERGFELD:  Thank you very much.  Dr. Ostrove, before you leave, if I could ask a question or so.
		DR. OSTROVE:  Sure.
		DR. BERGFELD:  This has been enacted essentially one year, and what is the FDA's experience with the distribution and the monitoring of the distribution?
		DR. OSTROVE:  We have very little experience at this point.  
		One concern, obviously, is going to be distribution and monitoring.  There are a couple of ways to look at that.  One way is to put in place a compliance program to go out and see whether this is being distributed.  Another way to deal with it, of course, is by ensuring that the drug is packaged in unit-of-use, in which case the medication guide is already in there, and prescribers don't generally take out the information if something is in unit-of-use.  They just give it to the patient.  So that way you're almost assured that the patient is going to get it.  Almost.
		DR. BERGFELD:  The second question I have is how many drugs does this now apply to? 
		DR. OSTROVE:  Currently this applies to two products.
		DR. BERGFELD:  And they are?
		DR. OSTROVE:  One of the products is Lotronex, alosetron, which is used to treat -- I've forgotten what it's used to treat. 
		VOICES:  Irritable bowel syndrome.
		DR. OSTROVE:  Oh, everybody here knows.  This is very good.
		(Laughter.)
		DR. OSTROVE:  It's actually the example I gave with regard to serious complications of constipation.
		The other drug is Ziagen, abacavir, which is used in HIV treatment and causes a serious hypersensitivity reaction.  If the patient is rechallenged with the product, takes it again after having the hypersensitivity reaction, they can die within hours.
		DR. BERGFELD:  Now, the third question then and my last question is if there are only two drugs that are now on your current list to have this medication guideline apply to it, are there other drugs, foreseeable in the future, that would have this?
		DR. OSTROVE:  Yes, there are, but I'm not at liberty to say what they are at this point.
		DR. BERGFELD:  But you will be unfolding those over time.
		DR. OSTROVE:  Yes, we will.
		DR. BERGFELD:  Thank you. 
		DR. OSTROVE:  Thank you. 
		DR. BERGFELD:  Yes, Dr. Branch.
		DR. BRANCH:  What are the implications within a hospital practice of distribution of this information?  Because I've not heard of any mechanisms that have been introduced into hospitals to make sure that the patient has their informed consent or the information for this.
		DR. BERGFELD:  Is that just a statement of fact, or are you asking for a request of information? 
		DR. BRANCH:  I'm asking.  If a patient is an inpatient, is there the same obligation for distribution of information to that patient? 
		DR. OSTROVE:  Generally it was envisioned that medication guides would be primarily for outpatient use, but I think that conceptually, yes, they would be under the same obligation to give that information to the patient.  The products for which medication guides have been required by the agency at this point have all been outpatient products.
		DR. BERGFELD:  Yes, Dr. Greenhill.
		DR. GREENHILL:  Just a simple question.  What is the mechanism for reviewing the applicability of a medication guide to a product?  Does it come from the sponsor?  Does it come from FDA?  Does it come from the public?  What is the method or the chain of events that might lead to that being included as part of the review?
		DR. OSTROVE:  The regulation envisions that the FDA would notify the sponsor in writing of its determination that a medication guide is necessary.  Certainly the FDA is always open to hearing from the public.  There's the whole citizen petition route, and in fact we have gotten citizen petitions on this matter.
		Does that answer your question or was there more to it?  I'm sorry.
		DR. GREENHILL:  Is this a standard part of every review when there's potentially serious adverse events?  I don't understand how it might be introduced in the review process.
		DR. OSTROVE:  Okay.  That's a very good question actually, that piece of it as well.  This is something that all review divisions have been educated about, and they are aware of the mechanism.  So, in doing their reviews, at a relatively early stage, they ought to be looking at whether, in fact, the product, its benefits and its risks, is one for which one of the triggering circumstances would apply and discuss that.  In fact, they would then bring that up to a higher level within the center, and there is a coordinating committee at this point that looks at whether in fact a medication guide is appropriate.  So, this is not the kind of rule that simply will be applied haphazardly.
		DR. BERGFELD:  Seeing no other questions then from the committee, we'll move on to the specifics, the Accutane associated psychiatric events.  Roche is going to present.  Dr. Russell Ellison is the leader, and he will begin.
		DR. ELLISON:  Thank you, Dr. Bergfeld and members of the advisory committee and FDA.  We're pleased to be able to be here to put the psychiatric events associated with Accutane into perspective. 
		In February 1998, the product labeling was changed from a listing of adverse events to a bolded warning, which was based on a review of spontaneous reports of psychiatric events with Accutane.  Basically we had a signal which had yet to be confirmed.
		From February 1998 up to really now, Roche has been very diligent in trying to evaluate and trying to confirm this signal.  We had a pharmacoepidemiological analysis of reports conducted by Dr. Robert Nelson, who will present this to you, which is to put the individual reports into the context of science and medicine.
		We had a clinical review of reports of suicides and related events conducted by Dr. Jacobs because this does need a special clinical rigor in evaluating these cases.
		We also conducted two retrospective epidemiological cohort studies in two very large databases which are very often used to evaluate safety signals, the Uk General Practice Research Database and the Saskatchewan database.
		Finally, in parallel with this, we re-reviewed the biological and clinical literature.
		We believe that the evidence from these investigations does not support a causal association between Accutane and psychiatric events, including suicide.  That is, the signal has not been confirmed by these investigations. 
		We also believe that these investigations have revealed and shone a light on the fact that patients with acne, depending on age, gender, and prior history, come from a cohort that may be at high risk for concomitant psychiatric illness.  We believe that this has led to the opportunities to improve the overall medical impact of dermatologic practice.
		After my introduction, Dr. Jacobs will review the clinical context overall for the evaluation of psychiatric events and Accutane.  Dr. Nelson will review with us his pharmacoepidemiological evaluation of spontaneous reports.  Dr. Jack McLane, our Director of Medical Science and Safety, will review the epidemiological studies and the biological issues associated with this, and I will follow up with a brief discussion of risk management options.
		Thank you.  Dr. Jacobs?
		DR. JACOBS:  Good morning, members of the advisory committee and the FDA.  I'm a psychiatrist and suicidologist.  I have been studying the problem of suicide since 1972 when my very first patient attempted suicide in a hospital by hanging himself, only to be saved by another patient. 
		My work has included using principles of a psychological autopsy in reviewing over 300 suicides on an intensive basis.  I've also developed National Depression Screening Day, which is the first ever national program for screening for mental disorders.
		I will first present a clinical context for understanding the psychiatric conditions presented in the MedWatch reports, specifically suicide and depression, first in the general population, then in the major Accutane population, ages 15 to 24.  
		I will then discuss the dual use of the term "depression" as an illness versus depression as a symptom, particularly as it applies to medications.  
		Dr. Nelson will then present an epidemiologic analysis.  
		I will then return with a clinical analysis of the suicide reports using principles of a psychological autopsy.
		In terms of suicide, I'll provide an overview of the clinical and demographic correlates, the clinical features of suicide, suicidal behavior, as it relates to the spontaneous reports, addressing some of the definitional issues, then talk about depression illness versus symptoms, depression's relationship to suicide, and then go into depression/suicide in the Accutane population addressing the epidemiologic risk factors and the diagnostic issues.
		In understanding suicide, it is important to understand that it is a multifactorial event.  No one factor causes suicide.  Over 90 percent of persons who commit suicide are reported to have a major psychiatric illness.  70 percent have comorbidity, particularly with substance abuse.
		The factors that go into suicide include:  severe medical illness; personality traits; access to weapons; features of hopelessness; the relevance of family history not just from an environmental standpoint, but also from a genetic standpoint; life stressors; suicidal behavior, its relevance, impulsiveness; and neurobiology.
		In terms of Accutane, I've examined from a clinical perspective, psychiatric illness, neurobiology, impulsiveness, and suicidal behavior.  
		You see up here in the corner, I have "no apparent psychopathology."  This is particularly important for understanding the MedWatch reports, specifically in young people.  I will address that further when I talk about suicide in young people. 
		This is U.S. data.  The incidence of suicide has remained about the same for the past 10 years.  We have seen a slight drop, but the basic incidence is that there are about 30,000 suicides per year.  80 percent of suicides are in males, and it is the third leading cause of death in young people, representing 20 percent of suicides, approximately 6,000 per year.
		In terms of the clinical features of suicide, suicide is associated with severe depression.  The majority are not in mental health treatment.  75 percent have seen a physician in the previous six months.  As I mentioned earlier, no one factor is predictive of suicide.  60 percent of persons suicide on the first attempt, and no medication has ever been proven to cause suicide.
		If we apply these two areas to the profiles of suicides in the Accutane reports, we see that 80 percent of the suicides were in males.  The majority were not in mental health treatment.  75 percent had seen a physician in the previous six months, and the suicides that occurred were primarily on the first attempts.
		In terms of suicidal behavior, suicidal ideation, which again is listed in many of the reports -- and there are two primary definitions.  There is the non-specific, which includes thoughts of death, and then the specific, which is the more serious and how we look at suicidal ideation.  That's not only the thought of death, but it's the thought of death accompanied by an intent to die with a plan. 
		The prevalence of suicidal ideation is about 2.6 percent, and that's from NIMH data.
		Thoughts of death, which occurs approximately in 28 percent of the population, obviously is 10 times the incidence and, in my view, appears a lot in the case reports.
		Suicide attempts.  Much more difficult to study.  The basic distinction is self-destructive behavior that is accompanied by suicide intent versus self-destructive behavior that is reported regardless of intent to die.  This has particular relevance in the young population.  In the general population, there are reported to be approximately 18 to 1 in terms of attempts per completion.  In the young population, anywhere from 100 attempts to 1 completion.  Many more self-destructive behaviors, the intent much more difficult to establish.
		In trying to put suicidal behavior into some perspective in terms of suicide completers, we believe  that there are approximately 5 million people who have serious suicidal ideation.  The majority do not go on to attempt suicide, and a very small group, less than .6 percent of people who experience suicidal ideation go on to complete suicide.
		Depression is a prevalent disorder.  Approximately 12 percent.  Again, these are U.S. figures.  Approaching about 20 million people.  Depression is under-diagnosed and under-treated.  Only 20 percent of persons with a recent episode get treatment; 40 percent lifetime.  20 percent of persons with depression appear in general medical practices, 50 percent of whom are undiagnosed.  Therefore, in terms of the MedWatch reports, it would not be unusual for a person to be either currently depressed or in the beginning of a depression and appear in a dermatologist's office.
		There has been a decreased age of onset since World War II, and the male/female ratio is 1 to 2.
		It is important again, in understanding the  MedWatch reports, to understand the distinction between depression as an illness versus depression referring to depressive symptoms, "the blues."  When we talk about depression, we're talking about an illness, a syndrome.  In the DSM-IV, it is five of nine criteria.  There's severe social impairment.  The symptoms have to last for two weeks or more.  It is an episodic and persistent illness.  The symptoms not only have mood, loss of interest, biologic symptoms, including sleep, energy, appetite, but cognitive symptoms, including feelings of worthlessness, drop in self-esteem, and the most serious, thoughts of death and suicide. 
		Whereas, with the blues, which are a normal reaction to life events, the prevalence is twice as much, about 25 percent.  The symptoms are singular, usually affecting mood.  They're temporary.  They rarely produce suicidal thoughts and usually time will heal or a good listener, where the illness of depression requires medical and psychiatric treatment. 
		The issues of medication and depression.  I put depression in quotes because again we're dealing with the dual use of the term.  The question, are medications that are reported to cause depression, which are approximately 100, associated with diagnosed depressive disorders or depressive symptoms?  
		The majority of medications that are reported in the literature come from case reports.  When there have been attempts to look at these medications from empirical evidence, the reports are inconclusive.  Beta-blockers are the major example.  There have been multiple case reports of beta-blockers "causing depression."  When one looks at the literature, the literature is inconclusive and, in fact, states that they are not associated with clinical depression.  If they're associated with anything, they're associated with depressive symptoms.  The clinical significance of depressive symptoms is minimal.
		Adolescent depression.  Dr. Nelson will talk about the prevalence, but to state that adolescent depression is a prevalent disorder, its features make it particularly difficult to diagnose, including increased moodiness, irritability, argumentativeness, increased self-criticism, increased talk of death and dying, and threats of suicide.  Normal adolescents often appear moody, frequently argue.  The symptoms of depression overlap with traits of normal adolescents.  Parents, teachers, and other adults label it troubled teenage behavior.  
		I've bolded this last item because this again is relevant to the MedWatch reports.  Adolescents conceal symptoms from parents and caregivers, which makes it particularly difficult in understanding depression and specifically suicide.
		In terms of the relationship to stressful events, depression can occur in adolescents and in adults 50 percent of the time with a stressful event, 50 percent of the time without. 
		Here's a chart that looks at the suicide rate for all persons compared with the suicide rate for persons aged 15 to 24 from 1900 to 1995.  I've highlighted 1950 and 1980 because since 1950, from 1950 to 1980, the suicide rate has tripled in the young population, ages 15 to 24, from 4 per 100,000 to 12 per 100,000.  As of 1995, unfortunately, the suicide rate in young people has exceeded the suicide rate in the general population. 
		In applying the model that I showed earlier to adolescents, there are specific issues.  If we look at the age-specific stressors, that is where severe acne comes in in terms of its impact on self-esteem, but other issues in young people are academic problems and the role of a disciplinary crisis and humiliation.  But in order to understand suicide in young people, we have to look at exposure to suicide, conduct disorder, access to weapons.
		Now, again, no apparent psychopathology.  We believe that about 5 to 10 percent of young people on the surface, when one hears about a suicide, there is no apparent psychopathology.  It is not uncommon to read newspaper stories where the suicide occurred out of the blue.  
		But if one conducts a psychological autopsy and looks at these suicides, we see that there was subsyndromal psychopathology.  There was a past history of suicidality.  There was a familial psychiatric disorder.  There were legal/disciplinary problems, and there was presence of a firearm.  The important point here is that one cannot understand these particular suicides unless one conducts a psychological autopsy.
		I will now turn the podium over to Dr. Nelson who will present an epidemiologic analysis and then I will return with my suicide review.
		DR. NELSON:  Thank you, Dr. Jacobs.  Madam Chairman, committee members, Dr. Woodcock, and former FDA colleagues, good morning.  I'm pleased to be here to discuss this important issue.
		Over the 18 years of Accutane marketing, there have been many reports received through spontaneous reporting systems, which describe psychiatric symptoms or disorders in temporal relationship to the administration of Accutane in patients with severe acne.  Reviews of these issues were conducted in the past, and the current labeling reflects the most recent understanding of the regulators.
		Last year I was commissioned by Roche to review these reports as a pharmacoepidemiologist.  My full report was submitted to the agency earlier in this year, and a copy of the main body of the report, without its 20 appendixes, is included in the materials that the committee received as appendix 13.  By nature and necessity, this presentation will skim over most of the analyzed data and detail contained in the full report.
		This is the presentation overview.  I'll follow this format. 
		The objectives are to determine the nature and the extent of any relationship between Accutane therapy and psychiatric morbidity, to describe the types of reported psychiatric disorders, identify all associated risk factors, assess the magnitude of those identified risk factors, and to evaluate causality within a pharmacoepidemiologic framework. 
		The overall method of risk definition, when utilizing observational data from these spontaneous reporting schemes, is to identify a signal, attempt to confirm that signal in external databases, then if confirmed, strive to quantitate that confirmed risk.  Unlike an experimental setting, these three steps require different logic and the use of different data sources for their proper execution.
		The methodology I used is on this slide.  An extensive literature review, of course, was an important component of this review.  This is a complex area, as Dr. Jacobs showed you in his multifactorial slide.  Over 250 citations were used in this report, extensive review of the etiology and epidemiology of psychiatric conditions, including suicidal behavior.  And I tried to conceptualize and propose the interrelationships between the various factors in this model. 
		I reviewed the spontaneous reports to evaluate them for category, quality, and content, and to determine the value of spontaneous reports in explaining the proposed relationships that were developed during the literature review.
		Then I reviewed the epidemiology and conducted some epidemiological analyses to evaluate the relative likelihood of all the risk factors identified and to derive the relevant conclusions. 
		Dr. Jacobs already provided a summary of the literature review that's in the report, so I'll move right on to the spontaneous report review.
		Spontaneous reporting systems were designed 35 years ago to identify new, unusual, serious, and rare reactions.  These reports are anecdotal, and when they are from health professionals -- and not all of them are -- they are an index of suspicion of clinical observation.
		In the United States, most of these reports are received first by the manufacturer and placed into a corporate database by something known as the reporter term.  That's an extraction of the verbatim language in the reports and matched to a coding dictionary to file it away in a database.  Roche uses the coding dictionary of WHO-ART currently.  So, what I did in my review is look at all the psychiatric cases within the WHO-ART system organ class, which included every report that Roche had in their database. 
		It's important to understand that these reporter terms are filing terms and not necessarily analytical terms.  To understand this concept of the reporter term is key because if the reporter is a physician or a parent, the verbatim language is used.  For example, if a physician calls a particular episode "major depressive disorder" that gets coded as depression.  If a parent says my son was depressed, that also gets coded as depression.
		I took the reports in the Roche database and I organized them by the eight functional categories outlined in the DSM-IV.  I reviewed each and every report that was received by Roche between 1982 and a data lock point of April 30, 1999, and I reviewed all the reports worldwide, not just those in the United States. 
		Reports of psychiatric events represent approximately 9 percent of all the reports received for Accutane, and the vast majority of these reports were, as you can see here, for mood disorders or symptoms.  53 percent fell under the collective DSM-IV umbrella of mood disorders.  Now, because I put them under there, doesn't mean that they were all mood disorders.  They were descriptions, whether they be symptoms or diagnoses that fit under that general umbrella for categorization purposes.
		We focused in the review on mood disorders, psychotic disorders, and suicidal behaviors because those are the three entities that are in the current labeling.  The details of the terms I excluded are in the report.
		Now, when you try to assess the relationship between a drug and an adverse event, there are eight reasons that you go through intellectually to sort them out.  
		The first, obviously, is the temporal association.  
		You then look to see if there's a dose-response event occurring in these cases.  
		You look for a dechallenge.  That is, if the drug is removed, do the symptoms abate?  You look for rechallenge.  If the symptoms have abated and you reintroduce the drug, do the symptoms come back?  When you have a positive dechallenge and a positive rechallenge in a spontaneous report, that is usually considered your strongest evidence of a causal association. 
		You also look to see if there's a mechanism of action that's known and understood and plausible.  Although biological plausibility is not necessary, it is helpful to have one. 
		You look at class effects.  Are there other drugs in this pharmacological class that have reports or hopefully better evidence for a causal relationship? 
		Then, of course, you look for alternative explanations.  If you have no reasonable alternative explanations and many of the items on this chart, you have a very good case for causality.
		So, you look at the individual reports.  You assess their coded reporter term.  You assess the quality of the data, consistency of the data, including all the data elements, including things like onset and offset.  You relate the reports to the seven reasons I had on the prior slide.  You group like reports and you review them as a case series for content and consistency, and then you make your causal assessments. 
		This is a very important slide to understand.  When spontaneous reports are well-documented and for rare adverse reactions that have background rates that are low, spontaneous reports yield their most defensible data.  Spontaneous reports are of very diminished value when the outcome has a common background rate.  Spontaneous reports can be a very powerful tool.  However, they can also be misunderstood and abused as a tool.  Spontaneous reporting was never intended and cannot be used as a quantitative tool and has little interpretative value when the natural history of the outcome is common. 
		Again, I reviewed and analyzed and evaluated all the reports, and there are 100-plus pages of detailed analysis in the submission.  Having said that, I'm going to go right to the results of what I found. 
		There were 1,247 total reports under the DSM-IV domain of mood disorder.  Of those reports, there were 367 that had a dechallenge that was positive.  What I'm trying to do here is boil down and find the best cases amongst them.  Of that 367, I identified 23 cases that had both a positive dechallenge and a positive rechallenge.  As I defined before, these are the best cases.  37 of that 367 had a diagnosis for a mood disorder subsequent to the exposure.  The rest of them did not have a diagnosis, and I used that term very conservatively.  Whether a physician reported a diagnosis or whether a treatment was given, I considered that a diagnosis. 
		Most of these cases, especially the 23 here, are very strong, and I'm sure that the clinician that reported them was convinced that these were a cause-and-effect relationship, and when you review them at the individual case level, that's your conclusion.
		What I want to show here, because subsequent to the report, FDA had given us a list of additional reports that they considered to fall in this category, so we created a master list of the original 23 and the unique ones that FDA had sent.  Some of the differences accounted for -- some of them came indirectly to FDA through the MedWatch.  They also used a one-year-later data lock point.  So, that explains some of them, and the other ones were just a difference in judgment because, again, this is an interpretation of a spontaneous report. 
		I make this slide just again to illustrate the point that while most of them are from health professionals, only 4 out of the 34 cases had a formal diagnosis.  The rest were most likely reports of just symptoms. 
		Without going into detail, I'll tell you -- and you'll hear a little bit about it this afternoon -- that these dechallenge and rechallenge cases, both levels, have tremendous amount of diversity and inconsistency.  I could find no pattern of data within them.  
		So, what my summary is from the review of the individual cases is that at the individual case level, a small number -- and whether that's 23, 34, or 41 -- you'll hear different numbers this afternoon -- the conclusion is the same.  At the individual case level, a small number of cases imply a causal association between depressive symptoms and/or mood disorders and Accutane.  This conclusion is consistent with the reviews you'll hear from FDA this afternoon. 
		Psychotic disorder results.  I'm going to go through this a lot briefer.  There were 120 total reports under the DSM-IV domain of psychotic disorder.  20 of those had a dechallenge.  5 had a positive rechallenge and dechallenge.  3 of the 20 had a diagnosis.  Of the other reports of lesser quality, there were 9 additional diagnoses, for a total of 12 diagnosed cases out of the 120.  When I reviewed each of them in a case series, I can find no consistency on any of the parameters. 
		So, my conclusion from a review of these reports is that, again at the individual case level, there are at least 3 -- at least 3 -- that imply a causal association between the described psychotic disorder and Accutane administration. 
		Suicidal behavior reports.  Here I've included both suicide attempts and completed suicides.  Suicidal ideation is under DSM-IV as a depressive case. 
		There were a total -- and this is worldwide total -- of 168 reports before the data lock point.  104 were attempts; 64 were completed suicides.  
		Overall, the suicide reports were poorly documented, and none had anything close to a psychological autopsy performed.  I could find no relationship amongst the data in these reports and no dose relationship.  The male/female ratio is 5 to 1 for the completed suicide reports.  The ratio is quite different for the attempts. 
		In summary, I could find none of these 168 reports that imply a direct causality.  Let me explain to you a minute what I mean by direct causality.  It means that it does not include an intermediate stage of a psychiatric disorder.  So, none of them implies a direct causality between suicidal behavior and Accutane administration at the individual case level.
		Dr. Jacobs will come back in a few minutes to go into those cases in detail, as he said before. 
		What I'm going to do now is go into the epidemiology and the epidemiological analysis.  What I need to do is set the stage a little bit over the next few slides.  I'm going to focus in on the age group 15 to 24.  That's the modal age group.  That's where about 70 percent of the Accutane users are, including 85 percent of the males and 55 percent of the females.  I'm going to focus in on that group because that's where my comparator data are and I want to have like cohorts for those comparisons because I'm going to assess these cases in light of the natural history of the disease. 
		From the National Comorbidity Study here in the United States, I will take the 1-year prevalence, 12-month prevalence, of major depressive disorder and use that in my analysis.  Now, I'm going to be very conservative.  From here on in, I'm going to use major depressive disorder.  I'm not talking about the symptoms.  I'm going to focus down for comparisons on both the case level and the natural history level on major depressive disorder.  Very conservative.  
		Again, these data are from the National Comorbidity Study which is considered the best epidemiological study on psychiatric morbidity.  These are U.S. data only at this point because that's a U.S. study.
		Notice the male to female ratio of 1 to 2.
		I need to set up the slide for you because this is very important to my argument.  We take the cohort of Accutane exposed individuals in the United States.  Roche has estimated that to be, at the time of this study, 3.2 million individuals.  I take 70 percent of that to create a cohort of 2.5 million individuals in this age group that have received Accutane over the last 18 years. 
		The specific calculations for all these charts are on page 42 of my submission in appendix 13, if you have any specific questions about how I got these numbers and what calculations I used. 
		If at time 1 you have a 2.5 million person cohort that has not yet received Accutane, what would you expect as far as psychiatric morbidity related to major depressive disorder only at that time?  What you would expect, based on the epidemiological evidence, is 152,000 individuals with current active major depressive disorder.  You would expect an additional 240,000 individuals of that 2.5 million cohort to have a history of major depressive disorder but not actively symptomatic at time 1.  The vast majority of the individuals have no history and no active disease, 2.1 million. 
		I'm going to take these three sub-cohorts and pass them through a 6-month exposure to Accutane.  I know that most of them get it 4 months.  We used 6 months to have a good comparator.  What happens?  Of the 152,000 with current disease, no change.  In other words, disease will go the entire 6-month period in about 30,000, 20 percent.  You would expect 80 percent of those cases, since depression is a cyclical disease, to abate.  But 35 percent of those that have already abated would have reoccurred in that 6-month time period, to give you an additional number of 42,700 at time 2. 
		Of those with a history of disease, but no active disease at time 1, passed them through the 6 months, and you would expect again a 35 percent reoccurrence of disease, to give an incidence of reemergence of symptoms here of 84,000 from this subgroup.  
		Of the 2.1 million that have no history and no active disease, using an incidence rate of 1.2 percent, you would expect a true incidence of 25,290 to have occurred first time within that 6 months.  These are amazing numbers.
  		You add these together, and at time 2 you have a prevalence of 182,500 with a total incidence -- new incidence, plus all reoccurrence of disease -- of 152,000 cases.  That means that during the 6-month period of exposure to Accutane for these 2.5 million individuals, 152,000 had a reemergence of major depressive disorder.
		Now, how does that relate to the cases?  If you take the new incidence of 25,000 and contrast it to the newly diagnosed cases in the database -- and again, the 102 is going to be very conservative.  When in doubt, I put it in -- you get at most 102.  When you contrast the total incidence of 152,000 to all the cases in the database that could be considered new incidence or reoccurrence, this is the contrasting figures.  These are the cases, the vast majority of them which were not, by any stretch, a diagnosable disease.  They were symptoms. 
		Now, take the 152,000 and let's populate a scatter plot where you have the y axis being the quantity of cases, the x axis being time to onset or offset or re-onset or re-offset, and then the z axis, the dose.  This is an illustration.  This is not data-driven.  This is an illustration.  Please understand that because we don't have the data on 152,000.  But it's an illustration to prove the point that on a dose duration matrix, every one of the possible data points have hundreds, if not thousands, of cases that can explain what you see on clinical observation regarding onset, offset, or rechallenge.
		So, every onset and offset -- in other words, a positive dechallenge or positive rechallenge seen in the spontaneous reports -- could be accounted for by hundreds of background cases of this cyclical disease.  Therefore, given this extreme density, it is difficult to value even the most rigorous individual case report.  It is very easy to be misled by coincident individual clinical observation here. 
		In addition to that very high background rate of disease and even higher background rate of symptoms, there are a number of very substantial risk factors that need to be taken into consideration in this population.  These data that I'll present now are again U.S. data from the U.S. Substance Abuse and Mental Health Administration's National Household Survey. 
		For this age group -- and we're still talking here U.S. -- that survey estimates that 7.2 percent of these individuals will be heavy alcohol users.  That's defined in the survey as 5 or more ounces of alcohol 5 or more times a month, substantial alcohol consumption.  That's a cohort of about 180,000 from the 2.5 million.  Approximately the same number will be illicit drug users.
		Assuming extensive comorbidity, combined alcohol and drug abuse, you can estimate that to be about a quarter of a million or about 10 percent of the total exposed cohort of young Accutane patients would be expected to either be a heavy alcohol user or a substance abuser or both.
		So, you put these alternative risk factors together and you have a quarter of a million alcohol/drug abusers amongst that cohort.  Many of these abusers, of course, are comorbid with the 152,000 incident cases of mood disorder.  So, you have a total number of persons in this cohort with some form of DSM-IV disorder that could be up to 20 percent or one-half million individuals. 
		Psychotic disorders.  I'm going to do this one real quick.  You would expect in that cohort that we've been examining a prevalence of about 1 percent, possibly less.  A male/female ratio, unlike depression, is 1 to 1.  These are basically schizophrenic patients, but given the amount of exposure, you would expect about 25,000 cases, prevalence. 
		In the older group, you have more prevalance.  This is a figure with the age and gender adjusted distribution of Accutane users.  You would expect an additional 14,000.  If you add the covariates of alcohol/drug abuse and age and gender adjust them, you would get an additional 4,000.  Assuming some comorbidity, of course, you can estimate that of that 2.5 million person cohort, you would have expected 40,000 prevalent cases of psychotic disorder.  We had in the case reports, 120 case reports, 12 of which were diagnosis.  
		Suicidal behavior.  My first chart here is from a reference by Beautrais, et al. in 1996.  I put it up to show you some empirical data.  These are suicide attempts and the relationship of psychiatric disorders to suicide attempts.  This is just for females, this part of the chart, under 30, over 30.  You'll see odds ratios here ranging from 21 to 58, depending on age of the female for mood disorder.  That's interpreted if you have a mood disorder, you are 21 to 58 times more likely to have a suicide attempt than if you did not have a mood disorder.  That's an attributable risk of about 80 percent, and it's brought up here to show that -- and then you add the other psychiatric conditions.  Suicidal behavior without depression or psychiatric morbidity is rare. 
		Take the cases that were in the database and compare them to their comparable national estimates.  There were 64 cases in the database.  I take the 38 that were from the United States for this analysis.  All I've done here is take the death data from the National Center for Health Statistics, 1997 mortality data, and I age and gender adjusted them and spread them along the bottom part of this chart and called them "expected suicides," and then took the cases in the database, the 38 U.S. cases, and put them across age and gender on the top. 
		If you didn't know the context, you would see 38 cases and you would comment that that possibly is an excessive amount.  What you see is you expect nearly 400 cases in that cohort of individuals.  Suicide is rare but it does occur.  So, there's no excess in the reports in the  database, and you can see the gender and age distribution to be very representative of what would be expected.  My conclusion by looking at these case reports and looking at these kinds of data is that it's very likely that these reports are a sample of what would be expected.
		Conclusions.  There are a small number of reported cases that imply causality between depressive symptoms or mood disorders and Accutane administration at the individual case level.  There's no question there's a signal. 
		However, an assessment in the context of natural history and alternative risk factors provides strong evidence that the described symptomatology and disorders are much more likely to be associated with factors other than Accutane.  So, I failed to confirm that signal.
		Unfortunately, analysis with these kinds of data do not allow any potential risk factor to be completely ruled out no matter how unlikely it may appear.
		My conclusions for psychotic disorders.  Again, there are a very small number of reported cases that imply causality between the described psychotic disorder and Accutane administration at the individual case level.  However, an assessment in the context of natural history and alternative risk factors provides strong evidence that the described symptomatology and the disorders are much more likely to be associated with factors other than Accutane.  Unfortunately again, these type of data do not allow any potential risk factor to be completely ruled out no matter how unlikely it will appear.
		Conclusions for suicide.  There are no reports amongst these 168 reviewed that imply a direct causal relationship between the administration of Accutane and suicide or suicidal behavior.  An assessment in the context of the natural history and alternative risk factors provides strong supporting evidence -- the evidence is not as strong as in depression -- that the reported cases are much more likely to be due to the factors other than Accutane.
		Dr. Jacobs will return in a minute to give you a detailed clinical evaluation of these cases because that's where the real strength lies. 
		My overall conclusions.  Given no clear biological plausibility, no consistent pattern in the data that I reviewed, complex environment of background symptoms, very high background rates of disease, very high background rates of alternative risk factors, I conclude that there is no evidence in these data to support a causal relationship between Accutane administration and psychiatric disorders.
		Thank you very much for allowing me the opportunity to place these data into proper perspective.
		Dr. Jacobs?
		DR. JACOBS:  While I was here, I did want to specifically answer your question you asked yesterday, Dr. Malone, about Accutane and CNS.  There's no scientific evidence that Accutane affects the neurotransmitters at all, and Dr. McLane will address the issue of biological plausibility after I'm finished. 
		What I've done in my clinical analysis of the suicide reports is I asked the following questions.  Is there any pattern to the suicide reports in relationship to Accutane in terms of gender distribution, in terms of on/off Accutane?  What is the significance of the temporal association with "depression"?  Does Accutane exacerbate underlying psychopathology and lead to suicide?  As you'll hear later on this morning, there were a number of suicide reports which had preexisting psychiatric illness.  Does Accutane cause impulsive suicides?
		I broke the suicides down into various categories in terms of their relationship to Accutane use, the concealment of symptoms, which I mentioned earlier in terms of the youth suicides, the confounding factors, the preexisting psychiatric history, the issue of no apparent psychopathology, and miscellaneous.
		In terms of the relationship to on/off Accutane, there were 30 cases on Accutane, including 4 that were on over 6 months, 24 cases off, 10 unknown.  No evidence of a predominance of on/off factor.  In terms of gender -- and these are worldwide.  These are not just the U.S. cases -- of the 64, 53 were male, 11 female.  The total suicides, as mentioned earlier, are consistent with the known demographics of suicide.  In looking at the on/off ratio, again the gender distribution is the same.
		Further, some case examples of relationship to Accutane.  There's a case described of a 22-year-old male, no relevant findings.  Committed suicide by firearm.  I should mention that these are typical of a lot of the suicide reports.  There's very little information.  But if we compare this with a 19-year-old male who committed suicide, the same method, had a preexisting history of psychosis, there's evidence of school stressors, and was on Accutane for 6 months.  While he's on, there's no evidence of exacerbation of his underlying illness.  He commits suicide 9 months later.  My analysis, no consistent relationship to Accutane, if you compare these cases.
		Depression occurring while on Accutane.  17 out of the 64 reports indicate "depression."  10 of the cases committed suicide on Accutane, 7 off, and only 1 case had psychiatric treatment.  Again, no consistent relationship with the term "depression."
		What about concealment of symptoms?  And there are a number of cases unfortunately like this.  This is a case of a young boy, 14, who was on Accutane for 2 months.  No reported psychiatric history.  No evidence of depression or suicidal ideation while he was on Accutane.  However, there is evidence of preexisting depression and suicidal ideation.  This was discovered by a diary after the suicide.  Depression with suicidal ideation requires psychiatric treatment.  Therefore, the depression and suicidal ideation was concealed from family and physician.
		Prior psychiatric history related to on/off Accutane.  In my view, this is very compelling information about the Accutane story and suicide.  What is the impact of Accutane on this at-risk group for exacerbation of underlying illness leading to suicide?  There were 21 cases that I could find that had preexisting psychiatric history.  9 committed suicide on Accutane, 12 off.  
		What I did is I looked at the cases off of Accutane.  One could think about it, in a sense, as a controlled case.  These were patients who were at risk.  They did commit suicide.  Obviously, they were given Accutane.  One could not do a study like this. 
		The duration that they were on Accutane varied from 3 months to 18 months.  In terms of the time off, it's anywhere from 6 months to 10 years.  While these persons, again at risk, were on Accutane, they did not develop symptoms of their underlying illness.  Accutane did not precipitate symptoms.  The suicide, therefore, was unrelated to Accutane and was clearly related to the underlying psychiatric disorder. 
		A case of no apparent psychopathology.  Here's an 18-year-old male, was on Accutane less than a month, no history of depression, mood swings or stressors.  He committed suicide by inhaling pellets placed in a canister attached to tubing and a face mask.  If one analyzes this, certainly this is risky behavior.  The method was suggestive of getting high, and then there's a whole question here about the suicide intent and was this an accidental death.
		These are some miscellaneous cases.  This is a tragic case of a murder/suicide, of a woman who was on Accutane for 8 months and was off it for 4 months.  At the end of that 4-month period, she killed herself and her child by drowning.  The child had not been exposed to Accutane.  There was a prior history of postpartum depression.  The Accutane was stopped because of "delirium," hospitalization offered but refused.  
		In analyzing this case, infanticide is consistent with psychotic depression.  Postpartum depression occurs in manic-depressive illness.  The delirium described was most likely a psychotic episode.  The events here were related to a severe underlying psychiatric disorder.
		In terms of impulsive behavior, here's a case of a 21-year-old male with a psychiatric history.  The patient had been in and out of substance abuse rehabilitation treatment.  Was on Accutane for 6 months.  During that period of time, there was no report of depressive symptoms nor of drug relapse.  He committed suicide 1 year off of Accutane.
		In terms of my analysis, substance abusers are at risk for mood disorders and impulsive behavior.  Accutane did not cause relapse of any of these symptoms.  Therefore, the suicide was related to the preexisting psychiatric condition and happened a considerable amount of time after the discontinuation of Accutane.
		In summary, there's no alteration of the gender distribution in the suicide cases.  There's no impact of on/off Accutane.  There's no significant relationship to concurrent depression.  There's no exacerbation of underlying psychiatric disorders.  The lack of warning signs seen in many of the cases is consistent with what we know about youth suicide, and there's no evidence of a impulsive factor.  
		Thank you.  I will now turn the podium over to Dr. McLane.
		DR. McLANE:  This is where we are in the series of talks.  I'm going to present a couple of different types of analyses in order to confirm the signal.
		When we look at the material that we have, Dr. Jacobs and Dr. Nelson have looked at the post-approval analysis.  They've looked at the spontaneous reports and have done this type of analysis.  We had also initiated, when we started looking at the signal, a series of epidemiological studies.  One of them was to look at the relative risk.  Another was to look at the prescribing behavior.  I'm going to show, very quickly, the results of this information. 
		We've also gone in and looked at the prospective analysis, using our clinical trial that we were running with a new formulation, to see what type of information we could obtain on patients that were being treated with Accutane at different doses.
		The first analysis was a retrospective epidemiological analysis.  The purpose of it was to determine the relative risk for psychiatric disorders.  This was a population based epidemiological study with matched control cohorts.  It involved an analysis of the prevalance rates for a variety of psychiatric disorders and suicide and suicide attempts.  There were not sufficient numbers in the suicide and suicide attempts in order to do an analysis. 
		It also brings up that there were a number of caveats within this type of study.  These have been presented in your briefing document and will be presented later this morning.  But it involves the types of codes that you can use for ascertainment of the psychiatric conditions, the actual type of acne the patients had, the history of the patients, and also even the power.  These types of studies are at best just supportive. 
		The two different types of databases that we looked at within this are the Saskatchewan Health Database in which we were able to identify, using the definitions within the study, 7,000 Accutane users, and we compared this with antibiotic drug users in which we were able to identify 13,000 patients. 
		The smaller study, which I won't present any results from, was the United Kingdom General Practice Research Database, in which we had only 340 Accutane users and 676 antibiotic users. 
		Let me just show you the end results.  When we compare the relative risk for developing of psychiatric conditions compared to non-exposed Accutane patients -- these are the Accutane patients that were, by definition, prior to their exposure to Accutane -- you see that the relative risk was 1. 
		When you compare it with patients 3 months after their first prescription for Accutane, you also see that the relative risk was quite low, and basically the relative risk of 1 means that it was exactly the same as your comparison group. 
		When we looked at the antibiotics, you also see that the relative risk was very low.  The confidence intervals were wide enough to say that this was near unity.
		When we looked at the history of the patients that had development of psychiatric conditions, as expected, we saw that the psychiatric history was the only predictive factor for development further of additional psychiatric conditions.
		Another way to look at the information was to use other epidemiological tools.  There's a new tool that's been developed by Dr. Hallas and was published in the Journal of Epidemiology in which patients are evaluated for the prescriptions that they receive before a drug of interest versus prescriptions of antidepressants they receive after the drug of interest.  So, we looked at this information.  In the publication, this was used to confirm a signal for ACE inhibitors and for calcium channel blockers.  In order to look at the signal, what you do is you develop a prescription sequence ratio.  You're looking at the symmetry analysis of this prescription.  So, in our case, we were looking at the number of patients that were prescribed Accutane before their antidepressants, and you develop a ratio with the number of patients that were prescribed Accutane after the antidepressants.  A ratio near unity indicated no effect. 
		We also looked at this by relationship to all antidepressants, amines, the SSRIs, or other ones that were identified.  The database that we looked at was the Synergy Pharmacy Claims Database.  This database covers 30 percent and registers 30 percent of all prescriptions in the United States.  So, it's a very large database in which we were able to identify 17,000 Accutane patients within this.  However, for the prescription of having a co-medication for antidepressants as well as Accutane, we were able to get this type of ratio.  So, for all of the antidepressants, we had 1,300 versus 1,400 patients before and afterwards, and from that adjusted rate ratio, then we were able to see that this was near unity.
		If this was non-symmetrical, as it was with the ACE inhibitors, the adjusted rate ratio for ACE inhibitors was 1.29.  For calcium channel blockers, it was actually 1.31.  So, again, this is information that provides evidence against an association of Accutane use with antidepressants.
		We looked at this for comparison purposes for minocycline.  Minocycline in this age population is used predominantly for acne.  Again, we see the same type of near unity for the antidepressant prescriptions that are prescribed before and after the use of the minocycline.  This report will be submitted to the FDA.  We just received it in the last few weeks.
		Another way to evaluate this is to look at the prospective analysis of the signal.  In order to do that, we were able to use two tools within our study.  The first was a mood assessment questionnaire.  This is four questions that we asked at every monthly visit of the patients.  If the patient had two positive answers to these four questions -- these questions were developed by Dr. Jacobs and are just typical mood assessment questionnaires on sleeplessness, how they feel, and so on since their last visit.  If they had two or more positive answers in there, they were then asked to take the Beck's Depression Inventory at that visit.
		In addition, the Beck's Depression Inventory was used for every patient at the beginning of the therapy, at baseline, and at the end of therapy, which was at 20 weeks in this trial.  
		The Beck's Depression Inventory is a very useful tool in order to measure sensitivity of changes from one category of depression to another.  So, it was an appropriate tool to use.  It's also been a tool that has also been used to confirm other signals for drugs that have caused antidepressive effects. 
		The change of the scores that we were able to obtain within the trial showed that with the new formulation -- which the patients were exposed just once per day at .4 milligrams.  They had 250 times less exposure than the patients being treated with Accutane.  So, this also allowed us to evaluate a dose effect in this trial as well.
		What we see is that the majority of the patients did not change categories.  Here we're looking at just the categories which is the Beck Depression Inventory, which is minimal, which is 0 to 13, mild, moderate, or severe.  We had no patients that were severe.  And we're looking at the change in that category or the change in grade.  You can see that the majority had no change in their grade or score.  However, there were some patients that had a decrease in their grade, going from moderate to mild or mild to minimum or even moderate to minimal.  This would be the change of a grade of 2.  We had a few patients that also had a change in grade going from minimal to mild or mild to moderate.  There was a very good balance between the two different formulations, as well as the balance between change in grade upwards versus a change in grade downwards.  In fact, there was the trend of going downwards.
		When we looked specifically at the mean scores of the Beck's Depression Inventory, then what we find is that on the baseline levels on both of the arms of the trial, we had 3.5 versus 3.6, and at week 20 at the end of their successful therapy, we had a mean Beck's Depression score of 1.7 and 1.9.
		It's been known, for example, that pulmonary patients that are being treated with corticosteroids that have been measured with the Beck's Depression Inventory have had an increase in their mean scores.  We also know with digoxin that you also have an increased score with the Beck's Depression Inventory.  So, this is a tool that can be used.  And the case with Accutane is that we do not get a confirmation of the signal.
		Now, in the briefing document, you have a number of observational reports that are presented in the literature from a number of individuals that have been treated with high vitamin A doses or other retinoids and are trying to draw an association.  What we could not do is establish a linkage between the retinol treated patients or the other retinoid treated patients based on their biological plausibility. 
		What you need to be able to do within a plausibility is not only to show that there are systems available, but you have to show that there's functionality of the systems.  So, one of the things that we wanted to look at carefully was to evaluate what was the functionality of the retinoid systems within the brain and also what was the evidence that was presented from these patients that had high doses of vitamin A.  When you look at these anecdotal reports, then you see that these patients have been taking high doses for extremely long periods of time and are extensively elevated.
		What we have then is that when we look at these types of information, we know that to be able to detect receptors using messenger RNA, which is the very beginning part of the signaling system, you can find specific dopamine enriched brain regions that do have retinoid receptors within adult animals.  
		However, we also know that these are not necessarily functional because the localization of these proteins differ from the localization by messenger RNA.  You can have different detection methods to determine whether a receptor is present in the brain or not.  Just having a message doesn't mean that the protein is there, and if the protein is there, you don't necessarily have the functionality of that receptor.  If you had functional receptors, you would have different types of behaviors.  For example, with the dopamine enriched areas, you would expect some of the symptomatologies to be tremors or Parkinson's-like syndrome.
		We also know that there are a number of different receptors that do have retinoid response elements.  That means these are elements that can be regulated by retinoids.  Dopamine receptor genes are one of the receptors that are pointed out.
		Dr. Adams has mentioned that in the embryonic brain that there are a number of receptors that are responsible for hind brain.  These are, for example, the Hox genes or the homeobox genes that are responsible for normal development.  Well, the dopamine receptors that have been detected with active receptors are from cells that were embryonic or they were cells that were only in culture which have embryonic-like features.  It's most likely that perhaps the dopamine receptors only respond to the retinoid when they're in the embryonic stage.
		We also know that there's information that isotretinoin can be found in the brain after injections into animals.  That's not surprising.  It's a lipid soluble molecule, and many different types of lipid soluble molecules can bypass the blood-brain barrier.  It doesn't imply that there's a functionality of that molecule in the brain.
		So, although some of the component factors are in place, retinoids have not been shown to activate genes to induce behavioral or psychiatric changes.
		One of the other pieces of evidence that you can add to that is in mice lacking retinoid receptors, there's no major behavioral changes in these animals.  They needed to do special studies in order to determine that in these animals the only effect they were able to observe was long-term memory changes.  These were identified as long-term potentiation or long-term depressive changes, and these might have been involved during the development of the embryos when these receptors were absent during the embryonic development of the brain.
		There's also a lack of evidence demonstrating the functionality of the retinoid signaling pathways in the mature central nervous system.  There's no evidence in the literature of any of these signaling pathways being present.  This was pointed out by Dr. Adams earlier yesterday in her discussion.
		All of the available evidence then does not confirm a system.  The biological plausibility of the signaling pathways with the retinoids has not been established.  However, the background disease rate in the population warrants attention to signs and symptoms of the psychosocial disturbances by dermatologists.
		At this point then, I'll turn this over to Dr. Russell Ellison.
		DR. ELLISON:  I will try to be brief to keep on schedule.  Thank you for this opportunity to wrap this up.
		Just to review, the evidence that you've seen that we've generated to try to put these issues into perspective we do not believe supports a causal association of psychiatric illness with Accutane.  The signal generated by the spontaneous reports that we discussed could not be confirmed.  Indeed, specific information related to possible risk of events, even in an associated context beyond the known risk factors for disease, is lacking.
		What we have observed is that patients with severe acne or acne in general come from a cohort which, depending on age, gender, and prior history, may be at high risk for concomitant illness.  
		So, when we're evaluating risk management issues around psychiatric events, where we have a degree of uncertainty around the causal association and we have little information about risk factors, we have to ask what information do we want to convey with what desired actions to be taken by whom and in what circumstances.  We believe that to focus prescribers and patients only on the Accutane issues, particularly with respect to the uncertain causality at present, may lead them to miss the very high level and the likelihood that people could have psychiatric disease irrespective of their acne treatment.  
		So, we see risk management in the context of psychiatric disease as a concomitant illness where, for example, with continuing medical education, you would alert the prescriber to this phenomenon with the possibility that he can use the treatment venue as an opportunity for identifying possible problems, that is to say, to enhance the overall medical impact of his practicing in this group of patients.  But this would be applicable to all high risk patients and Accutane information would certainly be included so there can be a degree of vigilance. 
		For example, to ask the same questions about labeling.  We think there's an opportunity with the professional labeling to certainly include the new Accutane data, to talk about the symptoms so that we're more informative, to talk about discontinuation if we can decide, indeed, what to do, and also to use this opportunity again to alert professionals to the comorbidity in all high risk patients. 
		For patients, we think there's an opportunity to certainly communicate the Accutane information that we know, to have them be alert to symptoms which can be described in laymen's language, to alert them to inform their physician of previous history, to be alert to the possibility of psychiatric illness, irrespective of Accutane treatment as well.  Not to do this would be to miss an opportunity to prevent disease and to manage it.
		I haven't dealt with all of the options put forward in the questions, but I think these are fairly important ones.  With respect to informed consent, this is an interesting issue because of the issues of the relative strength of a causal association compared to the other serious adverse events in the label which do not appear in the informed consent.  I think more importantly is what would we be informing patients about, which would be relevant for them to be giving their consent to treatment without a strong statement of cause or estimates of risk.
		Now, let's apply the same parameters to assessment before and during treatment.  This would be monitoring in the questions that you have.  Simple questionnaires, which can, in fact, be implemented in the waiting room, are available to identify the possibility of psychiatric illness, but simple screening tools cannot confirm or rule out this illness in the hands of a non-psychiatrist.  So, for all high risk patients, this could become part of the dermatological assessment as a signal to refer the patient for psychiatric help irrespective of the treatment you're going to give them, but also you would include vigilance about Accutane itself in this regard.
		The concern that we would have about this, which would need to be addressed, would be the potential risk of conflict with the time needed for pregnancy prevention in women.  We had a discussion yesterday about the time taken to provide the education, in the physician patient context, for a clear, known risk, with a very, very important job to do to prevent pregnancy.  And adding more burden to the physician in this regard may, indeed, dilute this particular issue.  This is a very hard call to make, but hopefully if one was going to do something, the waiting room questionnaire and the review for high risk patients, people coming from a cohort with a high background of disease may be helpful.
		Now, finally formal studies.  Before I go on to the details, which I'll keep short -- we can provide more information in the question period.  I think it's first important to ask what will we do with the answer because then asks the question of what kind of answer do we need and what strength of an answer do we need, which then leads to the issue of what questions do we need to ask and how do we need to ask them. 
		With this respective problem, there are the following interesting difficulties.  We have a unique drug, unique in the sense that for many patients nothing else will work.  This has a lot of implications for the question we're going to ask and how we're going to ask it.  We have a relapsing, remitting illness.  Even major depressive disorder is relapsing and remitting.  We have soft endpoints to evaluate which are very susceptible to observer bias and placebo effect in patients, and as we've noted, we have a very high background prevalence rate with a low de novo incidence rate.  So, this leads to problems. 
		We believe that it's probably almost impossible to definitively rule out or to confirm the signal with further studies.  We think it's going to be very, very difficult to define, characterize or quantify the risk.  We think it may be possible, to some extent, to decrease uncertainty, but again I'm not entirely sure what we would do with that answer.  So, let me go through this.
		First of all, from the prospective clinical trial question, I'll be brief.  Obviously, with a unique drug, we have a problem with randomizing to a control group where only Accutane may be effective in someone who is facing lifelong facial disfigurement.
		The hypotheses and sample size also become problematic for several reasons.  First of all, with a low de novo incidence rate of about 1 percent in a 6-month period, we're looking at very large numbers.  We have actually looked at an open design around this as an example of the difficulties, which we can speak to in the question period.
		Finally, blinding of patients who are taking Accutane when 93 percent of them get Accutane side effects, many of which are easily identifiable as mucocutaneous effects, makes a blinded study almost impossible for inter-observer and patient bias.
		With respect to open cohort studies, these would seem, on immediate inspection, to be more feasible and perhaps more interesting.  The first problem is we will not find a matching cohort with respect to severity of disease because of the uniqueness of the drug, or at least it will be extremely difficult.  The severity of acne, as we've heard from dermatologists, clearly relates to having depressive symptoms or disturbances of mood.  Management of that disease can change those depressive symptoms or mood.
		So, it really is going to depend on the specificity of the question you would ask and again the confidence you would need in the answer.  Certainly these are going to have to be prospective.  I think that is what was intended by the question. 
		I think in terms of time and feasibility and ability to further clarify these issues, perhaps you would imagine that retrospective epidemiological cohort studies would provide our best bet, and they may well do so.  The question is going to be to find a good database, an available database that has the right size, specific coding, and population definitions, and the methodology to manage the analysis of that database.  The studies we did, even the power was probably only good enough to look at a risk that was two- or threefold the current prevalence.  So, I think we would want to know a number that was much lower than that.  So, I think the challenge there is going to be to define databases where we can indeed do this. 
		With respect to the last point, which is in vitro and in vivo preclinical studies, I think the issue here is to be careful that we are looking at specific models for specific psychiatric illnesses versus looking at general toxic reactions in the brain which have been observed with many drugs at very high doses that cross the blood-brain barrier because the sort of toxic reaction is not connected to the plausibility of causing major depressive illness or suicide.  I think there are perhaps some models available.  We have to be very careful with the dose so that we have extrapolatability and very careful about the extrapolatability of the model. 
		So, I think that sort of summarizes where we would go with studying this issue.  It is fraught with problems.  For the major answer, we believe it's essentially impossible. 
		Finally, our conclusions are again that the evidence does not support a causal association between Accutane and psychiatric illness.  The signal that was generated by the spontaneous report reviews which implied causation has not been confirmed by further evidence.  Additional studies might somewhat clarify but certainly not definitively resolve these issues.
		Now, much has been learned about psychiatric disease in acne patients and we believe there's an opportunity to enhance the overall medical impact of the management of all acne patients in a dermatological practice.
		Thank you for your attention.
		DR. BERGFELD:  Thank you very much. 
		Our agenda shows us that we're going to break now for 15 minutes, after which the FDA will present with their multiple presenters, followed by the discussion of the committee.  So, at this time I would like to call a 15‑minute break and we will reassemble here at 10:35.
		(Recess.)
		DR. BERGFELD:  Would you please take your seats?
		I'm going to be changing the agenda slightly.  We will have the FDA presentations, followed by the open public hearing.  We will then adjourn for lunch at 12:15.  We only have a half hour lunch today.  So, it's 12:15 lunch.  12:55 we will reassemble, at which time we will have committee discussion, answer of the questions posed to us by the FDA and a vote.  Then at 1:55 we will move on to Accutane New Formulation.  Again, we're changing the format, moving the public hearing up after the FDA presentations.
		So, at this moment we will go forward with the FDA presentation.  It's my understanding that Dr. Alan Byrne will speak to us on isotretinoin and depression.
		DR. BYRNE:  Thank you, Madam Chairman.  Good morning.
		I'm going to talk today about isotretinoin and depression.  This basically is the clinical experience I've had in relation to my exposure to this drug.  I'll give a little bit of a background now, if I could see the next slide, please.
		I was working in the University of Alberta in the Psychiatry Department in 1993 and over a period of about 3 months, I was exposed to three cases of depression in young individuals.  One of the most important factors I felt in relation to these individuals was they had all recently received isotretinoin therapy for acne, and their depression presentation was atypical. 
		I didn't know a whole lot about isotretinoin at that time, and I was alerted to the fact that it was a vitamin A derivative.  This sparked a thought in my mind in relation to a lecture I had in university in pharmacology where we were told about Arctic explorers in the early 1900s having developed psychosis following eating polar bear liver, which apparently has very, very high levels of vitamin A in it.  So, it sparked my interest and I decided I would do a little bit of background work.
		In relation to the cases, these there three young individuals.  There was no previous history of depression, no family history of depressive illness.  In all cases, there had been an abrupt deterioration in mood.  The individuals had associated irritability which was very pronounced.  They were very aggressive, particularly with family members, and this was out of character and new.  As I mentioned, all three had recently used isotretinoin for acne.
		I'll describe the individual case reports that I described initially first.
		The first individual was a 28-year-old lady.  She complained of low mood and agitation for approximately 8 months.  She described marked irritability with family members to the extent that this had actually caused a deterioration in her relationship and the breakup of her marriage, but the irritability had predated the marital disharmony.  She described poor sleep, poor appetite, and anhedonia, or a total absence of joy in her life.  She had had a 4-month period of treatment with Accutane during the year, and the depressive symptomatology had commenced during that period of time.
		The second case was an 18-year-old male who had presented with having had an abrupt onset of depression whilst receiving isotretinoin therapy.  He was aggressive with family members again, and he had had violent thoughts and violent outbursts.  He had suicidal preoccupation, and by the time he actually was referred to me, he had actually taken an overdose of tablets, from which he had recovered.  There were no obvious precipitants in this young man's history.  He had no previous history of any psychopathology.  There was no family history of any psychiatric illness.  And he had biological symptoms consistent with a depressive illness which were altered sleep and appetite which had been present for some weeks at the time I saw him. 
		The third case was one of the most impressive in terms of my deciding that there might be an association with isotretinoin, and I'll expand on this now.  It was a 21-year-old girl who had severe, resistant depression.  She had had months of agitation and aggression which was evident at home.  She described poor appetite, poor sleep and weight loss, and her response to antidepressants from a general practice perspective had been very poor, so she was referred to the university for assessment.  
		She actually had to be admitted to hospital, so severe were her depressive symptoms, and whilst in hospital, she was taking isotretinoin of her own that she had brought into hospital, which we were unaware of, and her symptoms remained unresponsive until we stopped the isotretinoin, took away her supply, continued her antidepressants, and the depression responded.  Again, this lady was treated with antidepressants and she remained well on antidepressants when she got off the isotretinoin.
		So, in relation to my queries and concerns in relation to isotretinoin, I discovered that it has a very extensive list of ADRs.  It's a fat soluble vitamin A derivative.  The mode of action is unknown.  And in making inquiries in the university, the dermatologists on staff were completely unaware of any problems in relation to mood or psychological disturbance in relation to this drug. 
		So, we did a literature review.  At that time in 1993, there were almost no articles of note in English.  There were several articles in the French literature which questioned the possibility of psychological disturbances in relation to the use of isotretinoin.  One of the articles in English that was pertinent I felt was one by Scheinman.  He indicated that he seen depression in 1 percent of users of isotretinoin.  Out of 700 cases, 7 people had become depressed and had to be withdrawn.
		There was further a letter by Gatti and Serri who described a case of suicide in an individual who had recently received isotretinoin. 
		And Bravard in France described a case of suicide in a young man receiving isotretinoin, and he urged caution in relation to the use of this agent.  That article was in French and had to be translated for me.
		So, further to the discovery that there was actually a precedent in relation to psychological disturbance in relation to the use of this agent, I published a letter in the Canadian Journal of Psychiatry in 1993 alerting my psychiatric colleagues to the fact that there was a possibility that depressive symptomatology might emerge in people receiving Accutane therapy, isotretinoin.
		I actually left Canada in 1994 voluntarily.
		(Laughter.)
		DR. BYRNE:  And I returned to work in Ireland where I actually was exposed to further cases of individuals who had depressive symptomatology following use of isotretinoin, and I published a series of cases in the Irish Journal of Psychological Medicine in 1996 along similar lines to the cases I had seen in Canada.
		Since 1995, by virtue of the publications I have had in this area, I've had an increasing number of contacts from patients with depression who have associated their depressive symptomatology with the use of this agent.  Individuals generally tend to describe depressive mood, agitation, not infrequently suicidal ideation, and they have also described behavioral change which can often be very bizarre and very unpredictable.  One of the major factors that was a concern to me is that these individuals tend to describe a chronic apathy and dysthymia that extends far beyond the use of the drug and appears to continue over time, often without treatment because it hasn't been recognized or diagnosed by people they go to see.
		One major concern I had was that obviously if people developed depressive symptomatology, the reality is they're not going to mention this or go with this to a dermatologist per se, and therefore it was important, I felt, that people in the psychiatric arena would have knowledge of the fact that this agent might be associated with depressive symptomatology.
		As I've said, in relation to my other clinical experience with isotretinoin over the last 5 or 6 years, I've seen more than 20 cases in total.  Most of these are young individuals.  Most would have had recent use of isotretinoin, but there can be quite a considerable variation, a little bit like postpartum depressive illness which can come on late after the birth of a child and carry on then for some time.  I've seen individuals who have described mood change some months after discontinuing isotretinoin and then this mood change has been pervasive and persistent over time.  
		The ratio in the individuals I've seen is approximately, female to male, 2 as to 1 in terms of depressive symptomatology.  
		One observation I have made, which may or may not be of tremendous significance is that this seems to come on in thin, physically fit individuals.  The only rationale or the only theory I've had in relation to that is because isotretinoin is lipid soluble and the relative lipid content of the body will be lower vis-a-vis body to brain in fit individuals, as opposed to more obese individuals, and that more of the drug might end up in the brain fat tissue as opposed to in the body fat tissue in the thin or fit individuals. 
		The other observation I've made is that the symptoms can be extremely protracted, and I still have a number of individuals who I am treating with antidepressant medication for protracted periods at the moment. 
		Therefore, in relation to isotretinoin, my clinical observations have been that this agent can influence mood in certain individuals. 
		My feeling is that the effects on mood may be very persistent, and obviously anything that can precipitate a depressive illness may be life-threatening because there is a significant risk of suicide with depressive illness.  
		My observation as well is that the effects seem to be most pronounced in thin, athletic individuals who have a low body fat content, and I feel that this probably relates to lipid solubility.
		Thank you. 
		DR. BERGFELD:  Thank you very much. 
		We're going to proceed then to the second presenter which is Dr. Erick Turner, drug-induced depression.
		DR. TURNER:  Well, thank you. 
		The title of my talk is Drug-induced Depression.  The purpose of the talk is to give basically an overview of depression and drug-induced depression primarily for the benefit of the non-psychiatrists, of whom I am certain there are many here today. 
		So, this will be the first of several FDA talks.  The talk after mine will be a case review by Dr. Marilyn Pitts, followed by postmarket experience by Diane Wysowski; biological plausibility and options for risk management by Dr. Kathryn O'Connell.
		Now, before talking about drug-induced depression, I'm going to back up and talk about what we probably know a lot more about, and that's major depressive disorder.  Major depressive disorder is what psychiatrists usually but not always mean when they talk about depression or what lay people probably usually mean when they talk about "clinical depression."  There are other types of mood disorders certainly and even other types of depressive disorders, but this probably the one recognized as the most frequent and most serious.  So, I will lead in with a discussion of that.  
		I have up there DSM-IV diagnosis, and let me just quickly explain what that refers to.  DSM is the Diagnostic and Statistical Manual, Fourth Edition, and this is a manual which the field agrees upon contains the criteria by which we diagnose various types of mental disorders and that facilitates agreement between clinicians so that we all know that we're literally on the same page, as well as various researchers so that again we know we're all studying the same thing.  Otherwise, before the DSM series came out, the meaning of the word "depression" was very idiosyncratic. 
		So, the DSM-IV criteria require a duration of at least 2 weeks.  The symptoms have to be present most of the day nearly every day, so it has to be a pervasive mood disturbance.  And they must be clinically significant.  This is more than just a bad hair day, if you will.  It has to cause significant distress or impairment in one's social or occupational functioning, so perhaps affecting one's marital or family relationships or even interfering with one's ability to function effectively at work.
		Now, this is a somewhat busy slide, but I'll walk you through it slowly.  First of all, the title "Symptoms of Depression," this is not all depression.  Depression again means different things to different people, but here I'm referring to major depressive disorder.  This is to be contrasted with drug-induced depression which I'll move into later.  
		I have nine symptoms listed here and I have them broadly categorized into two categories.  You won't find this categorization in DSM-IV, but it may be useful as a way of understanding them.  First of all, the psychological symptoms and the neurovegetative symptoms. 
		Among the psychological symptoms, we have depressed mood.  Loss of interest or pleasure, and by that, a person may experience that as a decreased motivation, a loss of interest in one's work, they don't enjoy their job as much as they used to, for instance.  Feelings of worthlessness or guilt, and also suicidality or thoughts of death.  Again, these symptoms are not all required but just five of the total number of nine here on the list.
		Let me come back to the first two symptoms I have listed there, depressed mood and loss of interest or pleasure in things.  The reason I have those underlined is because at least one of those symptoms is, in fact, required to make a DSM-IV diagnosis of major depressive disorder.  So, in other words, if they have several neurovegetative symptoms and even theoretically suicidality, it's possible not to qualify for an official, if you will, DSM-IV diagnosis.
		I also want to highlight that I said "or," depressed mood "or" loss of interest or pleasure.  Some people may not express depressed mood.  They may not even experience depressed mood when specifically asked about that, but they may have anhedonia, again this loss of interest or pleasure.  So, that's perhaps more likely to be missed than someone who spontaneously complains of depression.
		The neurovegetative symptoms are what we might think of as the more biological symptoms.  The depression is evidence of this being a true biological process going on in the body with a life of its own, so to speak, again more than just a bad mood.  They include changes in appetite and weight, and that can be in either direction.  It can be decreased appetite or increased appetite, likewise with weight.  Sleep.  You can have insomnia or hypersomnia.  The person might be slowed down or agitated, and according to DSM-IV, the person should be visibly slowed down or agitated, not just subjectively so.  Energy is often decreased.  The person feels tired.  They might think that they have anemia, for instance.  Concentration might be decreased or they might have difficulty making decisions.
		One other thing is to highlight again the depressed mood or the anhedonia.  Not only is one of those two symptoms required to make the diagnosis of major depressive disorder, but to make a formal DSM-IV diagnosis of substance-induced depression, that is about all that's truly required to make the diagnosis.  So, it seems that the threshold is higher with DSM-IV, at least with regard to the symptomatology, to make the diagnosis.  
		The neurovegetative symptoms are conspicuously missing, and perhaps the reason for that is one would have to have sat on the DSM-IV committee, but just to speculate, various medical conditions and medications might cause various neurovegetative symptoms.  You can imagine drugs which cause a change in appetite or insomnia by themselves, and that might just confuse the picture.  So, I think my speculation is that the committee didn't want to get tied down saying that the neurovegetative symptoms were required to make a formal diagnosis of drug-induced depression.
		The first two are, of course, symptoms, if you will, of both major depressive disorder and drug-induced depression.
		The time course of depression -- again, I'm talking about major depressive disorder.  The symptoms often develop over days to weeks, and the DSM-IV requires at least 2 weeks of symptoms.  
		If left untreated, the full syndrome can often last for 6 months or more.  So, it may be almost as if a switch has been thrown and it may go for a longer time than seems to be warranted by the psychosocial situation.  Indeed, the biology seems to have kicked in. 
		Residual symptoms can last months to years. 
		If treated -- and by this, I mean pharmacologic treatment -- a clinical response usually becomes evident in 2 to 4 weeks.  So, this is the party line.  Certainly not everyone responds to antidepressants, but 60 to 70 percent of people will respond to a given antidepressant.
		Depression is a common disorder, and this point has been made previously by Dr. Nelson, I believe Dr. Jacobs as well.  This is problematic, also as mentioned before, because it makes detection of drug-induced depression by spontaneous reporting especially difficult.  We're not talking about a very, very rare entity such as Stevens-Johnson syndrome or hepatic necrosis, but something on the other hand that has a lifetime prevalence of about 15 percent.  The numbers will vary according to one's source and the time frame one is looking at.  But anyhow, a fairly common, current prevalence of 3 to 6 percent among adolescents, and a 5 percent neighborhood consistent with overall prevalence.  
		I'd like to point out that these rates are gathered via epidemiological methods using random sampling of the population in which a sample is queried on all symptoms of depression using perhaps, going through formally the DSM-IV symptoms or using some other questionnaire that comprehensively covers various symptoms.  If, on the other hand, one waited for spontaneous reports to emerge, undoubtedly the rates would be much lower waiting for patients to go and say, doctor, I believe I may be suffering from major depression.
		Just a related point, I guess Dr. Nelson I believe mentioned that many of these spontaneous reports frequently don't have a formal diagnosis, and I guess that might be expected if psychiatrists aren't the ones making the diagnosis and they don't have the training to be familiar with the DSM-IV criteria.
		So, depression is not only common, but it's under-recognized.  The symptoms are often not recognized as part of the depressive syndrome especially, for instance, the neurovegetative symptoms that I mentioned.  Some people may not recognize concentration, decreased energy in the absence of depressed mood.  And again, depressed mood is not strictly required for a diagnosis of major depressive disorder.  You can have just have anhedonia.
		Symptoms are often not obvious and cannot be proven with an x-ray or lab test which may lead to some increased reluctance on the part of the person to come forward and they might dismiss it thinking, well, maybe it's all just in my head.  Maybe I'm just not trying hard enough, which is a point which comes below that symptoms often get dismissed, by both the person experiencing the depression, as well as perhaps family members or possibility even health care professionals.  Symptoms might be dismissed as an appropriate reaction to stress, evidence that the person is not trying hard enough, or even a conscious attempt to achieve secondary gain.
		Only about half the persons with major depressive disorder ever receive treatment.  Dr. Jacobs had a somewhat lower number, about 40 percent.  That's the "ever" category, and the current episode was down around 20 percent. 
		Adolescent depression may be especially under-recognized.  Again, I apologize for the redundancy, but these are points that keep coming up.  Dr. Jacobs was making this point.  Adolescents often will present atypically.  They seem to be less likely than adults to display the neurovegetative symptoms and more likely than adults to show social withdrawal, irritability, or behavioral problems.  And I believe Dr. Jacobs mentioned that adolescents might often conceal symptoms.  So, all this adds to the under-recognition, under-reporting of depression and perhaps more so among adolescents.
		Use of drugs and alcohol may be seen as the reason for behavioral changes.  Drugs and alcohol can certainly be a confounding factor.  On the other hand, drugs and alcohol might also represent a method of self-medicating one's depression or simply a co-existence or comorbidity of the two diagnoses.  Perhaps they have no relation whatsoever.  But in any case, if drugs and alcohol are present, they may be identified as the reason the person seems to be exhibiting these other symptoms, and there may not be a systematic probing into the other symptoms in consideration that the person might have serious depression.
		The signs of depression often are seen as normal mood swings typical for the age group, and there may be a reluctance to label adolescents with a mental illness diagnosis.  This is the stigma issue that has been talked about quite a bit in psychiatry over recent years and applies to adults as well as adolescents.  Depression and mental illness in general, for that matter.
		Depression and suicide.  Suicide is certainly the ultimate adverse outcome of depression.  The Adverse Event Reporting System -- that's what AERS stands for, and that's what we've been talking so far today and we'll continue to talk about the spontaneous reports -- can generate signals, but the system should be considered inadequate for establishing or ruling out a link between Accutane and suicide.  Again, it can generate signals and put us on the right path. 
		One reason that this may be the case -- there are several reasons, and I don't want to go into any detail.  Although suicide is certainly a tragic outcome of depression, as we'll see on the next slide, which I'm not quite ready for unfortunately, is not nearly so rare as the sorts of disorders that are easily picked up by the adverse event reporting system, again the very rare things.  Again, AERS is a voluntary system. 
		15 percent of mood disorders subsequently end in suicide, and 45 to 70 percent of suicides have a mood disorder.  So, this is a mood disorder that's broader than major depression and would also include bipolar disorder as well. 
		Outside of mood disorders, the other 30 to 55 percent of people completing suicides include diagnoses such as schizophrenia, alcohol dependence, other substance dependence and personality disorders. 
		A bit about the epidemiology.  Again, I fear I'm being redundant, to some extent, with Dr. Jacobs' talk.  The rate is about 30,000 per year.  This seems to be a fairly consistent number, and it's the eighth leading cause of death.  These numbers I got from the CDC website, the Centers for Disease Control.
		For adolescents -- now, the absolute number will vary according to the age range one chooses.  If I remember correctly, I chose a range of 11 to 20 for adolescents, which was the definition of adolescents according to a textbook I referred to.  I believe others have used a range of 15 to 24, and you'll get higher numbers.
		But in either case, it doesn't matter the absolute number here, but rather it's the relative number.  It's the third leading cause of death among adolescents, and this is after accidents and homicide.
		There's a gender effect.  Women and girls have more attempts, but men and boys have more completed suicides.  So, they attempt less often but succeed, if you will, more frequently.
		Moving a bit more to drug-induced psychiatric disorders, this gets to be a bit murkier for several reasons.  Diagnosis is rarely clear-cut.  The clinical features can vary with different drugs.  I have different mechanisms.  Perhaps I should have said different pharmacologic effects.  It's possible some day in the year 2100 or so, when we truly understand depression, we will understand the mechanism for depression and understand all the various drugs and other causes, if you will, of depression all go through some final common pathway.  So, we don't really truly understand the mechanism of depression.  We do know some things that seem to be associated with depression.
		But different drugs will have different pharmacologic effects, and so it can appear very differently and it's hard to come up with a set of criteria and something to tell clinicians what they should be looking for. 
		The clinical features can vary not only with different drugs but also with the same drug.  One example of that is corticosteroids which can cause mood changes in either direction, depression or mania.  They can cause anxiety symptoms or even psychosis.  Overall I would have to say there's a lack of consensus.  The evidence is inconclusive and conflicting.  I don't think this is by design.
		Let me take this second point first, the lack of rigorously collected data, and say when these drugs are being developed there's very rarely, if ever, an a priori suspicion that the drug might cause depression.  So, it's not rigorously looked for.  Usually this comes up postmarketing, and they're picked up as case reports by clinicians, as we've heard Dr. Byrne, just previous to my talk, noticed some cases in which he thought there might be an association. 
		When trials are done, they tend to be retrospective and observational rather than prospective, randomized and controlled, which are the type that are generally relied upon to make more definitive statements about causal links.  Case reports again might be considered a signal-generating mechanism.
		Studies that are done rarely employ established observer-based rating scales.  I'd like to contrast that with the lack of any rating scale with spontaneous reports might be used in some studies.  As opposed to observer-based, they're self-report scales.  An example of that is the Beck Depression Inventory, which was used in one of the studies mentioned earlier this morning.  
		Self-report instruments are usually regarded as sensitive and certainly easy to use and user-friendly, but they're not regarded as being that specific and can give some false positives which can be good and it can be bad.  The low specificity can give you a high rate of noise, which can be confusing.  The false negatives can just obscure any possible signal-to-noise ratio.
		Here's a list of drugs implicated in depression.  I want to emphasize the word "implicated."  I don't think any of these have been proven to cause depression for the reasons that I mentioned before.  These were picked up postmarketing again and the lack of rigorous studies.  Several of these surface again in the literature, but as you dig into the literature, you'll frequently find that they ultimately rest upon case reports and you'll find even different conclusions on that, I believe as Dr. Jacobs mentioned, even for beta-blockers which are on the list here.  None of these are rock-solid.  There are reports on either side. 
		Corticosteroids, ACTH, sedative-hypnotics, alcohol, L-dopa, anticancer drugs, oral contraceptives, the antihypertensives mentioned before, and reserpine, which is no longer on the market, but it's the observation of association between reserpine and depression.  Whether it was real or not is another matter.  But the observation of a possible association led to the implication of norepinephrine in depression and subsequently led to further research into the possible role of norepinephrine in depression.  Now we know that even some of our older antidepressants, such as desipramine, act on norepinephrine, desipramine being a potent norepinephrine reuptake inhibitor.
		So, not is all bad when we see an association between drug and some adverse event.  In the case of depression, it might lead to further research and might clue us into the pathophysiology of it and how it might be treated. 
		And interferon is last on the list.
		This is my next-to-the-last slide, although it says "summary."  So, many drugs with various mechanisms, such as those shown on the last slide, have been implicated.  In theory any drug that can cross the blood-brain barrier and bind brain receptors can affect the brain, can possibly in theory.  
		However, there are few rigorous studies of drug-induced depression.  So, anything is possible but it's another matter to really rule something in or rule something out.  
		There's a lack of consensus on causality and the scope of the problem, the problem being drug-induced depression again. 
		This is my last slide.  So, depression is common but under-recognized, making it difficult to make definitive statements based upon any signals we might see.
		Depression may be especially under-recognized in adolescents.
		Suicide is a leading cause of death, especially among adolescents.  Again, it was number three.
		And the spontaneous reporting system or the Adverse Event Reporting System, or AERS, referred to earlier, underestimates the number of adolescents with drug-induced depression for various reasons.  We know so little about drug-induced depression.  Adolescents might be especially under-reported and depression in general is certainly under-reported as well. 
		And that's it.  Thank you. 
		DR. BERGFELD:  Thank you. 
		The next presentation is that of the case review by Dr. Marilyn Pitts.
		DR. PITTS:  Thank you.  Madam Chair, Dr. Woodcock, committee members and guests, good morning.  My name is Marilyn Pitts.  I'm a safety evaluator in the Office of Postmarketing Drug Risk Assessment.
		My objective today is to describe the positive dechallenge/rechallenge cases of Accutane associated depression, depressive symptoms, and mood disorders. 
		The top 10 adverse events for Accutane include depression, ranked number 6.  By contrast, we looked at tetracycline, which is another agent used for less severe acne.  We have 8 cases of depression and 2 deaths, and we looked at Claritin in the AERS database where we have 10 cases of depression and 2 deaths.
		In evaluating spontaneous adverse events, positive dechallenge/rechallenge cases provide the best evidence to support a relationship between a drug and an observed event. 
		Today I will discuss the FDA's principal data source for detecting rare drug adverse events.  I will provide reasons for suspecting a drug/adverse event relationship.  I will describe the dechallenge/rechallenge cases included in the 1998 case analysis, as well as cases included in the year 2000 analysis.  I will also present a case summary for the 1988 and the year 2000 case series. 
		The FDA's Adverse Event Reporting System, or AERS, is a computerized database of adverse events reports.  The database is searchable by drug names and key words.  The database was established in 1969 and updated in 1997.  Individual records within the database are based on submitted MedWatch forms.
		MedWatch forms are voluntarily submitted by pharmacists, physicians, nurses, and other health care professionals and consumers.  Approximately 94 percent are submitted directly to the manufacturer, and the remaining amount are submitted directly to the FDA.  The manufacturer is required to submit all MedWatch forms to the FDA.  Serious unlabeled events are expedited and submitted to the FDA within 15 days.  All other events ar submitted on a periodic basis.
		The strengths of the adverse event reporting system is that the system is simple.  The system is sensitive.  A small number of cases can lead to the detection of a signal.  The system is good for detecting rare and unusual events, such as hepatic failure or aplastic anemia.  And the system is relatively inexpensive when you compare it to alternative surveillance strategies.
		However, there are limitations.  One limitation is that incomplete data is submitted.  On the data form, there are many fields missing.  For example, race is not encoded.  When reported, race is usually reported in the narrative.  In addition, even coded information can be missing.  The narrative information can vary in quality and in quantity of the documentation submitted.
		Another limitation is under-reporting, which is substantial.  The FDA receives notification of only a fraction of adverse events.  The amount of under-reporting cannot be quantified or predicted.  However, under-reporting estimates have been as low as 1 percent. 
		Some possible reasons for under-reporting may include limitations in recognizing an adverse event, limitations in associating the event with drug exposure, and the burdens of reporting.
		Additionally, there's variability in reporting.  Reporting may increase or decrease with serious or notable events, with a publication of a Dear Doctor letter or with scientific or lay press publications.  The year of reporting and also the length of time a product has been on the market also influences reporting.
		In summary, despite the limitations of incomplete data, variability in data, and substantial under-reporting in this voluntary system, we have a system that is sensitive to rare events, that provides an excellent source of case material, and is useful for hypothesis generation.
		Adverse drug event reports may be submitted when a drug/adverse event relationship is suspected.  Some reasons to suspect a drug/adverse event relationship include the temporal, or the time relationship between administering the drug and the development of symptoms, a dose response, or a mechanism of action or biological plausibility, or a class effect, or the absence of alternatives, and dechallenge, or the abatement of symptoms when the drug is discontinued, and rechallenge, the recurrence of symptoms when the drug is reintroduced.  Again, dechallenge and rechallenge provide additional evidence of a relationship between a drug and an adverse event.
		In 1998, OPDRA analyzed spontaneous adverse drug event reports of positive dechallenge/rechallenge cases of depression, mania, psychosis, and suicide attempt.  The 1998 case series supported the Accutane labeling change, which included a warning concerning psychiatric disorders.  The warning stated that Accutane may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts, and suicide.
		There were 20 cases in this report.  19 were U.S. cases.  There were 14 cases of depression, 5 cases of psychosis, and 1 case of a mood disorder.  The cases were evenly distributed between male and female.  The median age was 20 years.  5 cases had a psychiatric history, and 5 patients required hospitalization.
		I'm going to spend some time on this slide.  This table compares the first and second course of Accutane with respect to total daily dose, time to onset of symptoms, and time to recovery.  This information was not provided in every report.  The n refers to the number of reports that provided the requested information. 
		During the first course of Accutane, there were 13 of 20 patients reporting a median daily dose of 50 milligrams.  The 50 milligrams corresponds to a dose of 0.7 milligram per kilogram per day in a 70 kilogram patient.
		13 patients reported a median time to symptoms of 31 days.  
		6 patients reported a median time of recovery of 3 days.  19 patients reported recovery.  9 reported recovering after discontinuation of Accutane, 4 recovered after completing the Accutane course, 3 recovered after discontinuation and medical intervention, and 2 recovered on a lower dose.  From the first course, all 20 patients went on to receive a second course.
		During the second course of Accutane, 13 patients reported a median daily dose of 40 milligrams. 
		12 patients reported a median time of onset of symptoms of 36 days, and 4 patients reported a median time to recovery of 3 days.  
		11 patients reported recovery from the second course of Accutane, of which 3 recovered after discontinuation of the medication, 3 recovered after completing the course of therapy, and 4 recovered after discontinuation and medical intervention.  4 patients reported a persistence of symptoms after discontinuation and/or medical intervention.
		This is an example of a case report from the 1998 case series.  This is a 19-year-old male described as cheerful with an uneventful medical history and was receiving no concomitant medications at the time of receiving Accutane.  The patient had three courses of Accutane to treat cystic acne.  During the first course of therapy, the patient developed depression, mood swings, and personality changes.  The Accutane course was completed with no intervention.  At the completion of the course, the patient's symptoms cleared.  
		The patient went on to receive a second course of Accutane.  Again, depression, mood swings, and personality changes developed.  The course was again completed with no intervention, and again the patient's symptoms cleared upon completion.
		The patient went on to receive a third course of Accutane.  Depression, mood swings, and personality changes again developed.  The course was again completed.  However, the symptoms persisted after the course was completed, and the patient was referred to counseling.
		In support of this meeting, OPDRA analyzed dechallenge/rechallenge cases of Accutane-associated depression, mood changes, and suicide attempts.  Spontaneous adverse event reports were reviewed for positive dechallenge/rechallenge cases.  We found 41 cases.  20 cases were from the previously reviewed 1998 case series and 21 new dechallenge/rechallenge cases focusing on depression and suicide attempt were found.
		There were again 21 cases in this case series.  17 of the 21 cases were from the U.S.  There were 14 cases of depression, 3 cases of depression with suicidal ideation, and 4 cases of mood changes.  There were 16 females and 5 males.  The median age was 23 years.  5 patients reported a psychiatric history, and 1 patient required hospitalization.
		Again, this slide will compare the first course and second course of Accutane.  The table will compare the dose, time to onset of symptoms, and time to recovery.  This information again was not provided in every report.  The n refers to the number of cases that provided the information. 
		During the first course of Accutane, 16 of the 21 patients reported a median daily dose of 50 milligrams of Accutane.  14 patients reported a median time to symptoms of 30 days.  6 patients reported a median time to recovery of 8 days.  21 patients reported recovery.  10 patients reported recovery after Accutane was discontinued.  3 recovered after the course was completed.  2 recovered while receiving a lower dose of Accutane, and 2 recovered with discontinuation and medical intervention.  4 patients did not report the method of recovery.  All 21 of these patients went on to receive a second course of Accutane.
		During the second course of Accutane, 9 patients reported a median daily dose of 30 milligrams of Accutane.  This corresponds to 0.4 milligram per kilogram per day for a 70 kilogram patient.  8 patients reported a median time to symptoms of 9 days and 5 patients reported a median time to recovery of 7 days.  13 patients reported recovering.  3 reported recovery on discontinuation.  2 recovered on discontinuation and intervention.  1 recovered after the course was completed, and 2 recovered with a lower dose.  5 patients reported a persistence of symptoms after discontinuation and/or medical intervention.
		An example of a case from the 2000 case series is this 18-year-old male who received Accutane for cystic acne.  He was receiving no concomitant medications, and a relevant medical history was not stated. 
		During the first course of Accutane, the patient received a total daily dose of 80 milligrams of Accutane.  The time to onset of symptoms was 29 days.  The patient had developed depression and poor school performance.  Accutane was discontinued, and the patient reported a clearing of the symptoms in 8 days.
		The patient went on to receive a second course of Accutane.  The total daily dose was lowered to 40 milligrams.  The time to onset of symptoms was 5 days.  The patient had again developed depression and poor school performance.  Accutane was again discontinued, and the symptoms cleared in 7 days.
		Therapy was later restarted at 40 milligrams every week without a recurrence of symptoms. 
		When you combine the 1998 and the year 2000 case series, we have 41 cases of positive dechallenge/rechallenge.  During the first course of Accutane, 29 patients reported a median daily dose of 40 milligrams.  27 patients reported a median onset of symptoms of 30 days, and 12 patients reported a median time to recovery of 4.5 days.  40 patients reported recovery.  Of the patients reporting recovery, 19 recovered after Accutane was discontinued.  7 recovered after the course was completed.  5 recovered with discontinuation and medical intervention, and 4 recovered on a lower dose of Accutane.  All 41 patients went on to receive a second course of Accutane
		During the second course, 22 patients reported a median daily dose of 30 milligrams.  20 patients reported a median time to symptoms of 10 days, and 9 patients reported a median time of recovery of 7 days.  24 patients reported recovery, and 10 patients reported a persistence of symptoms after discontinuation or medical intervention.  2 patients recovered on a lower dose.
		In summary, we have 41 Accutane associated dechallenge/rechallenge cases.  76 percent were without a reported psychiatric history.  The median time to onset of symptoms during the first course of Accutane was 30 days, and a median recovery time of 4.5 days.  During the second course, or the rechallenge course, the time to onset of symptoms was shorter in the cases that provided the information.  Also, after the second course of Accutane, depression persisted in some patients after discontinuation of Accutane and/or medical intervention.  There was a possible dose-response to Accutane observed in 6 patients.
		In conclusion, dechallenge/rechallenge cases provide strong evidence to support a link between a drug and an observed adverse event.  We have presented 41 cases of positive dechallenge/rechallenge which provide further evidence to support a relationship between Accutane and depressive symptoms. 
		Thank you. 
		DR. BERGFELD:  Thank you. 
		We're going to take the questions during the discussion time.
		Moving on to the next presentation by the FDA, Diane Wysowski, Postmarketing Experience Suicide and Depression.
		DR. WYSOWSKI:  Today I'll be summarizing reports that FDA received of suicide and depression in patients treated with Accutane.  Reports are from the United States only with Accutane as the suspect drug entered in the FDA's database from marketing in 1982 to May 2000.
		Over the 18-year period of marketing, the FDA received reports of 37 U.S. patients who committed suicide, 24 on Accutane and 13 after stopping the drug.
		Individuals who committed suicide were mostly male.  The median age was 17.  The median time on Accutane to suicide was about 3 months.  For individuals who committed suicide after stopping the drug, the median time to suicide after stopping Accutane was 2-and-a-half months.
		22 percent of suicide cases were reported to have a psychiatric history.  About 57 percent had other possible contributing factors for depression.  These included personal relationship problems, stressful life events, substance abuse, family history of psychiatric disorders, and others.  Together, 62 percent were reported to have either a psychiatric history or possible contributing factors.  About half of the reports, 49 percent, were received in 1998 after suicide and depression were added as a warning to the product labeling.  The median peak dose was 1 milligram per kilogram of body weight per day, which is within the U.S. recommended dose range for Accutane of .5 to 2 milligrams per kilogram per day.
		In addition to the suicides, the FDA received reports of 110 U.S. Accutane users hospitalized for depression, suicidal ideation, and suicide attempt, 85 on Accutane and 25 after stopping the drug.
		Individuals hospitalized for depression were more likely to be female.  The median age was 17.  The median time on Accutane to hospitalization was about 1 month.  For those hospitalized after stopping the drug, the median time to hospitalization after stopping Accutane was 3 months. 
		44 percent were reported to have a psychiatric history.  52 percent had other possible contributing factors for depression, and together 69 percent had either a psychiatric history or possible contributing factors.  41 percent of reports were received in 1998, the year depression and suicide were added to the labeling.  And the median peak dose was 1.1 milligram per kilogram of body weight per day.
		About a third of patients had positive dechallenges with psychiatric treatment, and nearly a third experienced persistent depression after drug discontinuation.  One person had a positive rechallenge, while three others were rechallenged and were able to continue on Accutane with alcohol abstinence, dose lowering, and continued use of an antidepressant.
		As of May 2000, the FDA received reports of 284 U.S. Accutane users with non-hospitalized depression.  45 percent were received in 1998 after depression and suicide were added as a warning to the labeling.  About half of the non-hospitalized patients reported accompanying side effects such as dry mucous membranes, headaches, hair loss, and joint and muscle pain.  About 50 percent of reports were from consumers and relatives, a higher proportion compared with most reports for most drugs. 
		The top 10 adverse events reported for Accutane include depression that ranks number 6.
		Of course, the degree of under-reporting is unknown and may be quite substantial.
		There are several pieces of evidence supportive of a possible association between Accutane and depression and suicide.  These include the relatively large number of reports of serious depression, more than for most drugs in the FDA's database, the temporal association between use of Accutane and onset of depression, positive dechallenges in individuals who felt better once Accutane was discontinued and psychiatric care was obtained, and positive rechallenges in individuals who experienced symptoms again after restarting the drug.
		Also, some individuals had no reported psychiatric history or possible contributing factors, and there are similar case reports of depression and suicide in Accutane users in the medical literature.
		However, there are several complicating factors.  Some individuals had previous courses of Accutane without depression.  There are high rates of depression and suicide in the teen years, making the independent contribution of Accutane with depression difficult to assess.  And many cases had a psychiatric history and other factors, including acne itself, that could have predisposed them to depression.
		Also, most serious cases did not improve with Accutane discontinuation alone.  Psychiatric intervention was frequently required.
		Lastly, a large retrospective cohort epidemiological study, referred to as the Jick study for the principal investigator, Susan Jick, that was funded by Hoffmann-LaRoche, found no increased risk of depression in individuals prescribed Accutane compared with those prescribed antibiotics for acne.  However, the study had some important limitations.
		Patients were not interviewed, so depression was under-diagnosed and under-ascertained.  
		The study did find an increased relative risk of 2 for suicide attempts and suicides in patients prescribed Accutane.  The relative risk had wide confidence intervals of 0.4 to 10, and was not statistically significant.  It's possible that a larger sample size could have resulted in a statistically significant relative risk with Accutane. 
		That brings me to my next point, the lack of data on acne severity or the patients' perceptions of acne severity.  This is an important potential confounding variable for an association with Accutane.
		There also were no data on dose collected.  The recommended dose of Accutane is higher in the United States than in the United Kingdom and Canada.  So, the results from these two countries may not be applicable to the United States. 
		Further, the U.S. data, that was included in the study but was not mentioned earlier, did not include information on outpatient diagnoses, data on deaths after 1990, and data on antibiotics used only for acne.
		Finally, the investigators reported only the combined number of suicide attempts and suicides, and it might be informative to know the number and rates of suicide by drug to determine if any exceeded the population rates.
		Because of these problems and limitations, we believe the results of the Jick study are inclusive.
		So, in summary, the FDA has received reports of suicide and serious depression in U.S. Accutane-treated patients.  The case reports are suggestive of an association with Accutane, but do not allow definitive determination as to whether Accutane causes depression and suicide in treated patients. 
		DR. BERGFELD:  Thank you. 
		Our last presentation from the FDA is by Dr. Kathryn O'Connell, Biological Plausibility and Risk Management Options.
		DR. O'CONNELL:  Good morning or almost afternoon, everyone.  My name is Kathryn O'Connell.  I'm the medical reviewer in the Division of Dermatologic and Dental Drug Products, the medical reviewer for Accutane.
		As Dr. Bergfeld mentioned, I'm going to be talking briefly about this, but mostly I want to concentrate on the second talk, which is risk management, because that's actually why we're here today.  
		I think that you've heard from the sponsor's presentations and from ours that spontaneous reports can generate a signal, but when the thing that you're studying has a high background rate, you don't really expect them to give you a definitive answer about causality.  We're really not here today to ask you as a committee to tell us if there's a causal relationship here.  The sponsor has tried and we tried, and we already know that we can't do that.  The real question here today is what do we do with the information we have to convey the information we have to the people using the drug and how perhaps we can resolve the uncertainty. 
		So, in the first talk I want to just talk about a few things that we think about when we try to decide if the inconclusive signal that's generated from spontaneous reports warrants further investigation.  On the next slide, I'm only going to cover two topics that have been alluded to already, so I don't think we have to spend a lot of time on it. 
		The first thing is we asked ourselves are there any published cases of psychiatric adverse events occurring in association with Accutane, and the second thing we asked ourselves, are there any elements of biologic plausibility?  I'm going to use this in a broad sense.  Are there any elements of biologic plausibility that would worry us, that would cause us more concern?
		So, the first topic, published case reports, is easy.  It's one slide.  These are the references so that you have them on the slide.  You can read them.  They range from 1983 to the papers that Dr. Byrne referred to earlier in 1998.  These are only cases of depression.  There are some published things in the literature about other psychiatric diagnoses, but the vast majority are depression.  We've already referred to some of these papers, and I'll just talk a little bit about them as we go on. 
		The second thing that I said I was going to cover on the next slide was elements of biologic plausibility.  As I said, I'm going to use this in a broad sense.  It doesn't mean that I'm suggesting mechanisms here.  The question here is that are there things that we know about retinoids that make it not implausible that Accutane could have something to do with psychiatric illness.
		So, the four issues I'm going to talk about are do we see similar adverse events with pharmacologically related substances -- different drugs, but pharmacologically related substances -- that bind to the same physiologic receptor, which is obviously in this case the retinoid acid receptor.
		The second thing we want to ask ourselves, is there any evidence for a dose effect?  I'm not going to say much about that because we've already heard something about that. 
		The third thing is whether the temporal association that we've all talked about here already -- you ask yourself is it consistent with the pharmacokinetics of the drug, and we do know a fair amount about the pharmacokinetics of the drug. 
		Then the fourth thing we ask ourselves is, is there any reason to believe that retinoids would have anything to do with the central nervous system.  We obviously don't have time today.  We could spend a whole day on biologic plausibility in that sense, but we won't.  We'll spare you. 
		If we go to the next slide, the first item that I mentioned was we ask ourselves, do we see psychiatric adverse events?  Have they been reported with distinct substances that bind to the same physiologic receptor?  Dr. Byrne and several other people have already referred to the fact that it is known that high dose vitamin A, hypervitaminosis A, has been associated with psychiatric adverse events.  The first reference that I gave you there is actually a case where the indication for using high dose vitamin A was acne.  It's a very complete case report by Dr. Restak that was published in 1972. 
		The second substance is etretinate, which is a systemic retinoid which is used in the treatment of psoriasis.  The first reference that I gave you there is a very detailed reference.  It describes an aggressive personality change, profound depression, with a positive dechallenge with dose reduction.  And the second reference there has three very brief little case summaries, all of which I believe had a positive dechallenge.
		The third one is the only one I'm going to spend a little bit of time on because it came from a published trial.  It was a trial where these investigators added a high dose of all-trans-retinoic acid to an established regimen of interferon-alpha and low-dose ara C to treat chronic myelogenous leukemia.  The title of the paper is The Unexpected High Incidence of Severe Toxicity.  It's important to note here, as Dr. Turner actually alluded to, is that there is a fairly reasonable body of evidence that interferon-alpha itself may be associated with depression. 
		But if we look at the next slide, I think this study is interesting because the column furthest over here where it says "No ATRA" means that those were the patients that got the ara C and the interferon.  Then the other column, the first column, is where they got the interferon and the ara C, but they added the high dose all-trans-retinoic acid.  You can see that even with the imbalance between the arms, the arm with the ATRA being less subjects, there's a pretty impressive difference in the occurrence of depression, psychosis, headache, pseudotumor, and then overall CNS effects.  There was a case of ataxia and just a variety of other things.  But again, interferon itself has been implicated in depression.  The authors actually suggest that there was some sort of synergistic process going on here. 
		So, on the next slide, we're going to move on to the second topic I mentioned which is we ask ourselves, is there any evidence for a dose effect.  Again, I'm not going to spend time on this.  We don't have a lot of time.  The dose effect is clear for vitamin A.  That's why it's called hypervitaminosis A.  Normal intake of vitamin A doesn't cause these problems. 
		For isotretinoin and etretinate, as we've heard today here, there are isolated case reports that suggest a possible dose response.  And I want to emphasize this because I don't want people to go out here and say, oh, if I just reduce the dose here, everything is going to be okay.  We don't know that.  You cannot establish a dose threshold.  It cannot be ascertained from spontaneous reports for the reasons that everybody has already pointed out here today.  The spontaneous reports are incomplete and it just doesn't allow that kind of clinical judgment to be made.  All right.  So, that's the dose effect. 
		On the next slide, the third element that I wanted to consider was whether the pharmacokinetics of Accutane is consistent with what Dr. Pitts and Dr. Nelson presented about the offset of the symptoms when you stop the drug.  We know that the terminal elimination half-life of Accutane is 10 to 20 hours.  So, what I want to show you is that the pharmacokinetics of Accutane are actually consistent with the observed time to resolution of the psychiatric adverse events that we've observed in many patients upon drug discontinuation.
		On the next slide, this is from Dr. Nelson's report that he spoke about earlier.  He noted that a majority of the substantive mood disorder cases had offset within 30 days and that most of those occurred within 15 days.  I think he mentioned of the cases that he selected to analyze, for 25 cases with both onset and offset within 15 days, 23 had resolution within 7 days and 17 of those actually had resolution within 4 days, which is remarkably consistent with what Dr. Pitts just presented where I think it was 4.5 days.
		If you look in the published cases about time to offset, the most useful data -- actually the paper has already been referred to I think by Dr. Byrne and perhaps by the sponsor as well that was published by Scheinman, et al. in 1990.  I want to emphasize that this was not a trial done to examine the psychiatric adverse events of Accutane.  This was just 700 patients -- I believe it was an NIH trial -- that had received Accutane for various indications.  It wasn't even all acne.  7 patients in that group had enough psychiatric problems to come to attention.  Let's put it that way.  But of those 7 patients that they reported in this paper, it's notable that the symptoms in all 7 of them resolved within 1 week of stopping Accutane, and 1 of the patients was rechallenged and did have a positive rechallenge.
		There's another paper published by Hazen, et al. in 1983, earlier.  Again, this was not a trial to study this.  This was just 6 patients who presented with enough symptoms to come to attention out of 110 patients.  This paper doesn't actually state the exact time.  It just notes that of these 6 patients, 5 continued the drug despite the depression, but that when the treatment course was over, their symptoms rapidly resolved upon discontinuation.
		The last thing I wanted to talk about was biologic plausibility in the sense that I think Dr. McLane was referring to it, which is the more classic sense.  We don't have time, like I said, to go into this today.  He's mentioned some of the data that already exist, so I won't repeat it.  
		But the fact of the matter is we do know that retinoids enter the central nervous system.  We know that.  We know that retinoid receptors are present in adult brain.  As has been alluded to earlier, much more is known about the role of retinoids in the development of the fetal brain than is known about retinoids in the adult brain, but data are emerging.  It's a very active field of research, and we know that the substance gets in.  We know that the receptors are there.
		The other thing I want to point out is that the psychiatric adverse events that are reported with Accutane aren't occurring in isolation.  There are other adverse events that occur with Accutane, as with all drugs.  If you look at the organ system categories that adverse events are categorized into, there are 28 of them I believe.  For Accutane, the central nervous system, interestingly, ranks second only to psychiatric in the highest percentage of serious adverse events -- serious adverse events -- in the Hoffmann-LaRoche postmarketing database for Accutane.  So, I think it's clear that Accutane affects the central nervous system. 
		But on the next slide, I want to make it very clear that when we use biologic plausibility, we're using it in the sense that it's not biologically implausible.  There's no evidence we know of that makes it biologically implausible for Accutane to affect the central nervous system.  We don't know a mechanism for the psychiatric adverse events observed with any of the retinoids, as I think Dr. McLane already pointed out, but that an association is not biologically implausible we're pointing out.
		The bottom line here is that none of these elements that anyone has described this morning or that I'm describing right now -- none of these elements of adverse event assessment nor their totality proves -- proves -- in a rigorous sense that Accutane causes psychiatric disease.   But we're very concerned about the data that's been presented this morning. 
		This is another paper that Dr. Byrne already referred to.  I think this was three cases that actually Dr. Bravard and his colleagues reported in 1993.  In the last sentence in his paper, he advised us to be vigilant.  So, that's really why we're here today.  We want to explore what we need to do to be vigilant.  What's appropriate, what's feasible given the information that we have and how might we go about resolving the uncertainty.
		The last part of this is risk management and assessment, and I'm still Kathryn O'Connell.
		(Laughter.)
		DR. O'CONNELL:  Same division.  That hasn't changed.
		So, if we go on to the next slide, I just wanted to tell you briefly what the regulations are regarding this type of situation.  The thing to focus on here is the word serious.  This is the regulations for when you do a labeled warning, when you put a warning in the label.  The thing to focus on here is the word "serious."  It should be something serious.  And that as soon as there's reasonable evidence of an association and that a causal relationship need not have been proved.  So, this is basically the situation that we're in.
		On the next slide, as you know, in 1998 the sponsor voluntarily dealt with the inconclusive evidence and put this warning into the labeling.  "Accutane may cause" -- "may" used in the sense that we do not know -- "cause depression, psychosis and rarely, suicidal ideation, suicide attempts and suicide.  Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary.  No mechanism of action has been established for these events."
		So, on the next slide, I'd just like to briefly outline sort of a paradigm that we might use to discuss this today, and I think the sponsor has already talked about this this morning.  I want to point out that even though we're suggesting some ideas for how we might manage the uncertain risk, we're not limiting you to that.  We're here to get your advice.  These are just some things that we've been thinking about and obviously the sponsor has been thinking about.  
		We see it as really two goals.  The first goal is short-term.  We've got this data.  What do we do with it?  How do we manage the uncertain risk to make the use of the drug as safe as we can for patients? 
		And the long-term goal is really how to resolve the uncertainty.  We think it's important to resolve its uncertainty, especially because it's been suggested, as you've heard over the last two days, that there's the idea out there that perhaps the psychiatric disease that we're witnessing is somehow due to the indication for the drug and not to the drug, due to the acne.  
		I think Dr. Jacobs did a thorough job this morning of pointing out the very important difference between serious psychiatric disease diagnosis and what really is a normal situational response probably to a very stressful situation.  I'm not going to stand here and trivialize the suffering that severe acne causes, but suffering is not synonymous with a diagnosis of severe psychiatric disease.  
		We are aware of no adequate evidence that acne, even severe acne, causes the diagnosis of severe depression or serious depression.  But if, in fact, acne contributes to it or can cause it or whatever, then the last thing you would want to do, if there's no causal association with Accutane, is stop a drug that can, in many patients, cure the acne.  On the other hand, if Accutane does belong on the list of many drugs that have been implicated in causing psychiatric disease, then not stopping the drug could have very morbid or even fatal consequences.  So, we think it is important, in this case especially important, to try to resolve the uncertainty.
		So, if we go on to the next slide, how do we manage the uncertain risk?  There are two main topics that we'd like you to consider.  What kind of information or education for prescribers, patients, or parents might help us out here?  What would be appropriate given what we know?  The second main item would be intervention.  What kind of interventions might be appropriate, given what we know?
		The types of information.  We've already had an outline this morning of some of these.  CME programs for health care professionals and further changes to the professional labeling over what we already have. 
		For patients, we could think about a patient package insert, which is optional, as you heard this morning in the first talk.  There already is a brochure.  The sponsor has a brochure for Accutane already, and the brochure actually does mention the warning for psychiatric disease.  Are there things that we could do to that?  And then the medication guide concept that was discussed this morning.
		Then the third item under this menu here of information and education would be perhaps some sort of informed consent process. 
		On the next slide, the intervention category would include things like monitoring of patients, management, advice about how to manage the events, and drug distribution.  Again, we're putting everything up here that would fall into these categories.  This doesn't mean that we think that everything that is up here is appropriate or reasonable given the state of our knowledge.  We just want you to consider all the possibilities.
		On the next slide, we go to the final topic which is really how might we resolve the uncertainty.  It's clear from what we all heard this morning that we're not going to resolve the uncertainty with spontaneous reports.  I'm not going to spend a lot of time on this because I think the sponsor has already done a very good job of outlining the problems that we face in trying to get a handle on this with the gold standard, which is, of course, what everybody would like to see, a prospective controlled trial.  But the issues that have already been mentioned are very real.  How do you mask that trial?  How do you control that trial.  How do you avoid the bias of patients giving informed consent to be in a trial for a drug they know works for a very bad disease, but they're worried, oh, if I tell them I'm depressed, I'll be discontinued?  So, there are a lot of problems here.
		The other thing we'd like you to think about is what kind of basic science research might help us, again another open cohort study.  This we would think of in terms of collecting more data about what is actually occurring, what are the characteristics of the cases to really form hypotheses to inform more formal types of studies?  And then a well-powered, retrospective epidemiologic cohort study are really the four categories that we've come up with. 
		So, basically that's the end of my talk.  Oh, it isn't the end of my talk.  I'm sorry.  I'm telling you stories.  One more slide. 
		I just wanted to point out that there are some clinically important questions, really clinically very practical questions, that a formal study might answer.  Again, there's no guarantee it would, but if it did, I think clinicians and patients would be very grateful.  The first obvious question is, is there a dose threshold?  That would be wonderful.  If there is a causal relationship, which we don't know, but if there was, if there as a dose threshold that was still within the minimum effective dose for acne, we would have solved our problem. 
		Another practical question.  Is there an identifiable subset of patients at increased risk?  Then we don't have to apply risk management to everybody.  We just apply it to the people who need it. 
		Another question that I think people out there actually using this drug would very much like to know is, if symptoms do occur in this setting, is a dose adjustment or addition of treatment with antidepressants safe, or do you really have to discontinue the Accutane, which obviously has consequences for the patients who have severe acne that can lead to scarring if they don't get effective treatment?
		So, now I really am finished with my talk.  The last slide up here is just all of these items on one slide, if you'd like to use that during your deliberations.
		DR. BERGFELD:  Thank you very much. 
		We're going to move now to the open public hearing.  Again, to set the stage and the rules of order, each of the presenters has been allowed a specific amount of time.  Three of the presenters have been allowed 5 minutes and one 20.  We'll ask you to stick to these times.  We will run a timer.  
		After the presentations, we will adjourn for lunch and then reassemble 30 minutes later.
		Our first presenter is Margaret Hager.  I would like you to introduce yourself, who you represent, and if you have a conflict of interest.
		DR. HAGER:  Good afternoon, everyone.  I think it's afternoon by now.  My name is Margaret Hager, and although I am an M.D. family doctor, I'm speaking today as a mother. 
		In 1991 in my son's junior year at Princeton, treatment was commenced with Accutane for cystic nodular acne by a local dermatologist.  During the second course of treatment, Chris developed severe headaches and dizziness.  He was seen by a neurologist who advised stopping Accutane.
		During this time and after cessation of treatment, although the headaches abated, Chris began with severe treatment-resistant depression, with two hospitalizations for suicide intent.  Despite excellent psychotherapy and full therapeutic trials of numerous antidepressants, Chris' response, with the exception of a few brief periods of remission, has been only partial, resulting in his being homebound and on disability. 
		Three years after the onset of his depression, Chris developed bouts of acute recurrent pancreatitis and was subsequently diagnosed with cystic fibrosis, pancreatic mutation.  My educated hunch is that if this depression is Accutane-induced, it may be due to an interaction of the chloride ion channel defect of cystic fibrosis with the drug, and this might point the way to a vulnerable subset since the carrier state is very prevalent.
		My question to the psychiatrists present is this -- and I think Dr. Byrne answered one of these questions -- have any specific characteristics been identified in Accutane-induced depression?  And have any particular antidepressants or combinations thereof been found to be more efficacious in this kind of depression?  Have you seen depression such as this one associated with Accutane and persisting long after the drug has been stopped, suggestive of permanent neurological damage?
		Chris and I agree that if we had known that he would exchange a cosmetic problem for mind-destroying depression, we clearly would have chosen the former.  Thank you. 
		DR. BERGFELD:  Thank you. 
		Our next presenter, Kimberly Smith.
		MS. SMITH:  Thank you and good afternoon.  My name is Kimberly Smith.  I'm 36 years old, and I'm here today as an Accutane survivor.  Even though I'm grateful to be here, I know full well that this will probably be the most personally humiliating presentation I ever make.
		I went on Accutane November 4th of 1998, and I was on Accutane until April 26 of 1999.  I went on 40 milligrams of Accutane a day.  My dermatologist said to me that this was the most safe and most permanent drug used in treating adult onset cystic acne, which is what I was diagnosed with.  He said that he had been involved with the pretrial studies and had been working with Roche Labs for many, many years and he had an excellent track record with respect to Accutane.
		Six months later, after the Accutane treatment was over, my acne was gone, completely clear complexion.  But the problem was, in the meantime, it had completely devastated and almost destroyed my life. 
		Before Accutane I was very driven, goal-oriented, high energy, extremely positive, passionate about life and people, lots of friends.  I was in a serious relationship.  We were talking about getting married.  I was very motivated.  I put myself through undergraduate at the University of Delaware.  I also put myself through graduate school at Northwestern University.
		By the time that I had started my Accutane therapy, I had risen to the top of my profession.  I was the Executive Director of Strategic Marketing and Client Development for a large law firm in the City of Chicago.  This was also an industry that I had also helped pioneer 10 years earlier.  It's called legal services marketing.  When I got in the profession, there were about 15 to 20 of us.  Today the profession has grown to over 4,000.  I was the only non-lawyer appointed to the executive committee of a management team of a law firm, which if you know anything about the law firm structure, this is a fairly unique position, as most of the executive members are attorneys and partners.  I was making well into the six figures and very well compensated for my effort. 
		I had a love of exercise.  I was very physically fit.  I ran between 25 and 30 miles a day.  I even ran a marathon.  Loved to dance.  Had an adventurous spirit.  I earned a dance scholarship to fund part of my undergraduate degree, and also when I moved to Chicago and thought it would be an interesting way to initiate myself and make a life in Chicago, I as a part-time endeavor was a cheerleader for the Chicago Bull's first season and then went to graduate school while I was working. 
		When I was diagnosed with the adult onset acne, the dermatologist that I had been seeing did tell me about the pregnancy issues.  He asked me if I was planning to have a child within the next year.  I told him absolutely not, that that wasn't a problem.  I read a pamphlet and I signed a consent form, and that was the end of our discussion. 
		I did ask him if there were any other side effects that I should know about, and he told me that I may experience dry lips, chapped skin, dry skin, eczema, and he also said peeling feet, which in fact I did get.  But he assured me -- and this was probably the biggest safeguard ‑‑ that whatever happened would end as soon as I stopped taking the drug.  And given his considerable history with the drug, I felt very confident.  I thought it was a miracle drug.  Great, six months this is gone, and I was a very eager participant. 
		One month later, my behavior changed dramatically.  I went from this very determined, strong-willed person to this confrontational, edgy, stressed beyond imagination person.  Indicative of this, I impulsively resigned my position I think it was December 8th.  So, it was a little a month over after the Accutane.  This happened to be eight days before my annual bonus, which was fairly sizeable.  Trust me, in a rational moment I would have never walked away from an annual bonus that was part of my salary. 
		Fortunately for me, the firm rejected my resignation, and life continued.  But the problem was my behavior worsened.  I went from angry at the world, withdrew from friends and family, relationships spiraling downward, no desire to talk to people.  I was very short.  But then it grew into a position where I started to feel a major lack of confidence, self-esteem issues, memory problems, inability to focus, difficult sleeping.  And then ultimately thoughts of suicide occurred.  Mine were never violent thoughts.  It was basically thoughts of how good it would be to not exist anymore, that I didn't offer value to anyone.  I was ineffective and just basically believed that overall I was completely worthless.
		I saw my internist on February 11th of 1999.  I told him about my problems with depression and anxiety.  I never thought anything about the Accutane and never did throughout this entire time.  Never linked it.  So, I told him about this.  And fortunately, my internist had been my internist for about 10 or 12 years at that point in time, so we had a very long-established relationship. 
		I was blaming most of my problems on my job.  He suggested that I go on to Serzone and also suggested that I take a short disability from work, which I did.  I felt like a total loser. 
		My boyfriend at the time took me to Mexico.  He thought some time in the sun would help.  We went down for a three-day trip.  The trip was extended to seven days.  The trip was extended to 10 days.  And I could not get out of my seat.  I laid there on the beach with about seven blankets over top of me, miserable and crying the entire time that we were there.  
		Physically speaking it was horrible.  I have severe abdominal pains which no one to this day can address for me.  I've been to see two internists, an endocrinologist, a gynecologist just for the abdominal pains alone, and they've not been able to tell me what the problem is or recommend a treatment. 
		I have a loss of appetite, which I still have to this day.  I do make myself eat, but to be honest with you, I have no craving to eat. 
		I had a bleeding rectum for which I endured two rectal surgeries.  
		An overactive bladder.  I'm with my second neurologist trying to discern why this is the case.
		Severely dry skin and eczema which exists to this day. 
		Aching bones, which I still have, which prevent me from running as I used to do.
		Sensitivities with my teeth and gums.
		Major headaches.
		And I would vacillate between insomnia and then overall just fatigue.
		On March 15th, 1999, I got a call from Roche Labs, and it was completely unexpected.  But what I had done is I had elected to participate in a post Accutane study, during which I had identified the fact that I was depressed, not necessarily knowing that this was necessarily the reason, but I did disclose this. 
		Oh, you know something?  Hold on.  Let me step back.  I apologize. 
		On March 15th, 1999, I didn't get a call.  The call did not come from Roche.  It was a year later. 
		On March 15th, 1999, I got a phone call from a long-term friend who just called to check up on me to see how I was doing.  During the course of our conversation -- she had known that I was on the Accutane and she didn't know the depths to my despair.  At this point in time, I was on disability from work.  She told me that there's a tremendous amount of people -- she lives in New York -- that she knows and that many of them had been depressed and they had all been on Accutane.  So, that was the call, her phone call. 
		The next day I immediately called my internist and went to see my internist.  This was about 5 weeks before I stopped my Accutane treatment.  My internist told me that based on his information and the relationship that we had, he said it's a good thing that I knew you before you were on the Accutane.  He said this was definitely the cause of the depression.  And I said, well, there's good news.  My dermatologist has assured me that all the side effects go away with the cessation of Accutane, and I was very convinced that that would be my experience as well.
		So, he put me on Serzone.  He also suggested that I go see a therapist, which I did.  And I believed all would be fine and great when everything was done.
		I went to my dermatologist.  I told him of the depression that I had experienced, and he thanked me for ruining his perfect record.  He said that he had heard of people that had been depressed and that, essentially, he felt that everything would change in a few weeks.  So, I believed him.  
		A few weeks later, I did stop the Accutane.  10 days later, I impulsively quit my job, this time for good, thinking that it was the job stress, not necessarily the Accutane.
		As time went on, I struggled for the following year trying to get a job, thought that it wouldn't be that difficult.  Of course, I'm this driven person.  You just go out and get one, and the reality of the situation was, I had no confidence, I had no self-esteem and a complete inability to focus. 
		DR. BERGFELD:  I'll have to ask you to close.
		MS. SMITH:  Okay.
		I did receive a phone call the following year from Roche Labs, and it was February 18th, 2000, following up on the survey.  During that time, I had told them of my bouts of depression.  She already knew that.  I asked for additional assistance, if there was any programs that she could recommend, if they had any information.  No information was available. 
		I had been on the drug during the time at which the FDA talk papers and the Dear Doctor letters had gone out.  I got on the drug November 1998 and was on until April 1999, never received any new warnings.  This was completely devastating to learn that while I was talking to the Roche representative, I told her that my reason for participating in this was that I was hopeful that stronger warnings could be put out so that it not affect people in the future.  She told me that I should be really happy, that she had a new warning label, and I asked her to read it to me. 
		It was from that that I was absolutely shocked, did my own research, started talking to other people, and have subsequently found that this depression and these serious effects impact a lot of people.  The unfortunate part is they, like myself, have no idea that it's at all related to Accutane.  There is no information out there, and most of them go unreported.  I know 11 people that I can talk about just right now, if that were the case, that I could tell you they have not reported their symptoms. 
		I'm hopeful in the future.  Like I said, this drug did cure my acne.  Even if I had known about the side effects, I may have gone on the drug.  Who knows?  But at least I would have been able to assess and experience, as these side effects were persisting, what they were, and I could have received the proper help.  
		Thank you. 
		DR. BERGFELD:  Thank you. 
		Our next presenter, James Palazzolo.
		MR. PALAZZOLO:  Good afternoon.  My name is Jim Palazzolo.  I'm here today to express my concern that more may need to be done to make drug companies report foreign adverse events.  
		For example, how could it be that the French government warned about psychiatric adverse events 11 months before Hoffmann-LaRoche enhanced its warnings here in the United States? 
		My son Chris took his own life July 1st, 1997 while on Accutane, 8 months before the warnings were enhanced in the United States and 4 months after the warnings were made public in France. 
		Here in the United States, it is mandatory for a person who is prescribed Accutane to take a blood test for liver disorders, and women must take a pregnancy test because of birth defects.  Why not make it mandatory for people on Accutane to be monitored on a psychiatric basis?  It is my experience in the past that physicians have not taken psychiatric events associated with Accutane seriously.
		The present warnings in my opinion do not go far enough because they leave the cause and effect issue in question.  There is no doubt in my heart that the appropriate study will show an adverse psychiatric connection with Accutane.  I strongly urge the FDA to consider performing an independent study to confirm what I already believe, that Accutane can cause serious psychiatric side effects in some people. 
		Thank you. 
		DR. BERGFELD:  Thank you. 
		Liam Grant?
		MR. GRANT:  Good afternoon, ladies and gentlemen.  My name is Liam Grant.  I'm chairperson of an organization called the Roaccutane Action Group. 
		Our group was set up in 1997 to provide support for Accutane victims, to investigate all aspects of Accutane from the initial pretrial studies to review the literature, ADR reports, physician guidelines and so on in each country throughout the world where the drug is sold, also to fund and coordinate a series of scientific studies on Accutane to determine the mechanism by which Accutane causes so many severe physical and psychiatric side effects. 
		The principal side effects of Accutane based on adverse reaction reports and published studies include general side effects such as photophobia, muscle and joint pain, insomnia, lethargy, central nervous system side effects such as pseudotumor cerebri, which is described as a serious condition involving swelling of the brain, visual disturbances, hearing deficiencies, malaise, drowsiness, amnesia, hallucinations, and psychiatric disorders, which include behavioral disorders, seizures, psychosis, schizophrenia, depression, suicide ideation, suicide thoughts and actions, and also as we all know, it's a teratogen. 
		What is Accutane?  Accutane is an analog of vitamin A.  It's likened to an overdose of vitamin A.  There are many published studies showing that excess vitamin A causes a condition known as hypervitaminosis A.  The study I mention here is a 1972 study, and it showed that the ingestion of large amounts of vitamin A is known to cause depression and psychiatric illness.  In fact, we have also reports in the 1800s and the early 1900s of groups of people with high intake of vitamin A in their diet which caused major depression and psychiatric illness.
		Therefore, the manufacturers of Accutane, Roche, would have been able to predict with reasonable certainty the main side effects caused by Accutane, including psychiatric side effects and teratogenicity.  And that prediction could have been made with certainty prior to the drug ever being launched here in the United States or in other countries. 
		What do scientific literature reports say about Accutane?  Well, there are a substantial number of published studies linking the ingestion of Accutane to the emergence of psychiatric disorders as far back as 1983, less than one year after the drug was released onto the market.  I've only time to briefly refer to three of these studies. 
		The American Academy of Dermatology published a study in 1983 where the authors reported that 5.5 percent of patients experienced depressive symptoms while on Accutane.  In the case of one 21-year-old man in that study, the symptoms of depression and forgetfulness were severe enough to cause withdrawal of the drug.  So, within a few months of Accutane being introduced, the first independent study showed that 5.5 percent of patients experienced symptoms within 2 to 3 weeks of starting on Accutane.
		Another published study in 1990 in the same dermatological magazine set out details of serious psychiatric disorders suffered by 7 patients where treatment had to be discontinued because of the severity of the side effects, and they were listed, including manic depression, suicidal thoughts, fear of going insane, et cetera.  And remember, that was 1990. 
		Another study showed that adverse drug reaction reports for Accutane in the United States in the period from October 1982 to June 1985 represented the highest number of adverse drug reaction reports received by any agency for any prescription drug.  It also stated that 22 percent of adverse drug reactions for Accutane relate to central nervous system disorders, such as headache, depression, dizziness, personality disorder, and pseudotumor cerebri.  Now, that's 1985.
		Sales of Accutane from 1982 to 1985 were very small in the United States because of publicity on the number and serious nature of birth defects caused by Accutane at that time.  Accutane at that time had been likened to thalidomide.  So, Accutane with small sales at that time was attracting more adverse drug reactions than any other prescription medicine, despite the fact that some of these other prescription medicines were being sold to not just tens but hundreds of millions of people. 
		In 1983, Dr. Bravard and two other French dermatologists published a paper where they set out details on three different people who attempted or committed suicide which they attributed to the taking of Accutane.  The study resulted in a national inquiry in France between 1993 and 1994 in Montpellier, and the study was funded by Roche.  The results of that study have still not been made available to us and have never been published.  That's obviously something we're pursuing at present. 
		In 1998, we commissioned a study in order to determine whether five other prescription medications, representing 90 percent of the acne prescription market, were showing similar adverse drug reactions to those applicable of Accutane.  Dr. T. Middelkoop, who is a research scientist, investigated these five prescription medications:  minocycline, doxycycline, tetracycline, Dianette, oxytetracycline.
		This table shows some of the data produced in the study.  Now, you first of all must remember the data is May 1998, and therefore it's 2-and-a-half years out-of-date.
		The number of people prescribed Accutane worldwide, according to Roche at that time, were 6 million.  The number of people prescribed the other five medications was 300 million.  In fact, it was more we subsequently discovered, but 300 million.  So, you can see here that there were 170 cases of suicide, suicide attempt, and suicide ideation recorded at that time in connection with Accutane treatment, which we were told was 6 million people.  The other medications produced no reported case of either suicide or suicide ideation, and 3 cases recorded for suicide attempt.  And those are the medications, remember, that had been prescribed to 300 million people. 
		The study, which was published in 1999, also featured data for the United Kingdom.  You see here that there were 23 case reports of suicide, suicide attempt, and suicide ideation for Accutane in the United Kingdom, but the number of prescriptions were shown at 12,400.  The number of cases of suicide, suicide attempt, and suicide ideation for these other medications was nil.  Not one case of suicide, suicide attempt, or suicide ideation, despite the fact that these other medications represent 90 percent of the acne prescription market.  And yet, in this case you see 12,400 prescriptions, 23 cases of suicide, suicide attempt, and suicide ideation reports; 200 million prescriptions for the others, and no case. 
		The conclusion of the study was that Accutane is 900 times more likely to cause depression than the five other medications reviewed.
		How many adverse drug reaction reports are there for Accutane?  Well, in May 1998 Roche issued a letter to the Irish Medicines Board, which disclosed that there were 40,000 adverse drug reactions on the Roche database in respect of Roaccutane.  A review of all ADR data recorded since that time suggests that there may well now be 50,000 to 55,000 such ADR reports for Accutane on the Roche worldwide database.  
		Studies show that only 1 in 10 serious ADRs are ever reported.  In some countries, it may be only 1 in a 100.  If we apply a factor of 10 to the number of adverse reactions recorded for Accutane, we get a figure of 500,000 or more, more than half a million people, which I think gives some idea of the number of people and the scale of suffering caused by this drug. 
		Roche have not provided a full list of all ADRs held in the Roche database for Accutane.  The FDA and other national agencies have not received this full and detailed list of all ADRs, which I cannot understand.  Dermatologists who prescribe this drug on a daily basis have not got the full list of adverse drug reactions worldwide in respect to this drug.  Therefore, as I speak, I don't know and I doubt if anyone in this room, apart from the Roche people, knows the total number of suicides worldwide, suicide attempt, and suicide ideations recorded for the drug and also the number, up to tens of thousands, of psychiatric disorders recorded for the drug worldwide.
		I'm just going to briefly mention Norway in reference to a group of 32 very courageous people in Norway who, in 1988, set up an Accutane support group and went to the media to highlight the terrible side effects caused by Accutane.  We have the copy of the newspaper reports which are now 12 years out-of-date.  They sought from the medical professional to devise proper medical treatment for people who had suffered this severe physical and psychiatric side effects which are listed in those publications in 1988.
		As a result of this, the Norwegian Health Authority commissioned a study in 1992.  The study was financed by Roche.  The final report submitted to the Norwegian Health Authority in 1993 made no reference whatsoever to the scientific publications at that time linking the ingestion of Accutane and the emergence of psychiatric disorders and other items.  They did not disclose the number or the nature of adverse drug reactions held on the Roche database at that time. 
		The French government health agency increased the label warnings for Accutane on the 3rd of March 1997 in order to feature suicide as a listed possible side effect.  Roche did not inform the FDA or any other health agency that we've been in touch with of the increased label warnings applied by France featuring suicide as a possible side effect. 
		In the United Kingdom, Norway, Canada, Ireland, and many other countries, the label warning up to May 1998 simply featured possible mood change.  So, people right up to May 1998 who took Accutane in Ireland, in the UK, and in other countries, when they opened the packaging, they got a label insert.  The word "depression" didn't feature or other psychiatric illness.  
		Most countries applied the increased explicit label warning for Accutane in February to May 1998, featuring various psychiatric disorders, which are now pretty consistent, which say, on rare occasions, suicide, suicide attempt, and suicide ideation, as well as various psychiatric disorders. 
		This is the only prescription medication that I'm aware of sold by a pharmacist which features on the label insert suicidal thoughts and actions as a possible side effect.  And we've done extensive studies in many countries just to see is there any other product with a label warning which features suicide.
		Up to the last time of checking earlier this year, the Canadian label insert for Accutane contained no reference to depression, psychiatric disorders, or suicide.  The Canadian label warning simply featured mood change as a possible side effect.  So, despite the existence of label warnings in France for the past 3-and-a-half years, since March 1997, featuring suicide and psychiatric side effects, despite similar type increased label warnings in the United States and other countries since the area of 1998, it seems that Roche did not see the need to upgrade label warnings in Canada or to advise those patients in Canada who are taking this about current indications.  It seems to me that since 1982, Roche applied the minimum label warnings it could get away with.  Increased label warnings, of course, affect sales and they also affect profits. 
		Following the increased label warnings introduced by the FDA in February 1998, Roche placed advertisements in the media indicating that Accutane could alleviate depression.  That was their reaction.  On the 8th of March 1998, the FDA sent warning letters to Roche ordering them to withdraw the promotional material stating that they were false and misleading and promote Accutane for an unapproved use.
		Roche used similar procedures or maybe tactics in the United Kingdom, but time does not permit me to just deal with those in detail at the moment. 
		Also, Roche used similar advertising tactics in Ireland after the increased label warnings were applied and a feature on that is by Drs. Bickers and Jacobs.  And when we looked who were Drs. Bickers and Jacobs, we found that they had been employed by Roche in 1997 in order to try and persuade the FDA not to bring in increased label warnings. 
		It came to our attention that Accutane was for sale on the Internet.  Now, as far as we can determine -- and we've been monitoring the Internet for many years -- the drug was not sold on the Internet prior to the increased label warnings, featuring psychiatric illness and suicide.  To investigate the ease with which Accutane could be obtained online, we placed orders under the names of boys and girls in their teens.  Within 10 days, we were supplied with the drug from South Africa with a prescription from a doctor with a South African address.  Despite the restrictions for the prescribing of Accutane, such as blood tests, pregnancy tests, it is possible to get Accutane without a medical consultation.  All you need is a credit card.  No medical consultation.  No meeting between patient and a doctor.  No blood tests.  No birth control safeguards.  No monitoring of patients. 
		Now, Roche profits from sale of Accutane via the Internet could be in tens of millions and perhaps even hundreds of millions of dollars. 
		I would like to briefly refer to Roche pretrial studies for Accutane, which involved putting people on the medication and reporting on the results as part of the process for obtaining license in different countries, the United Kingdom, the States, different countries. 
		In one such study, 3 out of 76 subjects who developed adverse drug reactions to it were excluded from the results allegedly because they were dose-related.  So, here you have a situation, 76 people put on the drug.  3 of them we are told developed side effects, but they were excluded.  The side effects suffered by these 3 patients have never been disclosed to us, but we have investigated them and we are investigating them, as well as other pretrial studies in other countries.
		I find it extraordinary that apparently the Roche pretrial studies in so many different countries, as part of a procedure to obtain a license, did not show up depression and psychiatric side effects.  Yet, the first independent study within actually months of the drug being introduced come up that 5.5 percent of people on the drug developed depression within 2 to 3 weeks.  And this was followed by other studies, putting certain numbers of people on the drug and showing X percent and Y percent that they had suffered side effects, that the side effects are very real, that people who suffered the side effects were taken off the drug, psychiatric side effects taken off the drug, left for 8 to 10 weeks, put back on the drug, and then within a matter of weeks or months, those same serious side effects, including suicidal thoughts and actions, came back.
		Studies need to be undertaken by Roche or dermatologists to elucidate the mechanisms by which Accutane interacts with the central nervous system and other systems in the body.  This will give us an insight into the causes of the specific side effects and hopefully leading to developing proper medical treatment for the tens of thousands, if not hundreds of thousands, of people who have suffered and continue to suffer severe side effects from this drug. 
		Roche have stated publicly for the past 17 years in every country -- because we followed the PR statements from Roche and they're all the same, and they haven't changed, by the way, since 1983 -- we do not know the mechanism by which this drug works.  Therefore, there's no proof that Accutane causes depression or psychiatric disorders.  And they have no shortage of medical people and others who will go up with this statement. 
		So, here we have a product.  We know it causes the side effects, but why do they cause them?  Well, that's not our problem.  We don't know how it works.  Therefore, don't ask me about the psychiatric side effects and don't ask me about all the many, many, many physical side effects.  We as an organization now have to go out and are now spending our money because we know, of course, that the mechanism can be determined. 
		The final thing.  The license for Accutane states that it should only be used for severe recalcitrant cystic acne as a treatment of last resort when all other treatments have failed.  And that's the position in most of the countries, if not all of the countries.  We believe that more than 80 percent of patients prescribed Accutane have mild or moderate acne, which is in violation of the license.  Prescribing doctors should be required to certify that patient's acne is within the license guidelines.
		I'll just mention.  There was a survey on several hundred dermatologists, conducted by a professor well-known to this side of the house, which showed that 74 percent of patients were prescribed Accutane for mild or moderate acne.  We have other studies in France, and if anybody wants to have a look at them, we would provide them -- showing that between 70 and 80 percent of people prescribed Accutane have mild or moderate acne.  Of course, Roche know that.  Everybody knows that.  It's produced for severe nodular cystic acne.  Unfortunately, the FDA and other national agencies say that they really can't do anything about it.  It's the prerogative of the doctor.  
		Patients should have all the proper tests, blood tests, pregnancy tests, and so on which should be properly monitored. 
		Sale of Accutane on the Internet should be immediately prohibited. 
		Patients should be psychiatrically assessed, using the Hamilton Scale of Depression or a similar questionnaire, before and during Accutane treatment.  
		Independent studies urgently need to be carried out to establish exactly the mechanism by which this drug causes so many side effects. 
		An appropriate medical treatment -- this is probably the most important -- must be devised to counteract the side effects and to provide treatment for the many tens and hundreds of thousands of people who have suffered severe side effects from this drug.
		I want to thank the FDA very, very sincerely for allowing me to speak here today.  Thank you. 
		DR. BERGFELD:  Thank you. 
		The last public speaker is Richard Josephson.
		MR. JOSEPHSON:  Members of the committee and members of the FDA, my name is Richard Josephson.  I am with a firm called Baker and Botts.  I'm a lawyer and I have represented Roche on regulatory matters and other matters. 
		My reason for speaking with you today is a perspective that I may have that may be somewhat unique and that you haven't heard from the public sector.  That is, in looking at what is before you today, I think it's first important to understand that two of the speakers, including the speaker you just heard, are involved in litigation with the company.  We understand that they've suffered some personal tragedies, and I think it was important that you be aware of that.
		Second, I think that at this point in time the committee should focus again on the question that will be asked of you, in part, after the luncheon break, and that is the considerations from a risk management perspective regarding Accutane-associated psychiatric adverse events.  Is there sufficient concern to justify more risk management, and what additional messages need to be communicated.
		If I might point out to you just briefly, because it hasn't been brought out, but since 1986, as a result in large part of those case reports that you saw earlier and in some of the earlier papers, Roche has actually had in its package insert a statement indicating that of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.  In other words, there was an attempt prior to 1998, for almost 12 years, to capture in the adverse reaction section the depression cases, as well as the dechallenge and rechallenge cases. 
		After the FDA reviewed its database and ADRs in 1998, as you were told earlier, through meetings with the manufacturer, a labeling change was instituted.  That labeling change has been put before you several times, but it mentions virtually and captures almost all of the drug experience reports that had been reported to the company without regard to causation. 
		In addition, and I think most important, after that labeling change was made, the company began a verification process.  That verification process involved a look at the entire database of drug experience reports, a pharmacoepidemiological safety assessment of adverse drug reactions.  It also looked at a retrospective cohort study of databases.  It also looked at a prospective analysis of the new formulation compared to the existing Accutane formulation, and there was no verification of the signal.  Virtually all of the arguments that you've heard today from the FDA and from Roche indicate that at this time there has been no verification of the signal. 
		Nevertheless, when you consider actions that you may take or look at, you have a label currently in effect which captures the essence of the drug experience reports, even though we are sitting here today and everyone is acknowledging that there has never been a verification of the signal.  This is, as you were told, unprecedented.  The FDA, acting in its public health capacity, believes that that is necessary and physicians now have access to that information even though there is no verification of the signal.
		If I might turn to the last slide, in law and in science we have adopted your methodologies.  After years of not considering the scientific method in courts, we now have adopted from science the scientific method.  If you look just briefly at the scientific method, they ask on the question of the contention of whether Accutane causes psychiatric reactions, the extent to which the theory has been assessed based on scientific valid reasoning and methodology, whether the theory has been subjected to peer review, case reports versus peer-reviewed studies, whether the theory is only based on subjective belief or speculation, whether there is a potential rate of error in this case in the adverse drug reports, and whether the underlying theory or technique has been generally accepted as valid by the scientific community.  
		I merely ask you to consider the fact that you now have a label, which under the scientific method, no one here can conclude that Accutane causes those effects.  As you consider what remedial action, if any, is needed or additional action is needed, I only ask that you keep that in mind.
		Thank you very much. 
		DR. BERGFELD:  Thank you. 
		As you know, we have run a little bit late.  We will take a 30-minute lunch break which will bring us back here at 1:25.  We will then proceed with the discussion and the addressing of the questions posed to us by FDA.  The second part of the afternoon will then be Accutane's new formulation.  So, at this point, we are adjourned until 1:25. 
		(Whereupon, at 12:55 p.m., the committee was recessed, to reconvene at 1:25 p.m., this same day.)

	AFTERNOON SESSION
	(1:27 p.m.)
		DR. BERGFELD:  If I could have everyone take their seat, please.
		In an attempt to allow the committee to ask questions before proceeding to the questions, which are the events that we are going to do now, I would like to first call on the psychiatrists who sit at the table as part of the committee, since a lot of this has to do with their field.  Dr. Andrew Winokur has asked to speak first.
		DR. WINOKUR:  Thank you, Dr. Bergfeld.  I have three questions that I'll try to pose just in the interest of focusing the discussion. 
		The first, Dr. Bull, from the FDA perspective, we've heard a lot of very interesting discussion from the FDA perspective and from the sponsor perspective about the signal that has appeared that certainly pertains to psychiatric issues, especially depression, and suicide is most importantly coming out, and also from the sponsor some excellent discussions about the complexity in interpreting this in terms of the frequency of problems with depression and suicide in the population at hand. 
		One additional perspective that I'd be interested in, in terms of the AERS tracking system, which is part of how this signal has come to light from the FDA perspective, I'd be interested in hearing about other drugs that have been associated with depression as a side effect.  Dr. Jacobs mentioned that there are perhaps 100 drugs.  Dr. Turner also referred to a number.  But how other drugs that have been linked to depression are showing up on a similar tracking system so we have some sense of how the Accutane signal from the database that you're looking at fits in with other drugs that have known or suspected associations to depression as the side effect. 
		DR. BULL:  I think in part -- and I'll ask my colleagues from the Postmarketing, Drug Risk Assessment to also speak on this issue.  When we looked at our database, Accutane has a disproportionate representation for reports of depression.  I think in terms of things that are alerting signals relative to what you would expect for a drug, it was, in a sense, perhaps the level of association that brought attention.  
		I think additionally when you look at benefit and risk and for a drug approved for acne to have serious psychiatric adverse events associated with its use in a young population, you clearly want to make sure that you are helping to do all that we can in terms of shaping the safe use of the drug so that patients for whom it's indicated that they are being sufficiently advised and managed in terms of its usage. 
		DR. WYSOWSKI:  We did look at the rank order for depression of all drugs in the spontaneous reporting system and the Adverse Event Reporting database.  For depression, Accutane ranks number 4.  For serious depression, it ranks number 5, and for suicide attempt, it ranked number 10 of all drugs.
		DR. WINOKUR:  Thank you.  That helps give a little perspective to that. 
		My next question I think probably Dr. McLane might best respond to this, but perhaps Dr. Jacobs would have some response as well.  I was taking note of data that we were provided with about the clinical trial comparing the new formulation to the standard Accutane and the results with the BDI.  I was interested and surprised to see that the baseline scores for the subjects participating in the study was 3.5, which struck me as being extremely low.  We're told, for example, that a normative value in a group of college students was 12, and certainly in studies that I've seen in a cross section of a comparable age group, it's typically quite a bit higher.  
		This seems to go against something that we've heard about a lot over the past couple days, that patients suffering with this disorder tend to have a lot of emotional symptomatology.  I'm curious as to how you all are making sense out of this particular finding.
		DR. McLANE:  On the Beck's Depression Inventory, it was designed originally for psychiatric patients.  Many of the published materials on that include patients that are both inpatients and outpatients for that particular scale.  However, there have been a number of other studies that have looked at it in different population groups.  The one that you referred to we had submitted as one of the pieces of evidence within our NDA, and that was with college students.
		When I had talked to actually Dr. Beck on this particular score, he had said that when he had run that study, he thought because of the anxieties and pressures of the college students, that would be an expected score.  When he has looked at other normal populations, he gets scores that 5 to 10 or so for normal scores. 
		I think also what I would like to do is mention that on a clinical trial where you have people who are motivated to come in, that is perhaps a bias introduced on that aspect as well.
		DR. JACOBS:  Just to clarify that point, I also looked at the Beck scores.  I think there were 60 patients who had respond yes to the assessment questionnaires.  Of course, that was an average.  They had low average scores.  There were a few patients that had higher Beck's.  What was interesting, though, is that they didn't have the symptoms we associate with depression.  They had other depression-like responses.  
		What was significant, though, is that there were several patients who had preexisting illness, like I mentioned before, and throughout the study, they did not have an exacerbation of their underlying disorder.  There were a few patients on psychiatric meds.  They had a history of being on psychiatric meds in the past.  They didn't have a recurrence of it.  One of the people who dropped out of the study had an interpersonal crisis as the basis for the increase in the Beck and then dropping out of the study.
		DR. WINOKUR:  You may want to stay there.  I'll just make a comment, and then you may want to respond.  I'm struck by how low that score was in this population that we've heard repeatedly is prone to experience a lot of emotional symptomatology.  I'm also mindful of your comment in your presentation that especially younger people in this group, the adolescents, may be unlikely to disclose symptoms particularly related to emotional disorder. 
		As you well know and pointed out, this is not a diagnostic tool.  It's a symptom severity rating, and I might point this out as a potential limitation of much of, if not virtually all of, the data from such studies that we've seen so far, that there's really a lack of psychiatrically recognizable diagnostic information that we can use as a basis.  Certainly symptoms help us somewhat, but unless there are data from other studies that you might be familiar with, I find it difficult to extrapolate from the data that we had seen so far to having a firmer level of understanding of the presence or absence of psychiatric problems.  I think to a fair extent you made this point yourselves.  So, I don't think I'm saying something at odds with your presentation.  But I wonder if you have any different perspectives on that. 
		DR. JACOBS:  First of all, as you know, the Beck is a self-rating scale and it's not diagnostic.  I think certainly people who enter a study are different than people who have been either seeking treatment or not seeking treatment and may have been suffering for a different period of time. 
		My understanding of the literature of acne and psychiatric disorders is really having to do with symptom severity, of increasing depression, increasing anxiety as opposed to specifically being correlated with a major depressive disorder.  Anybody with a vulnerability I think will have a higher likelihood of developing a major depressive disorder, which is what I saw in a few of the cases having to do with an underlying vulnerability, as opposed to taking acne in and of itself.
		DR. WINOKUR:  My last question is for Dr. McLane.  This is related to the biological plausibility section of your talk, which Dr. O'Connell also picked up on a little bit.  To be honest, I find myself a bit confused with the slide that you presented on CNS relationships with retinoids.  I just wanted to pursue that a little bit farther because I think that trying to understand what biological and pharmacological sense we can make of this issue is another important part of the puzzle that we're being asked to consider. 
		Specifically you mentioned an association of location of some retinoid receptors with populations of dopamine systems.  You mentioned some other things that made it difficult to understand the physiological or functional significance of that.  
		I'm wondering is there an identified endogenous ligand, and are there known pharmacological agents that act on that receptor system?  And do we have any information about functionally how that system may be related to dopamine whether in terms of a synergistic or in terms of an inhibitory type function or that there's no information at all?
		DR. McLANE:  Let me break down your question into several parts.  I think one of the first things you asked is about the receptor presence within the brain.  Specifically what they had looked at was use of messenger RNA probes.  There are five different major types of retinoid receptors within the brain.  The original studies were looking at embryonic brains, and there's one study that looked at the message level of these different types of retinoid receptors within the adult brains of the animals.  These were the regions that they had specifically detected that message level. 
		A subsequent study then went in and used an antibody probe to those same proteins rather than just the message level, and found that in the brain localization many of these messengers, which would indicate a retinoid receptor was present, is no longer present as a protein.  Thus, if it is not present as a protein, it would not be functional. 
		Your second part of your question then refers to the signaling pathways of retinoids.  Isotretinoin is a natural endogenous compound that is found normally in every person.  Isotretinoin is a natural ligand for some retinoid receptors.  Isotretinoin has another name called 13-cis-retinoic acid.  The all-trans-retinoic acid has much better binding properties to these ligands than the 13-cis does.  Once the retinoid binds to the receptor, this type of receptor is a receptor that binds directly to DNA on the signaling mechanisms on genes, and it activates particular genes.
		Does that answer your question, or should I go further?
		DR. WINOKUR:  Almost all the way.  I finally asked you if there's any insight about functional or physiological effects on, for example, dopamine systems since you did draw attention to the localization in that area. 
		DR. McLANE:  Right.  No, actually that was the point.  The reason why the dopamine areas were recognized was in animals in which the genes for the receptors were specifically knocked out.  In there what they saw was those animals had a change in their gate.  It was reflected to their motor neuron function.  On those animals, when they then did any other type of behavioral changes is when they saw the long-term potentiation changes within memory.
		DR. WINOKUR:  Thank you. 
		DR. BERGFELD:  Do you have any further comments?
		DR. WINOKUR:  Well, the sort of additional comment from the line of questioning about the Beck is that, again, we've heard the different perspectives on the signal and the potential complications.  We're clearly not going to resolve all of this.  But it strikes me that part of the issue is a need for data that it sounds like are not really available that would address some very fundamental clinically relevant questions that perhaps at some point we could get into a discussion of what kind of studies and how.  But I think there are sound, thoughtful arguments on both sides of the issue of the signal.  We'll hear from the other psychiatrists, but I think the lack of some just fundamental, critically important dimensions of what we would need to hear about to think about how to take things further is very striking to me. 
		DR. BERGFELD:  Thank you. 
		I have on my list Dr. Malone and then Dr. Greenhill and then Dr. Byrne.
		DR. MALONE:  After listening to the presentations, I think it is hard to look at a disorder that has a fairly high prevalence and then find perhaps a side effect that could be clinically significant but not all that common.
		But I am still impressed by there being a signal because these are things that are often under-diagnosed in every population.  The only reporting was voluntary reporting.  So, when you look at voluntary reporting by a group of patients who often don't talk about their symptoms, I'm impressed that there is a signal, that it means something should be looked into.  I just wanted to make that statement. 
		Secondly, you had asked a question about other drugs that the FDA knew about that had depression and suicide.  Was that data pre-1998 or post-1998 when the labeling changed for the drug?
		DR. WYSOWSKI:  The rank order that I gave was post-1998, but we did look pre-1998 and pre-1998 Accutane was number 7 for serious depression.  So, this ranking, even if you look prior to 1998 when the labeling change came in, it was within the top 10.
		DR. MALONE:  I still think that is impressive.
		One of the presenters, Mr. Grant, had a slide where he showed the occurrence of suicide and depression with Accutane, then the occurrence in the antibiotics.  Has the FDA looked at their data regarding the rates of suicide and depression for those antibiotics?
		DR. PITTS:  Frank, could we put the overhead up?  The one with tetracycline and Claritin. 
		This overhead represents the total number of cases of depression, mood alterations, and depressive symptoms with the tetracycline actually since we received reports of tetracycline.  So, it's a total database, and it includes all of the tetracyclines, tetracycline, oxytetracycline, minocycline, and doxytetracycline.  There were 8 cases of depression and 2 cases of suicide.  One of the suicides was in an 85-year-old female and the other was in an 18-year-old.
		DR. MALONE:  What I thought was impressive about Mr. Grant's slide -- I don't know where the data came from -- was the large number of prescriptions for the antibiotics versus the relatively smaller number of prescriptions for Accutane.  I guess that would be true in your database also.  If you're looking at trying to figure out how many prescriptions had been given versus the number of serious adverse side effects reported to the FDA. 
		DR. BERGFELD:  Most likely that would be true because of the use in the dermatological community. 
		DR. MILLS:  May I make a comment on that?  I'm Jim Mills.  This is just an epidemiologist that couldn't keep his mouth shut here. 
		DR. BERGFELD:  That's all right.
		DR. MILLS:  If I remember the slide correctly, 1,400,000 prescriptions for one of the antibiotics with no suicides, no suicidal ideation.  Now, you tell me that there's a population of a million and a half people anywhere in this country where nobody has any of those problems.  It's a classic case of poor reporting.  I personally would make absolutely nothing out of the data there for that simple reason, that you're just not getting accurate reporting at all. 
		DR. MALONE:  Right, but if you're just trying to look at a signal for voluntary reporting, it might point towards there being a signal that there is a difference for Accutane.
		DR. WYSOWSKI:  Well, if you look at the Jick study that included antibiotics, patients prescribed antibiotics for acne, they did have suicides and suicide attempts in individuals on antibiotics treated for acne.  So, there was a possible twofold increase, non-statistically significant relative risk for Accutane, but again we were talking about sample size.  
		So, I would have to agree with Dr. Mills that it's a classic under-reporting of individuals who commit suicide or have depression with treatment with antibiotics.  I think there's selective under-reporting for the antibiotic class as a whole.
		DR. MALONE:  Just one more comment.  It's really about the use of the BDI.  When I read the report that was given to us, it seemed to me that they were looking for BDI scores that were only in the severe range.  I understand that this was not a clinical population coming for a depression study.  I don't do depression studies, but my understanding is that they usually use the Hamilton, which is a clinician report rather than the patient report used in this study.  In order to get into the studies for the treatment of depression, it would require a much lower score than they were using in this study.
		DR. BERGFELD:  Dr. O'Connell.
		DR. O'CONNELL:  I'd like to comment on that only because we're going to discuss that trial this afternoon because that data relates to the new formulation NDA, and that's not going to help you now if we discuss it this afternoon.
		I know we're incredibly tight for time here, but I just want to point out that that the objective of that trial was to study the new formulation.  It was just to compare the safety and efficacy in general of the new formulation of currently marketed Accutane.  The FDA did not help to design that trial to study specifically the adverse events due to Accutane.  
		Basically the issue was the trial was designed before the 1998 warnings but while we working up the problem.  Since the investigator's brochure was essentially the labeling which didn't have the warning in it at the time, we wanted to make sure that the patients' safety was monitored.  
		So, I think it's very wonderful for the sponsor to look at the data from that trial in an exploratory sense to learn something about, if we do future studies, to specifically address this issue, what we might learn about design and things like that.  
		We can talk about it this afternoon, but there are lots of reasons why I don't really think we can use that data to really form any sort of --
		DR. BERGFELD:  Are you through?
		DR. O'CONNELL:  Yes.
		DR. BERGFELD:  Dr. Mills?
		DR. MILLS:  Even though I'm a birth defects epidemiologist, I don't see too many other epidemiologists here, so I'd like to make some general comments in the area of epidemiology.  
		The first is it's very difficult, as people have suggested this morning, to find an effect when there are multiple competing causes and when the condition is common.  This is clearly the case here, particularly when we add in that cystic acne itself may be a cause of depression.
		However, it's important, if we can, to rule out a problem here because of the high exposure.  For example, the Roche people estimated that if there were no etiologic effect at all of Accutane, that just given the number of people who are exposed, that they would expect to see 150,000 cases in their population.  So, in other words, if the increase because of Accutane were as small as the relative risk of 1.1, we would be talking about an additional 15,000 cases.  
		So, it is important to try to answer this question.  A very large study would be needed to address this.  I think it's going to be extremely difficult to do that.  When I say "to address this," I mean either to identify an effect or even probably larger to rule out an effect.  
		A randomized cohort study where some people are given Accutane and some people are given a placebo would be highly unlikely to be done for several reasons.  First, because of the large number and the expense that would go along with doing that kind of prospective study.  Secondly, because there would be possible ethical questions and clearly difficulty recruiting people into a placebo study if they had severe cystic acne.  So, I don't think that's likely to happen. 
		I realize I'm coming out being against epidemiologic studies even though I'm an epidemiologist.  But I also think a case-control study would be very unlikely to answer the question.  As Dr. Wysowski pointed out, the Jick study had some major problems and those are not easily solved.  For example, you want your cases and controls to be virtually identical except for the exposure of interest, that is Accutane.  But that's unlikely to happen because they're also going to have cystic acne which is a risk factor that you can't control for.  So, a case-control study is never likely to have a proper balance and be able to address the question. 
		Which leaves me with the suggestion that we may not be able to get a direct answer to the question how much, if at all, does Accutane increase your risk for depression or other psychiatric illness.  
		But I would suggest that we might be able to get some worthwhile indirect data by essentially looking at a case series or just a cohort of people who were treated.  This would provide an opportunity under rigorous observation to look for the type of cases that were described this morning of people who develop the illness after treatment, and we would have the opportunity in this group to do a psychiatric evaluation prior to and then during or after treatment in order to establish that this was, in fact, incidence of new disease, not simply someone who had psychiatric problems all along. 
		It would also enable us to test in a more rigorous way people who have, as we heard previously, the experience of developing psychiatric disease on Accutane and then having resolution of psychiatric disease when the Accutane is stopped because this could then be studied in a very rigorous fashion while the people are treated, after the people are treated, and then they could be rechallenged.
		In the unfortunate event where someone does commit suicide, we would have a much better opportunity to do the psychiatric autopsies that were discussed this morning, but I hope more likely that we'd be able to do a good psychiatric profile of the people who develop psychiatric disease on treatment to account for other risk factors, such as family history or drug abuse.
		Then I think that Dr. Hager made a very interesting suggestion this morning, and that is within the cohort, if we looked at the people who on treatment developed psychiatric problems versus the ones who did not, would there be biochemical or genetic markers that we could test to see if there is a population with a predisposition.  Just as an example of that, retinoic acid receptors or something along those lines would be something I think would be quite intriguing to examine as an internal nested case-control study, if you will, within this population. 
		None of these will give us the most critical data, which is is the risk higher of developing psychiatric disease on Accutane than not on Accutane, but they will give us some very useful ancillary information that may indirectly answer that question. 
		DR. BERGFELD:  Thank you. 
		Dr. Greenhill?
		DR. GREENHILL:  I found the discussion today extremely interesting and vexing.  I just had a few questions before we move to the next phase that will help me. 
		From the FDA's point of view, what is the threshold for moving a warning that appears in bold in the package insert to the status of a black box warning?  I know this label has been suffering from label fatigue, so I'm not necessarily suggesting it.  I just wanted to know.  I'm thinking of, in child psychiatry, the case of pemoline that was moved to a black box warning with hepatic failure after 11 hepatic failures over 23 years and hundreds of thousands of cases.  That's a smaller number than we're dealing with now.  So, I wondered if different parts of the agency use different criteria to employ that kind of label modification. 
		DR. MURPHY:  First of all, I should say that you probably could find some variance, but the standard is that it's a serious and life-threatening event, particularly as you heard earlier.  We went over what the reasons for a black box were that you feel, again, that you can do something about it.  You want someone to make sure that they address this issue.  So, it is a high level disease that would be in the black box, meaning serious and life-threatening.
		DR. GREENHILL:  As I gather, a lot of the data that was gathered occurred through spontaneous reports for pemoline.  Is that one avenue that one might raise the possibility of black box warnings?
		DR. MURPHY:  Yes.  The route from which the data comes is not as important as the level of certainty or the evidence that's built to make one feel that one needs to do this.  I think, as you heard earlier though, we don't have to have causality, a direct link.
		DR. GREENHILL:  Thank you.  I have one other question. 
		Bipolar disorder in adolescents is becoming increasingly recognized as a source of tremendous impairment, morbidity, and suicidal behavior and death.  We know now that certain medications will intensify or trigger those symptoms.  There are a number of antidepressants, for example, paradoxically that will cause a switch into mania and severe problems. 
		I wonder if either the agency or the sponsor knew of any cases among that data set, however large, of reported depressive symptoms where bipolar disorder was a problem.  I'm bringing it up because it's, at least among my colleagues, well accepted that the medication can have a triggering effect on severe psychiatric disorder.  I'm not talking about Accutane, but it's a model for possible psychiatric reactions. 
		DR. BERGFELD:  Dr. Jacobs.
		DR. JACOBS:  Just to respond to that, in reviewing the cases of depression, psychosis, and suicide, the clarity of diagnostic information to really state it was a bipolar disorder was virtually nonexistent.  I did not see any clear-cut relationship between the administration of Accutane and the production of symptoms, and then it was confirmed that the person had, for example, bipolar disorder.
		DR. BERGFELD:  Is there an FDA response? 
		DR. PITTS:  Yes.  I'm aware of one case where we had a diagnosis of bipolar after Accutane and another case where we had a psychosis and mania after Accutane.
		DR. GREENHILL:  I think that just makes me stronger in support of the suggestion by, I think, Dr. Mills for the possibility of a rigorous study with diagnostic criteria and direct interview of all the patients who might enter into such a study. 
		DR. BERGFELD:  Thank you. 
		Dr. Byrne?
		DR. BYRNE:  I would only have about two comments.
		One would be that in relation to the earlier presentation that suggested that retinoids were detectable or isotretinoin was detectable in rat brain following administration.  I feel that's probably pretty significant in relation to what I had said before.
		And the other issue that I would mention is that, A, I don't know what the effect of that would be while it was there, and B, if isotretinoin can completely reverse the process that causes acne, what is the isotretinoin doing within the brain substance while it's there?  That would be my only comment in real terms.
		DR. BERGFELD:  Thank you. 
		I have several people on my list.  Dr. Rosenberg, Miller, King, Levin, and Branch in that order.
		DR. ROSENBERG:  Thank you.  I have two things. 
		One, like a lot of many other physicians, we don't just take care of diseases, we try to assess the patient and modify the treatment depending on the special needs of the patient.  While we've heard and certainly I've experienced sad, young people because of severe cystic acne, I must say that the most upset patients that we see with acne don't have the bad cystic kind.  Frequently they're young people who are terribly upset over what looks to me like really not much to be that upset about.  But they say, well, it's really an important thing in their lives.  And you start rattling off the names of the medicines that we use.  Used that, done that.  Is there anything else?  Then I will say, well, there's Accutane.  And I'll tell myself maybe for this patient it's worth it. 
		As I think about what we've heard today, are these people already suffering from some personality disorder or psychiatric disability that would place them at higher risk of a real serious reaction than the youngster with the bad cystic acne, in which case am I just asking for extra trouble by doing that?  And if I am, maybe we should indicate that somehow for other people so they don't fall into the same trap. 
		The other thing I was going to ask is it might be doable in the laboratory with rats or something.  I wonder if there's any comorbidity incurred by Accutane plus, say, either cocaine or methamphetamine or some of the things that are around out there that young people bump into.  We can't ignore the incidence of that use. 
		Thank you. 
		DR. BERGFELD:  I think there's a response from FDA.  Dr. Bull?
		DR. BULL:  It's more of a procedural question.  I wanted to just ask, because looking at our questions, some of these are being addressed in the discussion, and I'm sort of getting a sense that we are moving from clarifying questions to actually some that address the questions we have for the committee.  A lot of this discussion has taken that framework, and I don't know whether or not it might help us to sort of move the dialogue along if maybe we went ahead and addressed those.  I don't want to in any way impede discussion, though, or any other further clarifying issues that need discussion. 
		DR. BERGFELD:  Thank you.  I think that's a good attention getter. 
		I think what I'll do, though, is call upon the people that I have on my list and ask them to be brief.  Dr. Adams?  Is that who is waving to me back there.  If you don't mind responding next. 
		DR. ADAMS:  Well, my question was one for clarity, but then I have another one that is probably more appropriate for later. 
		I still need clarity on the interaction between retinoids and the D2 receptor gene as to whether or not dose-response is understood in brain tissue and whether or not retinoids have the ability to up- or down-regulate the production of the D2 receptor from that gene. 
		DR. McLANE:  There have been two studies in embryonic neural cells. 
		DR. ADAMS:  I'm sorry.  I wanted to focus my comment just on the adult. 
		DR. McLANE:  No, there have not been.
		DR. ADAMS:  I would see that as an area of need.
		DR. BERGFELD:  Thank you. 
		Dr. Miller?
		DR. MILLER:  I'll wait. 
		DR. BERGFELD:  You'll wait to the questions? 
		Dr. King?  Wait till the questions? 
		Dr. Levin?  Questions? 
		Dr. Branch?  All right. 
		Dr. Lammer?
		DR. LAMMER:  Yes.  Both Dr. Nelson from the sponsor and the FDA representatives listed among the criteria for trying to decide whether these reports might be causally linked to Accutane, one of the criterion they both emphasized was the possibility of a dose-response relationship.  Dr. Nelson didn't mention anything methodologically about how he concluded that there was no apparent dose relationship, and I'm pretty unconvinced by the FDA presentation that in their conclusion isolated cases suggest a dose-response effect.  
		I'm really unaware of any methodological approach that allows you to take a data set composed essentially only of adverse drug reactions and come up with a dose-response relationship, one way or the other.  So, I think for the purposes of the committee deliberation in trying to assess a possible causal relationship, dose-response effect here I think is just not an appropriate criterion to be looking at, considering that we're dealing essentially only with adverse drug reaction reports. 
		DR. BERGFELD:  Thank you for that clarification.
		Dr. Malone wanted to say something before Dr. Bull presents the questions. 
		DR. MALONE:  I was impressed with the epidemiology of depression presentations on both sides.  I just had one point to ask the Roche people.  In what you said, did you say that one of your plans was to increase CME about the presence of psychiatric disorders in patients that might need Accutane?
		DR. ELLISON:  Yes, it was.  Well, let me clarify.  We said that the high background incidence of the disease in the cohort from which acne patients come, depending on age, sex, and prior history, the 150,000 that you would see across dermatology in this period, is an opportunity to improve the impact of dermatology practice.  So, CME should include people who have those risk factors in general, not just people who you might want to treat with Accutane, so that we don't ignore them and just focus on people who would have uncertain risk.  That was the point. 
		DR. MALONE:  Because such a thing might do more for the treatment of depression than many of the other discussions we have if they did just a simple CME presentation on depression.
		DR. BERGFELD:  Thank you. 
		Dr. O'Connell, quickly.
		DR. O'CONNELL:  I just wanted to clarify that when we brought that up, we were thinking too not just CME for dermatologists, not just for prescribers of Accutane, but for health care providers who would be likely to see patients who present with the problem, in other words, psychiatrists, emergency room doctors, pediatricians, et cetera. 
		DR. BERGFELD:  Thank you. 
		Dr. Bull?
		DR. BULL:  Once again, our framework is that all these considerations are taken from a risk management perspective.  We have heard today, I think, a significant body of data, both from Roche, as well as from FDA, that I think clearly lays out issues attendant to an association of psychiatric adverse events and the use of Accutane.
		Our goal is to do we all that we can, to the very best of our abilities, to manage the use of Accutane such that we maximize benefit and that we minimize the risk associated with its use.
		Causation is not a necessity in this instance.  I would reference you back to the regulation that was read earlier to you by Dr. O'Connell where the standard in this instance is one of reasonable evidence, and I think clearly what we will need to frame our risk management discussion on is whether or not there's reasonable evidence for us to move forward in a more definitive way to address this issue.
		So, without further ado, our first question to the committee:  Is there sufficient concern to justify more risk management?  If yes, what additional messages need to be communicated and in what form? 
		John, if we could put up the options.  We're going to put back up again the slide at the end of Dr. O'Connell's presentation, and I'd like to bring to your attention to the elements here which I think are options specific to question 1 on education and information and potentially intervention.  So, if we can sort of shape our discussion around those as possible options for consideration. 
		DR. BERGFELD:  Do you want to read your second question as well so we know what we're about?  And then we'll go back to the first. 
		DR. BULL:  Okay.  Question 2:  Would further studies help to clarify the relationship between Accutane use and psychiatric events?  If so, what kind of studies?
		DR. BERGFELD:  Thank you. 
		I'll now open the discussion for question 1.  I have a list here.  Should I go down it again?  Dr. Miller, you wished to present on question 1 or the discussion of question 1?
		DR. MILLER:  Yes.  We certainly need a lot more data, and we've not gotten the data to this point.  I think one of the things that's apparent is that we have not been reaching all the prescribers of Accutane.  The educational tools have been there, and they don't reach all the physicians as they are.  I think that the educational tools have to support specific recommendations.  Again, using our situation as prescribers of Accutane and also teachers of dermatology residents, it's a very varied approach with a medication that has very serious implications.  
		What would help me and make my practice much easier would be to have a specific form that would be dealt with with each patient that would include the pregnancy contraceptive issues, that would include the appropriate questions that I would ask from a psychiatric standpoint because I don't know what those questions are, but those questions that the psychiatrists feel are appropriate.  And upon completion of that form, I would then be able to write a prescription for a patient.  But the fulfillment of the recommendations would be the sine qua non for my writing the prescription for Accutane.  I think this would help to eliminate those outliers who are really not going along with the recommendations, who don't have a good knowledge of Accutane, and who are not going to be reading the literature.  
		This would help us immensely because I think your data ultimately is going to come from the physician.  If I have those forms and they're on file and they're available to you, you're going to be able to see what I have psychiatrically, what's happened with the pregnancy issues.  I think it would eliminate the capriciousness of the current approach that we're taking with a very serious drug, and I really have concerns about that and it's a drug that I use. 
		DR. BERGFELD:  If I might intervene here, are you suggesting that the psychiatric evaluation be in part of the registry that was voted on yesterday, the pregnancy registry, the female who was entered into the Accutane therapy?
		DR. MILLER:  I think it should be, yes. 
		DR. BERGFELD:  And you were then saying about the educational materials, that have been so wonderfully presented to us from Roche, that incorporated into that massive group would be something on a psychiatric evaluation.
		DR. MILLER:  Exactly, yes.  I think we have the specific recommendations and the educational materials would support those recommendations.
		DR. BERGFELD:  Dr. King.
		DR. KING:  I'd actually like to expand on that theme, in the sense of that all change represents both a problem and an opportunity.  As part of this meeting, the three goals to address the issues of Accutane and adverse outcomes in pregnancy, this committee selected design number 3, which includes increased education of patients and prescribers, more detailed or more effective informed consent, and registration to include a pregnancy registry, surveys, external data, and more increased or more accurate or efficient pregnancy testing. 
		I'd like to expand on that in the sense of registration must be uniform to be most practical and useful.  Exceptions and subsets will not be easily captured.  You have in a doctor's office oftentimes with a dermatologist 60 patients being seen in a day, and if you have to figure out, with the various people on vacation and so forth, you really need to make it male and female all ages.  It moves the monitoring from a voluntary effort to a mandatory effort.  
		So, the registration is more intrusive, but the cohort studies and retrospective studies and other studies mentioned do provide the opportunity to capture this, but by extension also by including what Dr. Miller suggested, measuring depression and other CNS effects becomes possible. 
		Since the Accutane New Formulation studies already include a more complete evaluation of depression and other CNS adverse events, it may be that by starting the new formulation anew, we won't have black box fatigue.  We will put both these new changes of the pregnancy effects and depression, the CNS effects all as an integrated package.  So, oftentimes when I make change in my department, if I'm going to have a major change like a new boss, you also do some other things that may not be directly related because people are expecting change. 
		So, if we're going to make change, let's not piecemeal this.  Let's not make it hard on Roche who has done a great job of trying to identify the issues.  I don't know what the receptor is on retinoids, but I do know that hypervitaminosis A is real.  So, let's try to work out some solution where we're going to have an integrated package where we can modify and integrate what Roche is already trying to do both for pregnancy and depression and CNS and by having a mandatory registration, we'll have a database that we can monitor and go forward and retrospectively select out populations.  I think we're going to make it more cost effective and more likely to be followed if we do it this way. 
		DR. BERGFELD:  I have Dr. Abel next and then Dr. Honig.
		DR. MURPHY:  Can I just ask a clarification question? 
		DR. BERGFELD:  Yes.
		DR. MURPHY:  From what I understood both of you to say is basically you do want an informed consent, that universal approach here would assist in the efficiency of this process, and that that would involve an informed consent for everybody.
		DR. KING:  Absolutely.  One ticket, one show.
		DR. BERGFELD:  Dr. Abel?
		DR. ABEL:  I just wanted to comment on a couple of issues.  I agree with Dr. Miller in terms of patient evaluation and that dermatologists and dermatology residents in training need to be educated on how to evaluate patients from a psychological/psychiatric standpoint.  Whether or not this needs to be an official registry, I'm not sure because I am concerned about the intrusive nature of this, making it part of a registry. 
		The other thing is, what is the information that we need to transmit to patients about risk of adverse events?  One particular issue that I'm concerned about is duration.  I think we heard about the cases of depression and suicide, and with depression there was dechallenge and rechallenge.  And then there were some cases that occurred after discontinuation of the Accutane.  What information do we have regarding duration of side effects?  This drug has a short half-life, but is there some binding to receptors that causes concern for more permanent effects? 
		DR. BERGFELD:  I think some of that would be answered under question 2, but certainly your thoughts can be recorded and taken up again under question 2.  I think that some of it will be solved by the FDA in what they finally decide to do with our answers, unless you have a specific recommendation to make.
		DR. ABEL:  No, I don't, but one last question is clarification or information gathering on worldwide case reports and to what extent were these incorporated into the case reports by Roche.
		DR. BERGFELD:  Is there a Roche response?  Were the worldwide cases incorporated in your database that you presented to us?
		DR. ELLISON:  Yes, they were, and they were all reported to FDA as well.
		DR. BERGFELD:  Thank you.  And to the FDA as well.
		Dr. Honig?
		DR. HONIG:  I just wanted to follow up on Dr. Miller's comment, basically a plea for a standardized approach to prescribing Accutane.  I was wondering if you're interested in pursuing this a little further and you stop short of perhaps recommending a certification program for Accutane prescribers, there is precedent for that for drugs approved by FDA.  Tikosyn, dofetilide, the antiarrhythmic I think you heard about, is approved for use by certified prescribers of the product where they have to pass a competency checklist.  I'm wondering if you want to entertain that. 
		I know Dr. King has already in his institution put some standard operating practices in place for his trainees that are learning to prescribe Accutane.
		DR. MILLER:  Yes.  I think that's absolutely necessary.  And we've done that within the department.  We've set up standards.  But I think with a medication as serious as this, with all the implications -- and we want to save pregnancies and save children -- we need something official so that there's a uniformity to this, that it's not my department and Lloyd's department individually doing it.  I think it has to become official so that we're asking the right questions from a psychological standpoint so that we're doing the right things as far as the pregnancy and contraceptive issues are concerned.  What I see now is great diversity in this, some people not doing it and others doing it.  It's imperative that we do it, and it's the only way you're going to ultimately get data and have some consistency and hit every pocket, if we restrict prescriptions to the completion of this material. 
		DR. BERGFELD:  Dr. Moore, then Dr. Greenhill.
		DR. MOORE:  I just want to voice my concern.  Although I certainly have sympathy with the ideas that have been put forth of putting everything together in one package, I think the body of evidence, so to speak, for the psychiatric effects are in no way comparable for what we have for the teratogenic effects.  And to bundle those two in the same package I think probably puts us at risk for not having a successful program for the known birth defect risk and maybe puts us at risk for getting the kinds of information that Dr. Mills was talking about that we really need to assess whether or not there even is the risk for suicide or other psychiatric conditions. 
		DR. BERGFELD:  Thank you. 
		Before you go, Dr. Greenhill, I promised Dr. Winokur.
		DR. WINOKUR:  Actually to follow up on that question, I think we really need the kind of systematic prospective information that Dr. Mills was referring to before to make further headway on understanding the relationship.  So, hopefully a program putting together such information would be an important step in moving forward. 
		Just to step back to the original question of is there sufficient concern to justify more risk management, I think even from the perspective of Roche's presentation that this population is one that's fraught with potential for significant psychiatric events, even unrelated to what Accutane may convey, and that clinicians dealing with this population are, by and large, not trained psychiatrically extensively I assume in most cases.  And this would be a challenging population for those of us trained in the area.  I think having the more structured systematic approach could be very helpful and could be justified on those grounds alone, let alone the additional concerns about the potential for problems associated with Accutane.
		The one other element that I would underscore ‑‑ and I think it's been mentioned, but I just wanted to highlight it -- is I think paying real attention to what kind of information is provided to patients at the outset.  We've talked a lot about the information in the really beautiful program put together in terms of the contraception and avoiding becoming pregnant, and I agree that it would not be appropriate to have a comparable amount of attention at this point to the depression issue.  But I think some clear information about depression, again not necessarily saying that this will be because of being on Accutane, but just because of the circumstances of this phase.
		But we've heard again from Dr. Jacobs that this population in particular is likely to conceal or be uncomfortable about revealing symptoms.  Again, I'm alerted to the low, in my opinion, scores on the Beck Depression Inventory as perhaps another reflection of that.  I think from up front, they need a kind of clear, candid discussion that during the course of treatment, there may be some symptoms that arise and some examples should be given and some specific instruction to communicate about that and what to do about that.  And in addition, I assume that the clinicians might also need some help in terms of where to go once that comes up. 
		As a bridging comment, it strikes me that putting some of this together could be an extraordinary opportunity down the road to think about some other coordinated studies that would address another question that we'll probably get to with question 2, which is what do we do when problems do arise in the context of Accutane treatment and how do we most effectively treat or manage that.  It sounds like there's great need for better information to guide the field, and this could be a wonderful opportunity to start to build towards that.
		DR. BERGFELD:  Thank you. 
		Dr. Greenhill?
		DR. GREENHILL:  Just a couple of small points which I'm sure are obvious.  One is that the current consent form that's in the package insert has no information on the psychiatric possible problems that could arise, and in all my experience with consent forms, if there is an associated condition that has been found in the past, it's usually put into the consent process.  That's an opportunity to put in the warning signs of depression to remind both the practitioner and the patient what they might be looking for.
		The second thing is some of the comments made by Dr. King and Dr. Miller suggest to my mind that there might be prescriber practice parameters.  We have them in child psychiatry for administering stimulant medication.  I wondered if there are any dermatological practice parameters surrounding Accutane.  I'm sure there are but I just would like to know a little bit more about them because they may figure into this whole process that we're thinking about now. 
		DR. KING:  Actually thank you for that opportunity.  When we approached the original issue of Accutane monitoring, it had more to do with dermatology had no issues to monitor relative to the hospital quality assurance program except that we always report and follow up on skin cancer.  So, that put us at major risk in terms of legal.  So, we looked into Accutane and asked the issues of how many people, were we doing the pregnancy tests and following up. 
		I'd like to suggest that from my experience with dealing with a lot of smart kids and doctors' sons and daughters at Vanderbilt, if you put something in the PDR that says something about depression or anything else and you don't mention it in the consent form, they come back to you like crazy in these days of the Internet and the Web and so forth.  It's not like don't worry about that tiger back there, and oh, by the way, I'm not going to mention it anymore.  You cannot not put that there. 
		So, I agree we should not scare the hell out of folks for various kinds of "you may have this," but something in a consent that says there may be a risk and you should know about this and you should report this, not only can you have pregnancy, if you're a female, but you may have depression and you should report that because there are things we need to know about that and we may help you.  
		So, that was my integrated approach, saying if you're going to make the change for a new formulary, you're going to make the change for pregnancy, and you're going to address that issue of depression and get a population from which you can select out for better studies, I think you ought to do it all as a package.  
		So, relative to the issues in dermatology, the American Academy of Dermatology has a series where they basically describe what are the effective treatments recommended for acne, and it does suggest in many articles, as you've seen quoted here, that there are some problems.  So, I think you're worried more about the population not being reached, pediatricians, nurse practitioners, than you are about dermatologists.  No one, including me, wants to be sued because we did not talk about the issues.  
		So, I think there is some misinformation, but mostly lack of information outside dermatology.  So, I'd like to see an integrated consent form that addresses this in a proper way, negotiated between Roche and the FDA and perhaps even dermatology and general practitioners.
		DR. BERGFELD:  I have Dr. Epps and Dr. Levin.
		DR. EPPS:  Thank you.  
		In regard to the questions, I certainly agree that we definitely need information on the CME program that has already been suggested and discussed with Dr. King, through our academy, as well as publications, press release.  I know the FDA often puts out publications and suggestions.  Professional labeling is certainly indicated.  In the brochures from the company, absolutely it should be in everything that they discuss regarding the risk or that there have been reports, whatever language that you'd like to use. 
		I do have concerns also regarding confidentiality.  If you're going to document particular risks or possible indications of depression or psychiatric illness, maybe that shouldn't be on the consent itself or whether there should be yes or no.  There may be signs rather than each specific question that certainly psychiatrists could aid in the best screening type questions.  We can't get into great detail, but there are certain screening questions that may indicate there may be signs of depression or other problems.
		As far as, of course, patients would want to be closely monitored.  Perhaps through managing of events, we could emphasize that you need referrals not only for psychology but also for reproductive or contraceptive counseling.  Certainly I do not personally manage birth control pills or whatever.  I leave that to the gyn and the pediatricians and the family practitioners who do that on a regular basis.  There are contraindications for all of those things, and certainly I would not manage someone's psychiatric illness either.
		As far as formal studies, yes, yes, yes, and yes.  We clearly need data, retrospective and prospective.  Perhaps those cases that Dr. Byrne referred to, whether it's dose related, whether it's related to the body mass index, who knows?  But we could certainly get as much information as possible, maybe the dosing and advancing of the dosage, or whether it started at a large dose or advanced too quickly.  Who knows?  But if you get that data and look at it, perhaps we could go forward and make suggestions regarding patients who should or should not be treated that way, different ways the medication could be given to avoid the kind of side effects that people have referred to today.
		DR. BERGFELD:  Dr. Levin, then Dr. Branch.
		MR. LEVIN:  I'd just like to add to the mix my belief that Accutane become the third drug for which the FDA mandates a medication guide.  It seems to me a very appropriate drug for such a mandate not only in terms of the psychiatric adverse events, but other serious side effects and adverse events.  Clearly there's a lot of emphasis which is justified on the issue of preventing pregnancy and birth defects.  It's sort overwhelming I think the usual presentation of other information about the drug which is also very important. 
		A medication guide is a safety net.  It requires that if nothing else happens along the way, at least at the time the drug is dispensed, that the patient would get at the point of dispensing an information sheet or guide similar to what you've heard described today.  I think this is, again, a perfect example of a drug which meets the statutory criteria, and we would be well served by moving this to a mandate.
		DR. BERGFELD:  Thank you. 
		Dr. Branch?
		DR. BRANCH:  I come in with a slight tone of dissent.  I'm a strong proponent of evidence based medicine.  I think that it's extremely difficult to see the signal in the background of the psychiatric illness here.  I think the most convincing data is the dechallenge/challenge data that the FDA presented.  Having sort of seen the quality or heard about the quality of the various data sources, it seems to me it is likely that there is a small but real temporally related side effect profile in a minority of subjects.  
		I like the idea of doing future studies that look at the potential for pharmacogenetics to identify predisposed people, but we don't have the science to back that yet.
		I'm concerned that we're going to be taking what is a therapeutic opportunity to link dermatologists and psychiatrists to mandate something that may not be as simple as that.  
		So, my concern is that the patients are given a current state of knowledge in all its imprecise natures.  I am concerned that there is a rush to condemn when we don't actually have the requisite information.  I think the future studies could be designed and could really throw light onto both mechanisms, identifying potential people at risk, and being able to come up with strategies of what to do if you see something, but I think we need to be very careful that we tell people what we know and not what we feel. 
		DR. BERGFELD:  Thank you. 
		Dr. Gloria Anderson.
		DR. GLORIA ANDERSON:  I wanted to come back to question 1 and express my opinion.  First of all, I think I've heard enough to answer yes to this question.  I believe that there is, at least in my opinion, sufficient concern to justify more risk management.  I'm a physical organic chemist, so I'm not going to try to get into any details.  I do teach the doctors.
		In the area of education and information, I think that there probably is the need for further effort in that area.  However, I would suggest that you might want to, as you do that, look at the effectiveness of what's already out there.  I have a great concern for how effective educational and informational materials in terms of prescription and nonprescription drugs can be. 
		Intervention I believe certainly is an area in which we ought to be doing something.  It seems to me that one of the things I've heard a lot is that we don't know a lot about what's happening with a large number of patients.  Therefore, it seems to me like monitoring the patients and managing the events might be something that would give us some of the information that we've said we don't have.  
		So, my answer to question number 1 is yes, I think we should do that, and I think we should move in these two areas that are listed here. 
		DR. BERGFELD:  Thank you. 
		Have we heard everyone?  Because I'd like to call the question.  The first question is, is there sufficient concern to justify more risk management?  Is that all right to do?  All right.  
		I'll call the question.  All those in favor of yes, please indicate by raising your hand.
		(A show of hands.)
		DR. BERGFELD:  Unanimous.
		I think that we've heard detailed discussion on what possible considerations could be made and could be expanded and reviewed, but are there any other comments regarding this area?  Yes, Dr. Rosenberg. 
		DR. ROSENBERG:  I think we ought to separate the suggestions that forms be required for the patients to fill out which might or might not include the psychiatric depression index, as well as pregnancy.  That was mentioned. 
		Then there was also the question of certifying certain physicians to be able to handle this material.  These are two very separate issues.  I certainly would vote separately on the two of them, and I urge that we not mix them up when we vote.
		DR. BERGFELD:  I'm not sure that we need to vote on them.  You just needed to hear the discussion of what the experts think.  Is that correct?  Or would you like specific actions?
		DR. BULL:  Going back to Dr. Levin's comment on the medication guide, you may want to in terms of the part of the question in terms of messages and what form that may deserve.  You may want to consider taking a vote on how they're made because I think also it's been discussed about including this information in informed consent.  The medication guide, as you heard in Dr. Ostrove's presentation earlier today, is a document that would be required to be dispensed with the drug.  That would also be a mechanism of ensuring that the information is provided in a manner that is clearly understandable.
		DR. BERGFELD:  If I could take this apart then, it appears to me under "education and information," that Roche has supplied some very good materials.  There have been some suggestions made that they should be relooked at, perhaps they could be enhanced and some of the words taken out so it would be more simple, so it would be easier read and interpreted by all, both patients and physicians. 
		There needs to be continuous activity in education of the provider, which is the physician.
		Then we move to the question of professional labeling.  I think that you've already taken care of, and I think all of us in our conversations agree that the labeling appears to be appropriate at this time.
		The information to the patients then, the patient package insert you state here is optional.  Is there an opinion that that should be other than optional?
		DR. ROSENBERG:  But that's the question.  Should we move from optional to the medication guide which is required?
		DR. HONIG:  Right.  The point is that a PPI, a patient package insert, is optional that the patient receives it versus a medication guide where we know the pharmacist is required --
		DR. BERGFELD:  So, they wouldn't receive both. They would receive one or the other.  Is that correct?  Or they could receive both?  Dr. Levin?
		MR. LEVIN:  The medication guide is at the point of dispensing.  They could receive a PPI at any point from a prescriber or at the point of dispensing or by going to the PDR or going on the Internet.  So, there are a variety of ways.
		DR. HONIG:  From our perspective, a PPI is part of approved product labeling, and it's virtually identical in appearance to a medication guide.  The only difference is that with the medication guide it's required that the pharmacist provide that to the patient filling the prescription. 
		DR. BERGFELD:  Dr. Greenhill?
		DR. GREENHILL:  I had one question.  I understood that the medication guide could be avoided if the prescriber thought it was somehow not indicated.  How would the patient know that there was a medication guide that he or she was not being offered?
		DR. BERGFELD:  Is there a response? 
		DR. BULL:  What I recall of Dr. Ostrove's presentation is that it's required to be distributed at the time that the drug is dispensed by the pharmacist.  It goes with the package.
		DR. BERGFELD:  It could be overridden by the physician we heard, but the patient could request it and override the physician.
		DR. GREENHILL:  If the patient knew about it.
		DR. BERGFELD:  Right.
		DR. HONIG:  As Dr. Ostrove mentioned, there's a label on the vial saying that a medication guide is available for this product.
		DR. MURPHY:  I would suggest that you not mix the patient package insert and the medication guide.  The patient package insert is part of our labeling that we do things to.  There are very specific regulations for the medication guide, as were laid out this morning.  It has to be given, except in that circumstance just discussed.  There has to be a notification on the bottle that you're supposed to get one, and it has very specific language as to how we're supposed to address, as you heard this morning.
		So, I think that what Dr. Bull was trying to get us to focus on was are you saying, when you voted we need to do more, in addition to trying to coalesce some of the activities here and information exchange and education for professionals, when it comes to the patient, do you want a medication guide to be utilized?  I would say we're asking you for the psych aspects of this right now.
		DR. BERGFELD:  I think that's quite clear then.  The rest of it the FDA already is engaged in doing with the company. 
		So, let's go to the medication guide.  May I put the question on the table and see how it falls here?  All those that are in favor of a medication guide, specifically as it relates to the issues?
		Yes?
		DR. MOORE:  I'm sorry.  What would the guide say?
		DR. MURPHY:  Basically as Nancy Ostrove went through today, it has to have certain categories.  It has to be in language that the lay public can understand, and it has to answer questions like, what do I need to know and what should I do if?  It has very specific things that we have to put in it.
		DR. BERGFELD:  Dr. Levin?
		MR. LEVIN:  Just one quick comment.  The medication guide format is the result of conversations that have been going on since 1995 when the FDA first proposed medication guides for all drugs.  That was beaten back by an act of Congress.  I won't go through the long history of decades of trying to do this.  Although this particular statute is new, the notion of a medication guide and the format that's been developed has been around for a long time.
		DR. BERGFELD:  Dr. Greenhill.
		DR. GREENHILL:  Just a point of clarification.  Would the medication guide that's being proposed also include the information on pregnancy and danger to the fetus?
		DR. MURPHY:  We can determine that that is necessary after what we heard from you yesterday, but I think what we're asking you to vote on today is the medication guide as it is relevant to a discussion of psychiatric concerns.
		DR. BERGFELD:  Dr. Levin?
		MR. LEVIN:  Just a clarification.  Medication guides I did not think were focused to specific risks.  Are they?  They have to be consistent with the product label.  They're supposed to inform the patient.  It's sort of a risk-informing process, as well as other things.  It says these are the risks of the drugs you're going to take.  It may highlight the principal risk.  But unless I'm completely confused. 
		DR. MURPHY:  You're correct.  I'm trying to focus, because we were mixing the two, that we can put in ‑‑ and we had a long discussion yesterday about the risk for pregnancy.  Not that we would leave out things that need to be in there, but would you please address whether you think we need a medication guide as is relevant to the psychiatric risk here.
		DR. BERGFELD:  Dr. Moore?
		DR. MOORE:  The question I had earlier wasn't about what should be in there in the format, but how will you describe this risk to the patient? 
		DR. MURPHY:  Believe me, I couldn't do that in one minute right now.  I could not tell you that.  It takes the experts from the division, the technical experts.  It takes a group of people who look at risk communication.  There's a process that goes into place.  It's not something that we would do very quickly here. 
		What we're asking for is not what we would say, but do you think we should utilize this mechanism for this specific aspect?  Dr. Levin, you're right.  We would not just include this.  I'm just trying to focus the conversation.  Thank you. 
		DR. BERGFELD:  Dr. King?
		DR. KING:  I'd actually like to come back to what I proposed earlier, like load all the freight on one boat.  It seems to me that the purpose of this is actually to inform the patient as a follow-up to the consent form.  I agree with Dr. Rosenberg.  I don't think that it's practical to list all these things that we'd like to do to follow the potential etiology of psychiatry and all these scales and tests.  I just would like to know if my son gets this medication somewhere, that what he signed in the consent form is the same kind of information he's going to get when he gets the medication.  It seems to me that's the follow-up.  If you don't get educated at the point of prescribing, you should get educated at least where you pick up the medication.  That's why I was saying symmetry relative to telling people you may get depression and you should report it.  If you want that answer from me, the answer is yes, but I wouldn't want to say you can't get pregnant unless you're a male.  That's okay.
		DR. BERGFELD:  Dr. Rosenberg, did you have a comment?
		DR. ROSENBERG:  No.
		DR. BERGFELD:  We're coming back to the medication guide and specifically whether the importance of the psychiatric events that have been reported to us meet the guidelines to be included.  Should we recommend that a medication guide be done with all the other information regarding making it one unit package for us physicians who have great difficulty with these separated pieces?
		Dr. Greene?
		DR. GREENE:  I'd just ask one question.  It seems to me that the data linking Accutane with birth defects is far stronger and more compelling than the data linking Accutane and any of the psychiatric symptoms or diagnoses that we've discussed today.  I'd just like to ask why the issue of the medication guide wasn't raised with respect to the congenital malformations as opposed to it now being raised with respect to psychiatric issues.
		DR. BULL:  I think if you look back to our discussion yesterday, you really have engaged with the recommendation of the registry, the design that was chosen, a much higher level of risk management.  What we're talking about now is more of an informational tool and something that makes sure that this message on the possibility, the potential, and that there's reasonable evidence based on what you've heard from the postmarketing analyses to better inform patients about the possibility of mood changes, psychiatric adverse events, depression associated with the use of Accutane and the sufficiency of what threshold do we need to meet in order to sufficiently inform patients. 
		DR. BERGFELD:  I'd like to ask Dr. Kodish his opinion as the ethicist.
		DR. KODISH:  Good ethics starts with good facts.  I think Dr. Greene's assessment of the facts is something that I would concur with.  I think we're talking about apples and oranges here in terms of the real risks of the medication.  It seems to me that if you've come down on the side of a more forceful regulatory approach with regard to the congenital malformations, the medication guide issue is somewhat superfluous.  I think adding it to the consent form would probably be sufficient.
		DR. BERGFELD:  Dr. Malone and then Dr. Levin.
		DR. MALONE:  The evidence for it causing birth defects is very high, but I mentioned I think there is some signal that it may cause depression but it's certainly not clear that it does.  So, I think in that circumstance if you want to require patient guides for particularly important issues to avoid patient guide fatigue, I don't know if you'd want to use it for something that was not better demonstrated.
		MR. LEVIN:  I think Dr. Greene's point is excellent.  I would have raised it yesterday except I saw it was on the agenda today, frankly. 
		I think whatever the issue is with this drug, it is a drug deserving for a number of reasons of a medication guide, and the reason a medication guide is important, no matter what happens in a formal informed consent document -- and we've had some sidebar discussions about whether that's really informed consent or informed decision making.  Why it's important is because it's another opportunity to make sure that somebody gets information that they may not have gotten in the previous process.  We know from the literature that what goes on between prescriber and patient falls far short of what is desirable.  Therefore, this is a safety net mechanism.
		The medication guide needs to be thought of as a safety net.  We hope a lot more goes on before that point, but if it doesn't at least the patient gets some information that they can use to protect themselves if they've gotten no other information from anybody else in the process.
		DR. BERGFELD:  Is there anyone that disagrees with Dr. Levin's presentation?  I don't think we have to vote on this.  I think you've heard quite clearly where the issue is.  I think we'll move on. 
		I think we've heard quite clearly about the informed consent.  It should be consistent with the information given out to the patient and the physician.  The areas of interests and hazards should be mentioned. 
		I think we'll move on to intervention, and I think we've heard about monitoring the patients.  There is no one who has spoken who hasn't talked about monitoring the patients and the managing of the events, as best they can, unless there's someone that wants to add something to the discussion.  Dr. Anderson?
		DR. JENNIFER ANDERSON:  I'd just like to be sure that what we're talking about with monitoring of the patients is that what is meant there is a registry for all patients, not just for women.  
		DR. BERGFELD:  Well, we can break that out and discuss that specifically. 
		DR. JENNIFER ANDERSON:  But yesterday we thought we wanted to have a registry for the female patients.  Now it's a registry for all patients.  It has the big advantage that some of the questions that there's lack of information about with respect to psychiatric problems -- it may be possible to elucidate them given this kind of information that's gathered on everybody.
		DR. BERGFELD:  So, you're supporting a universal registry.
		DR. JENNIFER ANDERSON:  Yes.
		DR. BERGFELD:  Could I get a straw vote on who would support a universal registry just to get a sense of the committee, nonvoting and voting?
		(A show of hands.)
		DR. BERGFELD:  Seven.
		And those that would oppose it?
		(A show of hands.)
		DR. BERGFELD:  About even.
		DR. ADAMS:  With a number of abstentions to lack of understanding of what's being voted on specifically. 
		DR. BERGFELD:  I'm sorry.  I didn't see you over there, Dr. Adams.  I was wondering about the straw vote on a universal registry versus just a female registry in the use of Accutane.
		DR. ADAMS:  A universal registry for males and females that includes some level of psychiatric questioning as well as --
		DR. BERGFELD:  Well, that's the inference, yes.
		DR. ABEL:  That's my concern as to a breach of confidentiality if it includes psychiatric data.  What is going to be in this registry?  That's why I abstained.
		DR. BERGFELD:  Dr. Mills?
		DR. MILLS:  I voted against because I don't see exactly what we're getting out of this.  Having a registry and knowing that there are so many people with psychiatric diagnosis by a mechanism that isn't clear and how well the diagnosis is made not being clear I don't think is going to be extremely useful information. 
		DR. BERGFELD:  Dr. Holmboe?
		DR. HOLMBOE:  Yes, I would second that.  I'm also concerned that we don't know enough about the relationship here, about what the right instrument would be that we should use, whether it be Beck Depression, Hamilton, how it's going to be collected, et cetera.  I think with pregnancy it's much more straightforward, but this is an area that we don't even know what would be the appropriate tool to use at this point.
		DR. BERGFELD:  Dr. King?
		DR. KING:  Well, that was my original concept.  I think you're taking it beyond what's likely to happen in a dermatologist's office.  They're not going to do psychiatric screening.  They just want to know what patient prescribed what, and your nurse practitioner, your nurse or whatever is going to give them a universal packet.  So, the issue of whether you're pregnant or crazy is not actually the issue.  The issue is who got the medicine.  So, I think that then becomes a data pool from which you pull out this other information.  
		So, I agree that you're not going to do all that, but at least out of the population of the prescriptions, then you can go do the studies that Dr. Mills or anybody else would like to do.  If you're going to field a team, you've got to know the name of the players, and so the best way to get the players is to have them registered.
		DR. BERGFELD:  Dr. Murphy?
		DR. MURPHY:  I think we could define registry here as that the patient would have a unique identifier number.  That is one way of identifying a registry irrespective of the rest of those issues.
		DR. BERGFELD:  Dr. Abel?
		DR. ABEL:  If that is what the registry is, then I would agree with that because we talked earlier about further studies being done on a subset or a cohort of patients or those at high risk.  And I think it's nice to have all these patient identification numbers, but I think we need to do further in-depth, rigorous research in patients with baseline psychiatric, psychological profiles and then follow it up in a cohort.  So, we need more than just a registry.
		DR. BERGFELD:  Dr. King?
		DR. KING:  That was my concept.  Roche and the FDA can put out a request through the web or whatever for volunteers.  You have all the problems of epidemiology but at least you'd have unique identifiers.  It's much like going on the web with your American Express.  You trust that it's secure and so forth, but I think you have a bigger population to request volunteers from.  You can't request volunteers unless you know who the players are, and they have unique, unidentifiable secure numbers or non-identified people.  At least you've got a population to look for. 
		DR. BERGFELD:  Yes, Dr. Byrne.
		DR. BYRNE:  It would actually offer the opportunity randomly choose people and follow them with their unique identifier number.  So, you wouldn't necessarily be selecting, as some of the other processes have, people who voluntarily come forward.  This would be a nice way to randomize things.
		DR. BERGFELD:  Any other comments?  Do we need to revisit the straw vote on the universal registry with identifying numbers just as a database for the numbers of patients?  Dr. Branch?
		DR. BRANCH:  I remain concerned from the perspective that the objectives of this really -- the only advantage I can see to a patient going through this is that you're ensuring that they're having to sign an informed consent.  I don't see that there's any advantage to the patient.  What we voted on yesterday, there was a whole set of safety factors that were being built in.  
		What we're talking about today is now essentially a male-targeted program because women are already covered.  So, we're talking about informing a group of men about a set of information in which there is a tremendous amount of ambiguity and uncertainty. 
		I think that great care and consideration needs to be given to choosing examples where we're starting to increase the regulatory burden to make sure that the patients are actually being protected by that decision, and I'm unconvinced that we have enough information right now to really protect men going into this because I'm not sure what the issues are.  Yes, I think that there is a signal.  Yes, I think there is more to be done, but I have concerns about this. 
		DR. BERGFELD:  Dr. King, did you want to respond? 
		DR. KING:  Let me just finish that.  When you buy Windows, you buy it and register it with the expectation it's going to work, but as we all know, if you don't have a product identification number when some glitch shows up, which it always does, you have no recourse.  
		I'm not suggesting we do anything other than have the possibility of having a recall or some further information or randomized studies.  I'm not saying that Roche says or anybody says, FDA, that you're going to have psychiatric illness.  I just want to know that they know of the possibility that there are problems, and they should report them. 
		DR. BERGFELD:  Did you want to respond, Dr. Branch?  And then Dr. Greene.
		DR. BRANCH:  The problem with that is what do you do if somebody hasn't registered.  Does that mean they don't get the drug?  Who is going to enforce this?  Who is going to see that the whole process takes place?  When you put something in place, it costs.  It costs society in the long run.  I think there needs to be more than a research outcome of being able to identify a stable of patients to make a venture like this worthwhile.
		DR. ROSENBERG:  Could I reply to that?
		DR. BERGFELD:  Dr. Greene wanted to reply.  Then you can. 
		DR. GREENE:  Just one other quick thing.  The other thing is I think you have to think of what your outcome measures are going to be.  What are you going to look at?  People who are depressed, people who are more depressed than before, people who ultimately commit suicide?  What are your outcome measures?  And even if you do that, how many events are you likely to record?  Are you really going to shed any light on the problem?  It's just not clear in my mind that you've met any of those criteria.
		DR. BERGFELD:  Dr. Rosenberg.
		DR. ROSENBERG:  I was just going to say not to the merits of whether we should do it or not, but in terms of the technical aspects of how it would go.  As of now, at least in my experience, the pharmacist won't fill a prescription unless there is a consent thing that the patient has initialed and that I have signed.  You can make a photocopy out of the PDR and she initials it and I initial it.  Although last time we tried that, it didn't work.  They wanted something else for the pharmacist that I told him I'd learn about when I got here. 
		(Laughter.)
		DR. ROSENBERG:  But anyway, even now you can't just walk into a drugstore and get this without doing the other, which is I think a good idea.  It all relates to that.  Am I wrong about that?  Maybe it's just our druggist then that wouldn't fill it.
		DR. BERGFELD:  FDA, do you want to hear anything else about monitoring?  I think that we had a split vote. 
		Dr. Mills?
		DR. MILLS:  This is a very quick question.  If we came up with a registry for men, which just gave us the names and addresses or whatever of everyone who is treated, what can the FDA then legally do with that?  Can you take a random sample of those people and ask them to participate in a study?  In other words, what kind of power do you have to use that list?
		DR. BERGFELD:  Someone?  Dr. Murphy?
		DR. MURPHY:  We, first of all, would ask the sponsor, if we've asked them to maintain this registry, to report the registry to us, and we would ask them, if issues came up, how can we look at this information.  
		So, would we go out and demand?  No.  Would we go out and demand that they then take that population and randomize them and study them?  No.  I don't think we can then go out and tell people that they have to participate in a study.  That is not within our jurisdiction. 
		Again, I don't know why we think this is going to be just for men.  I know you're saying we already have women, but I'm just saying that certainly we're going to be looking at both men and women who would be registered.  What you want to know is, again, get a denominator and then, depending on how we then wish to look at information from this registry, we would hope that the registry would be involved with the medication guide that would information on it for the patient to call, be it an external source, as we've done in other situations where they would call if they have an exposure, they're pregnant, or they would call if they have a risk factor, in addition to calling their doctor, so that you always have on there to call your doctor, but here's another source too that people could call if they chose.  It's up to them to choose to call.
		DR. BERGFELD:  I'd like to resolve this a little bit.  We had a split vote on the last straw vote, and I don't want to make this an official vote.  I'd like to call the question again as a straw vote.  All those in favor of a universal male and female Accutane registry, if you'd raise your hand.
		(A show of hands.)
		DR. BERGFELD:  Eight.
		Those opposed?
		(A show of hands.)
		DR. BERGFELD:  It looks like 12 opposed. 
		Those abstaining?
		(A show of hands.)
		DR. BERGFELD:  So, abstaining, 1.  Oh, you want a question, Dr. Anderson?
		DR. GLORIA ANDERSON:  I guess I am.  I voted for it to begin with, but then after I heard all these explanations, I'm not sure because that wasn't what I had in mind when I read this document.  So, now I'm not sure.
		DR. BERGFELD:  That's all right.  You're allowed to abstain. 
		In regards to intervention, the drug distribution I think we already handled yesterday.  I'm not sure that anyone would disagree with how we handled the pregnancy problem, that we would change our perspective.
		A prospective controlled trial.  Everyone has said that's a need.  Unless there's someone disagreeing with that statement, I would say that we have closed the discussion on question 1.
		Then moving to question 2 --
		DR. GREENE:  Can I comment?
		DR. BERGFELD:  Yes, I'm sorry.  Dr. Greene?
		DR. GREENE:  Personally I couldn't imagine how a prospective controlled trial would be done to address the psychiatric aspects of this medication.  I can't imagine.  I'm sitting here trying to think how I would design the trial were I to run it.  I couldn't imagine how I'd do it.
		DR. BERGFELD:  Well, thank you.  I think that Dr. Mills proposed another format.
		DR. MILLS:  That's right.  I'd like to clarify that.  What I was proposing was not a prospective controlled trial because we couldn't get a control group.  So, I was proposing more of a case series or a cohort prospectively evaluated, but not a controlled trial.
		DR. BERGFELD:  So, the correction there would be a prospective case series trial?  Is that correct?
		DR. MILLS:  Yes.
		DR. BERGFELD:  Is everyone agreeable to that?  Or something else?  Dr. Branch?
		DR. BRANCH:  Can I put up another possibility?  It seems to me the strongest stimulus or the strongest signal is the challenge/rechallenge.  We've heard that about a third of patients go on to a second course of treatment.  It would seem to me that there is a possibility to refine a target group to look at a group of people who have actually experienced some symptoms during the first course of treatment, they still have severe acne, a second course of treatment is being proposed, and to do this under much, much closer surveillance and be able to measure a much greater number of endpoint measures, and that you would be able to get a comparative group of people who didn't have psychiatric events in the first course of treatment, now going out to the second treatment.  It would seem to me that if you really target the people who have the problem, you could really get some insights into it.
		DR. BERGFELD:  Dr. Greene, did you want to comment?
		DR. GREENE:  No.
		DR. BERGFELD:  I think you've heard what kind of study that's needed.
		Dr. Abel?
		DR. ABEL:  Regarding the drug distribution, we've heard of sales on the Internet.  Are there any controls to prevent sales of Accutane on the Internet?
		DR. BERGFELD:  Dr. Bull, Dr. Murphy, Dr. Wilkin?
		DR. BULL:  I think that that's an area that our compliance group is definitely looking at and is monitoring.  So, yes, that is being watched closely and where there are grounds that a case could be built, it certainly is in an area of compliance and enforcement.
		DR. BERGFELD:  Dr. Ellison?
		DR. ELLISON:  With respect to the international sources, over which, unfortunately, there's no jurisdiction from here, we have ourselves tried to shut down the supply of these places, and it has proven to be impossible.  We don't have any legal recourse to that either, and they're very difficult to track.  So, I think with respect to inside the U.S., I think that's going to be under control very quickly.  I think the concern that everybody has is ex-U.S.  That's almost impossible to deal with currently.
		DR. BERGFELD:  Thank you. 
		Dr. Abel, does that answer your question? 
		DR. ABEL:  Thank you. 
		DR. BERGFELD:  We'll move on to question 2, unless anyone has an objection or would like to discuss something else in question 1.  Seeing none, question 2.  Would further studies help to clarify the relationship between Accutane use and psychiatric events?
		I think that we have heard that answer to be yes.  
		And if so, what kind of studies?  We have defined the study under "intervention" as one.  We've also heard comment on basic science studies.  I suspect retrospective epidemiological studies are still in order.  Are there others that should be added that are not on the list or we have not discussed?
		Question.  Dr. Adams.
		DR. ADAMS:  Thank you. 
		I would like to add a comment regarding basic science studies.  I do think there needs to be further clarification or a determination of the role of retinoids in the adult brain, but of perhaps greater importance is the role of retinoids in the adolescent brain.  One thing that is widely accepted now among neuroscientists and certainly among neuroteratologists is that the adolescent growth spurt that occurs in the brain represents an additional time of vulnerability.  The tissue affinities, et cetera in the adolescent brain may look a little bit different than they do in the adult, mature brain.  I think it would be important for these basic science studies to look at those two ages.
		Thank you. 
		DR. BERGFELD:  Thank you. 
		Dr. Lammer, any additions?
		DR. LAMMER:  No.  I agree with that comment completely.  It sounds like there's really a dearth of information about the distribution of retinoic acid receptors and related chemicals that might be involved in a pathway with retinoic acid in the adolescent or the adults.
		DR. BERGFELD:  Thank you. 
		Dr. Greenhill?
		DR. GREENHILL:  Are there any suggestions about how these suggested studies might be implemented in the course of events?  Is it something that comes from the agency?  Would there be RFPs put out through other agencies to do the work?  How is that done?
		DR. BULL:  FDA, generally speaking, does not fund research.  We certainly are currently actively looking at enhancing our science based mechanisms to address questions that are of high regulatory significance, but this is probably going to be an activity that may represent an opportunity to take the question either to the sponsor and their research capabilities or perhaps to the NIH.
		DR. MURPHY:  I just want to confirm that we can only ask the sponsors to perform the studies.  If you look at the history of pediatrics, it's up to them unless you have a specific regulation, which we do now for children.  So, we'll ask. 
		There also is a level which, if we cannot approve the drug because the information they have isn't adequate to ensure the efficacy or the safety, then of course it is prudent for them to go ahead and perform those trials. 
		DR. BERGFELD:  Dr. Tan, do you have any comments to make?  We haven't heard from you today.
		DR. TAN:  I think clearly there is a need for a prospective study.  The specifics of the designs need to be worked out.  I think you can do a cohort study or a case-control study, but it's impossible to do a randomized controlled study.
		Also, the basic science research is important.  I think there has been some research I think in the cancer area where they have used 13-cis-retinoic acid for the neuroblastoma patients.  There might be some basic research going on already. 
		DR. BERGFELD:  Any other comments?
		(No response.)
		DR. BERGFELD:  I think that we've completed then questions 1 and 2 to the satisfaction of the FDA.  I seem them shaking their heads. 
		I think we will take a 10-minute break and reassemble here at 3:25 to proceed with the afternoon, which will take up Accutane New Formulation.
		(Recess.)
		DR. BERGFELD:  It has been an intense two days.  I think the issues discussed have been exceedingly worthwhile.  I think that this very large panel has participated at a very high level, and I thank all of them for their participation. 
		I've also asked, because we still have a formidable piece of material to review, that both the FDA and Roche shrink their presentations and just get to the meat of the facts so we can discuss the issues.  They have both agreed.  So, I thank them. 
		We're going to first lead off with the Executive Secretary's conflict of interest statement for the panel members.  
		I will ask the panel members who have any conflict of interest to declare themselves if that is appropriate. 
		MS. TOPPER:  The following announcement addresses the issue of conflict of interest with regard to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.  
		Based on the submitted agenda and information provided by the participants, the agency has determined that all reported interests in firms regulated by the Center for Drug Evaluation and Research present no potential for a conflict of interest at this meeting when evaluated against the agenda.  
		With respect to FDA's invited guests, Drs. Jane Adams, Alan Byrne, James Mills, and Edward Lammer have reported interests which we believe should be made public to allow the participants to objectively evaluate their comments.
		Dr. Adams would like to disclose that in the past she has participated in two research grants to study Accutane.  One was funded by Roche and the other was funded by NIH/NICHD. 
		Dr. Byrne would like to disclose that he has published articles on the subject of Roaccutane.  
		Dr. Mills would like to disclose that he is currently collaborating with Roche on an unrelated research project.  He has also written an article and attended a seminar which were unrelated to the particular matters at issue, but sponsored by Roche.  
		Dr. Lammer would like to disclose that in the past he has served as principal investigator on phase I and phase II longitudinal studies of infants exposed to isotretinoin in utero.  The studies, sponsored by Hoffmann-LaRoche, were designed to document the developmental toxicities of isotretinoin following inadvertent human use during pregnancies in North America.
		In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusion will be noted for the record.  
		With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose products they may wish to comment upon. 
		Thank you.
		DR. BERGFELD:  You may breathe now.
		(Laughter.)
		DR. BERGFELD:  We're going to go forward again with the Accutane New Formulation, and Roche is first presenting. 
		DR. McLANE:  My name is Dr. John McLane.  I'm going to try to go through this fairly quickly.  Since you have a copy of the presentations, I'm just going to do a couple of the first ones and then skip down to the hormonal contraceptive which I believe is labeled slide 24 in your package.  After I do that, then I will introduce Dr. David Young.  Dr. David Young has been working with us on the pharmacokinetic program, and then I will come back to finish up on the last part.  So, I will try to do this as quickly as possible. 
		Now, as you've heard, Accutane has been on the market successfully for the last 18 years.  It has been used at doses from .5 to 2 milligrams per kg.  It is the most effective therapy for severe recalcitrant nodular acne.
		However, there are drawbacks in our current formulation because of some of the dosing variability that's introduced in the way it is being used.  These drawbacks could lead to decreased efficacy or prolonged therapy.
		So, in 1995, we initiated a new formulation based on micronization properties of the isotretinoin.  With this new formulation, we're able to get increased bioavailability.  The modification of the new formulation results in a dose that could be taken once per day and it could be given either with food or without food.  That way it can accommodate the lifestyles of the Accutane patients that are using it.  The new formulation addresses the drawbacks of the dosing variability of the current formulation.
		There are a number of publications that indicate the efficacy of the current marketed formulation of isotretinoin, and these vary from the doses of .1 all the way up to 2 milligrams.  However, our label indicates that it should be used at .5.  The minimum dose is .5.  The reason for this is because that really is at the low end of the therapeutic range.  
		Some physicians prescribe Accutane at higher doses than 1.  It's used rarely but it is used for patients that have recalcitrant severe acne, for example, acne that's on their backs with nodules that do not clear up.  Predominantly the use is of 1 milligram per kg.  You'll see this slide later on when we explain some of the dosing relationships with various doses of Accutane.
		Now, the variability that we see with Accutane is due to we know that dosing without food results in a significant reduction in exposure with Accutane.  We have a survey in which we know that about one-third of the doctors do not recommend taking Accutane with food.  We also know that 21 percent of the patients are instructed to take Accutane only once per day, when they're instructed to take a most common dose, which is around the 1 milligram per kg.  We also know that prescribers report that only 33 percent of the patients do not take Accutane consistently with food.  We also have reports that 22 percent do not consistently take the second dose when they have the b.i.d. dosing regime.  The overall effect then is a significant patient variability in exposure. 
		Between this once per day and twice per day, with or without food, this creates some of the variability. We also know that the variability that can be affected is due to a dropout of the patients in practice.  We know that of the patients that drop out, we have some dose-related effects.  Those dose-related effects are the mucocutaneous effects, which 19 percent of the patients that do drop out report that as the reason why.  We also have triglycerides, which is also a dose-related effect, and we know that 17 percent of the patients that do drop out, drop out because of triglyceride elevations.  These are the most common single reasons for withdrawing from effective therapy.
		This overall compliance or noncompliance would result in some under- or overdosing which overall may affect the efficacy and safety. 
		The new formulation of isotretinoin addresses these concerns in the variability in this type of dosing. The dosing can be given with or without food, and it is given only once per day.  It has fewer and less intense mucocutaneous events, and it has fewer patients with elevated triglycerides.
		Overall then you have compliance with the dosing regime and there's more predictable exposure because the way that it is dosed allows a more predictable exposure which can decrease the impact of the individual noncompliance.
		What I wanted to just quickly jump into was this and the next slide. 
		The program that we have, which I will not go into the results because you do have these slides, is that we had a pivotal clinical program in which we had measured efficacy and safety, and within that trial we had looked at parameters which was 90 percent of the patients that cleared, the clearance of the papules and pustules, more particularly the primary criteria was the clearance of the nodules, how many nodules where clear.  We saw that the new formulation was absolutely statistically clinically equivalent to the current marketed formulation.
		However, the program had a design where we gave the new formulation in a slightly different format.  We gave it in a format in which the patients were given the new formulation only once per day without food, and it was compared directly with the marketed formulation which we know to be an effective dose which was twice per day given at 1 milligram per kg, and they were given with food.
		Consequently, we know that the exposure difference between the two formulations and part of the design of this clinical trial then was to identify the minimum effective therapy for isotretinoin.  In this equivalency between the new formulation and the current marketed formulation, we were able to identify what was the lower limit, what was the minimum effective therapy for isotretinoin.
		From the table that you have in your package, we know that there were some differences between these two formulations.  If we went down any further, we would have not reached statistical equivalency.  So, consequently, we do know that the new formulation is at this minimum effective dose.
		On the safety profile, just to quickly summarize, the safety profile was really quite comparable with the current marketed formulation.  As I pointed out, we had slightly fewer patients and patients that had less intense mucocutaneous events, and we also had patients that had less triglycerides and fewer elevations in their triglycerides. 
		I'm going to jump on to the other part of the program.  David Young will present the food effect on the bioavailability, but I'm going to go ahead and present the hormonal contraceptive interaction.  
		We had another program within this, and we did this in collaboration with the FDA in order to evaluate the hormonal contraceptives and the potential for any interaction.  We wanted to assure that isotretinoin, in either the new formulation or the current marketed formulation, does not alter the clinical pharmacology of hormonal contraceptives. 
		So, we had two components of the program.  We had an in vitro study with hepatocytes and microsomes in which we evaluated five different progesterone components that are found in hormonal contraceptives, and we evaluated them within live human liver cells, hepatocytes, and we evaluated them to both inhibit as well as induce enzymatic enzymes that would be involved with the breakdown of hormonal contraceptives or with the breakdown of isotretinoin.  These studies are in progress.  The last of these studies will be presented to the FDA the third quarter of 2001.
		We also have a clinical program in which we have two studies.  I think it's important to understand the program on this.  Let me just step through this quickly. 
		What we had is that we had a measurement to determine if isotretinoin affects oral contraceptives within patients.  We used the contraceptive Ortho-Novum 7/7/7.  We looked at pharmacokinetics of ethinyl estradiol and norethindrone.  We also measured the pharmacodynamics of markers, luteinizing hormone, follicle-stimulating hormone, and progesterone within the patients.  All of the patients being treated were females with severe recalcitrant nodular acne.  They are receiving the full course of therapy, the 20 weeks.
		The two trials are divided up.  One group of patients were receiving Accutane at the 1 milligram per kg.  The other was receiving at .4 milligram per kg.  The other was the new formulation as a single dose and the current marketed as two divided doses. 
		The design of the trial is that we have a oral contraceptive stabilization period in which the patients were taking oral contraceptives for at least 1 month in order to reach steady state level.  We then on the second month at two different points during their menstrual cycle, when we know that there are changes within the hormonal levels, we looked at, at day 6 and at day 20, the pharmacokinetics and the pharmacodynamic properties of the ethinyl estradiol as well as the surrogate markers. 
		We then would take these measurements.  These are our baseline levels before we treat with isotretinoin.  We started the therapy on isotretinoin.  The patients continued and were allowed to reach a steady state level of their isotretinoin in their metabolites.  
		We were then able to go ahead and -- in their fourth month of oral contraceptives, their second month of therapy on isotretinoin -- measure again the levels of pharmacokinetics and the pharmacodynamics at both day 6 and day 20.  We could then do a comparison then between the day 6 and the day 20 for all of these particular markers.
		These studies are in progress.  So far, there have been no serious or unexpected adverse events.  The last patients will be finished in these trials this month, and the reports will be submitted to the FDA in the first quarter of 2000.
		I'm going to have Dr. David Young come up to quickly explain the pharmacokinetics. 
		DR. YOUNG:  Thank you. 
		I'm going to really be talking about the pharmacokinetics and the dose exposure-response relationship and possible confusion issues with the different formulations we might have.  
		We did a four-way crossover study with Accutane and Accutane NF, and you have this report.  What happens here is that we took 80 milligrams of Accutane, 30 milligrams of Accutane NF under fed and fasted conditions. This really represents the different mean graphs.  The top one represents the fed Accutane, and the blue one down here represents the fasted Accutane at 80 milligrams.  You can see the very large difference.  This is a crossover.  So, within-subject variability is very large because of the food effect. 
		The yellow represents the fed Accutane NF and the red represents the fasted.  You can see there's very little variability compared to the large one that exists for Accutane.
		The results of that study were there's a 2.5 to 1 ratio between Accutane fed and fasted.  There's really inconsistent pharmacokinetics occurring if you have inconsistent eating habits.  And the between-subject variability is larger without food than with food.
		For Accutane NF, we have a 30 percent difference in exposure.  The variability is about 30 percent throughout, within-subject variability, between-subject variability, as well as the fed/fasted issues, all within approximately 30 percent variability.
		What we wanted to next do is we wanted to take this data and try to figure out what's happening in terms of exposure within our patient populations within the efficacy studies as well as with patients that we normally treat.  So, what we did is we took the data, using the principles of superpositioning for linear pharmacokinetics, which has been proven with this drug and these products, we simulated the concentrations for different doses under different conditions in order to compare the different doses and conditions. 
		This is an example.  This is the 1 milligram per kilogram divided dose that's the most common.  This is what was actually used in the phase III study, for example.  This is a simulation of what would have happened.  The red one here represents the NF drug, .4 milligram per kilogram single dose.  And the blue represents .5 milligram per kilogram divided dose.  So, you can see that, in fact, the NF has a very similar exposure to the .5 milligram per kilogram Accutane.  NF is red.  Blue is Accutane at .5 milligram per kilogram. 
		If we go back to this table, which Dr. McLane briefly showed, I want to kind of summarize this real quick for you.  First of all, what we've done is we've added the NF study at the bottom, which has 600 subjects, which is much more than any of the publications or even the total publications put together.  We looked at 1 milligram per kilogram Accutane under fed conditions, and we looked at .4 milligram per kilogram of NF under fasted conditions.  If you look at the other publications, I put the conditions as well as the doses investigated also.
		Now, what we have in our NF study is we have a situation where we showed therapeutic or clinical equivalence between the 1 and .4.  But we did show also there's a rank order between 1 and .4.  1 seems to be a little bit better than .4, though not statistically. 
		If you look at the same studies within the publications here, you find that .1 and .2 milligram per kilogram is always worse than everything else, and that's why you see the greater than sign here.  
		.5 and 1, though, in different publications sometimes it's better, sometimes it's not statistically different.  But the general trend of it all is that there's a rank order again.  1 seems to better than .5, sometimes not statistically but it seems to be better. 
		In terms of 2, this study here, though it's only 14 subjects, that was under fasted conditions, and again 2 was about equal to 1, though in a small number of subjects.
		Let's now look at the overall exposure for those doses under those conditions.  So, here we have a situation again where we have the .1, .2 under fed conditions.  That was some of the studies, and the area under the curve is 1,842/921.  But if you remember in that previous slide, we had rank orders between .5 and 1, sometimes statistically equivalent, sometimes just a rank order.  They didn't do statistics.  
		What you can see, though, is if you look at .4, .5, and 1 -- .4 NF under fasted conditions, .5 Accutane under fed, and 1 of Accutane under fed -- the areas under the curves of .4 and .5 are about the same, which we saw that picture before, the red and the blue curves, and you'd expect them to be the same.  And they had the same relative relationship to 1 in our clinical studies.  Over here .5 relative to 1 was sometimes equal, but generally rank order, 1 was better than .5, sometimes statistically different, sometimes not.  The same thing happened with the NF study.
		So, we can see from that, well, that makes sense because the area under the curve, the overall exposure to this drug, was about the same for both formulations.
		Now let's look at the risk management for the two formulations if we have both on the market.  If we have some confusion and we have both on the market, we have a situation where, in fact, instead of taking Accutane b.i.d., you may take it q.d.  Or instead of taking it with food, you take it without food.  You could also have the reverse for Accutane NF; instead of taking it once a day, you have b.i.d.  
		I'm just going to go through a couple of scenarios here so that you can see.  We'll go to this one here.  This is a situation again where we dosed the normal 1 milligram per kilogram under fed conditions, b.i.d.  You get an overall exposure, a daily exposure, of 9,209.  NF is down at the bottom; its exposure, 4,161.  Again, we saw that these were equivalent therapeutically, but again we saw a rank order in terms of the therapeutic response. 
		If you take .5 milligram per kilogram under fed conditions of Accutane, though, you get something again around the same area, 4,161 as Accutane NF, and we saw that previous slide too. 
		But if you take Accutane .5 milligram per kilogram under fasted conditions, your exposure is much less.  So, we've got exposure of 1,800 versus the 4,000 range which occurred with .5 milligram of Accutane and .4 of Accutane NF.  You can see that variability, and if I had an individual patient who at one time was taking Accutane at .5, and then all of a sudden the next month changed their eating habits and started taking it .5 under fasted conditions, I could have a completely different exposure one month versus another month, depending on their eating habits. 
		This is a situation where we actually mix up how we give the dose, q.d. versus b.i.d.  The green line here represents the 1 milligram per kilogram b.i.d., and the blue line up here represents 1 milligram per kilogram once a day.  So, if it's, for example, a 70 kilogram patient, it would be 70 milligrams.  The overall exposure is the same.  You can see the curve is very similar.  You have little higher peaks than this, but if the patient responds, that's fine.
		Now, let's assume that the patient is responding to this 70 milligram once a day dose.  Again, let's say they change their eating habits.  They go back to school.  They go back to college and they start eating differently, as we know they do.  What happens then?  That exposure of 70 milligrams once a day or 1 milligram per kilogram once a day would drop to this exposure down here.  So, we would wonder, in fact, is this exposure where we have efficacy going to result in efficacy down here.  Now, if this is efficacious for this individual patient, it may not be efficacious for that specific individual patient down at the bottom here. 
		So, overall what we found both in terms of NF and Accutane is that Accutane has wide variability in terms of its pharmacokinetics.  From day to day, it can change because of the fed/fasted conditions.  NF does not have that variability.  It always is pretty consistent, which allows us to keep consistent dosing in patients who may not be compliant from one day to another day in terms of their eating habits. 
		I'll now pass this to Dr. McLane in a hurry here.
		DR. McLANE:  Let me slow down for one second because you have some questions that you'll be voting on and I want to make sure that we can address those properly.
		One of the questions is, are additional dosing studies necessary?  Well, we know right now with the new formulation, we are at the minimum therapeutic dose.  However, the question is what happens if, for example, you have a confusion on the market and you take the new formulation twice per day rather than once per day?  You know from David's presentation that you'll actually have a dose that is still below the therapeutic range that is for the current marketed formulation.  So, if you take the new formulation twice per day, you know you're going to be in a range that has already been studied with the marketed formulation.  
		If you take the new formulation with food or without, it doesn't make a very big difference, a 30 percent difference in the dosing regimen.  We know that it's going to be up above. 
		If you skip a dose on the current marketed formulation, confuse it with the new formulation, for example, you're going to be under-dosed if you take the current marketed formulation without food. 
		So, the question is taking the new formulation with or without food.  We have no problem with that.  That's what we want to be able to do.  To be able to give it once per day.  That's what we want to try to get for a label on this.  If you do take it twice per day, you're not going to have an over-exposure with the new formulation.
		What we're going to be doing is then how do we differentiate between the products.  We want to make sure that we inform prescribers on the differences in dosing between the new formulation versus the current marketed formulation.  We'll be able to manage that risk.  With the new formulation being available on once per day or, if by mistake, could be taken twice per day.  It could be taken with or without food.
		We're also going to be able to differentiate it on the market by we're going to have very different packaging.  We're going to have individual pouches for these that are going to contain 30 for their monthly prescription.  The packages undergo the child-proof packaging.  There will be the informed consent within the box.  There will be the survey enrollment form within the box as well. 
		The capsules are different.  We have contrasting color schemes.  There will be identification marks and the capsule strengths are 7.5, 15, or 22.5 for the new formulation.  We have a distinct brand name for the new formulation that we've submitted to the FDA already.  It has not been approved at this point. 
		The new formulation is as safe and efficacious as Accutane.  It can be given with or without food.  It can be given once per day.  It has fewer and less intense mucocutaneous events, and it has fewer patients with elevated triglycerides.  
		That means more patients will remain on therapy in order to have better efficacy.  It will be much more predictable therapy.  This compliance, this predictable exposure from the new formulation decreases the impact of individual noncompliance. 
		So, are additional studies needed for dosing?  No. 
		Do we have a handle on doing additional studies on this?  We don't need to.  We know the range of the efficacy.  We know the range of safety of the marketed formulation.  
		Are we managing the risk for having the two formulations on the market?  Yes.  We have distinct packaging between the two formulations, and we will make sure that our prescribers know the difference between the two formulations on the dosing requirement.
		Thank you. 
		DR. BERGFELD:  Thank you very much.  I think we'll hold the questions and discussion to that period of time after the FDA presents.  
		The FDA will now present, and Dr. Jonathan Wilkin will be the first presenter. 
		DR. WILKIN:  We'll be talking ever so briefly about the new formulation of isotretinoin which is unnamed at present. 
		I would like to make one clarifying statement at the beginning, that everything we've talked about over the past two days up until this time really are systemic isotretinoin issues, and at some point in the future, the patent will run out and there will be generic competition.  So, there will be ANDAs, possibly 505(b)(2)'s.  What we are talking about and what we are hearing recommendations from the committee on the psychiatric issue and on the pregnancy aspect, teratogenicity, we will be incorporating into letters of approval and these sorts of things so that it will apply to other systemic isotretinoin forms in the future.
		DR. BERGFELD:  Thank you. 
		DR. WILKIN:  The Accutane New Formulation has all of the issues, of course, that we've discussed up until now, but it also has some specific issues that merit some consideration. 
		The first is dose ranging.  Dr. McLane has actually already prepared the way for much of this. 
		The hormonal contraception and concurrent marketing.  They've already introduced the topic.
		For those who are coming for the first time today, we are talking about isotretinoin, a drug substance that was approved in May of 1982, and the sponsor has just restated their goal of improving bioavailability and reducing the food effect. 
		The new formulation does consist of three different size capsules, 7.5, 15, and 22.5 milligrams.  The sponsor's recommended dosing, which they studied, was 0.4 milligram per kilo per day for 16 to 20 weeks.
		The new formulation development program did not have all of the features of a new molecular entity type of NDA.  We already know an awful lot about Accutane, and so the program really was designed to supplement the data that were already available for the currently marketed product.  The application included five pharmacokinetic studies and one multi-center clinical trial. 
		Isotretinoin background information.  We do know something about dose ranging.  The sponsor has just discussed this.  And we have the Orme data from 1983-1984, which is the only currently published information on the hormonal contraceptive/isotretinoin interaction potential.
		The current recommended dosing for the marketed product Accutane is 0.5 to 2 milligrams per kilo given in two divided doses daily for 15 to 20 weeks with food. 
		Now, this is a somewhat complicated slide, but it gives some of the information that the sponsor gave in tabular form.  Basically on the y axis is rate of recurrence, and it goes from 0 to 80.  So, if there is a high rate of recurrence, that's the need for retreatment, and subsequently longer exposure over time to isotretinoin.  So, the goal is to try to find a dose where the rate of recurrence is going to fall to an acceptable level. 
		These dots do not represent individual patients.  In fact, they represent individual studies.  The sponsor has mentioned some of these studies.  The break point for the current formulation seems to be at 0.5 milligram per kilo per day for 20 weeks.  That would give 70 milligrams per kilo as a total dose.  You can see that above that, the rate falls considerably compared to below that. 
		Now, at doses below .5 milligram per kilo per day, one can get suppression of the nodulocystic acne during the trial.  Unfortunately, there's a high rate of recurrence.  I think that's the difficulty.  In the present data set that we're thinking about today, recurrence rate really was not examined.  It was looking at reduction in the number of lesions during the trial.  So, one of our questions is going to be, where in the end is the new formulation going to play out in terms of rate of recurrence?
		Again, the goal in dose ranging is to obtain the optimal dose, and the optimal dose consists of two competing goals.  The first is minimizing the need for retreatment.  So, there needs to be a high enough dose to minimize retreatment.  On the other hand, one wants to give only that amount and no more because of the risk of dose-dependent toxicities.  
		The sponsor has addressed their program for the possible hormonal contraceptive interaction.  Again, the only data set that we really have from the literature right now is the 1983 Orme study in which there were 10 women taking 6 different oral contraceptives.  They were taking, again, the lowest recommended dose of isotretinoin.  2 of the women had a decrease in levels of the estrogen and progestational agent while they were on isotretinoin, and 1 of these 2 women had a progesterone spike, which was measured sometime between day 12 and day 15 which might not have captured the greatest spike. 
		So, the need for isotretinoin hormonal contraceptive studies.  The new formulation is projected to be more bioavailable.  There may be some concerns there.  The currently used hormonal contraceptives today are qualitatively and quantitatively different from the hormonal contraceptives in the Orme study.  We now have low estrogen preparations, progestational agent only type preparations.  We have the implantables, the injectables, and certainly we have a lot of new progestational agents.  So, these are areas for concern and for thinking about.
		Also we have the accumulating spontaneous reports of pregnancies coded compliant, and our thought is the original data really isn't sufficient to tell us that there is no interaction.
		Dr. Bashaw is the next presenter for the FDA.
		DR. BASHAW:  Yes.  As Dr. Wilkin has given the introduction already, the only study we had information on was from the Orme study and that study was just found, when you really started looking at it, to be a very inadequate study.  One of the issues that was raised yesterday, which Dr. Wilkin did not mention today, was in fact in those 10 women in that trial, 6 different hormonal contraceptives were used.  So, in fact, the fact that you had some conflicting results, you really had no certainty at all whether or not there was or was not an interaction. 
		What we wanted to do is to bring it up to modern-day time and use techniques that were not available at the time of the original study back in the early 1980s.  We started the program using both isoenzymes, also looking at hepatocytes to look for metabolic interactions not only with isotretinoin but with the oral contraceptives themselves.
		Again, Dr. Young has talked on this to some degree.  We have studies going on with recombinant p450 isoenzymes, pooled liver microsomes.  We've received some data to date regarding studies with specific substrates, medroxyprogesterone, primarily looking at implantable hormonal contraceptions, and to date we've seen no interaction there.  I just received last week, in preparation for this meeting, the draft report for the progesterone study.  So, I haven't had time yet to go through that one, although the sponsor showed there was no interaction, but that part is still under review at this time.
		Again, what we try to do with our in vivo studies today is try to make it today's quality. We are looking at both isotretinoin and its metabolites, looking at estrogen, progestin levels, dynamically looking at FSH, LH, progesterone levels, trying to make sure that if there's any kind of interaction, meaning it's an interaction with isotretinoin or on hormonal contraceptives or if it's an interaction with the endogenous hormones themselves, that we get a chance to look at them. 
		One thing that is a little different, it is a 4-month study, a four-cycle study.  Two trials are actually being done:  one with Accutane NF and one with current Accutane both at the recommended doses of 1 milligram per kilogram and .4 milligram per kilogram.  Again, as shown earlier, we are looking at levels of ethinyl estradiol, norethindrone, FSH, LH, progesterone, looking at both steady state levels.  We're getting single-dose Accutane levels and we're also getting steady state Accutane and metabolite levels at the end of this trial, trying to make it as strong of a trial as possible. 
		You notice there are some numbering differences between this slide and the slide the sponsor presented.  That's primarily the way you count the days from menses or after menses.  That's why you'll see some differences, day 6 versus day 12.  It's just a counting difference.  The trials are the same and how the sponsor had their slide earlier.  The idea was we wanted to try to get close to day 12 where you would see a spike of FSH/LH if ovulation was taking place.  That's why I've got that presented this way on my slide.  Again, though, we tried to make it as strong as possible to look for these kinds of interactions if they existed. 
		To date, we've only received two interim reports.  We received data from 9 subjects on the Accutane NF report, and there is 1 subject in there that does have aberrant data, does have a high progesterone level, higher and into the low normal range.  We've asked for some follow-up on that.  We've not yet received that data.
		With regard to the Accutane study, this was more complete.  We have PD and PK data from 22 subjects and we see no evidence of interaction either from a PK or PD standpoint.  But as the sponsor reported, they're going to be finishing up those reports and we'll be getting those final reports in the first quarter.  So, we should be able to come back with better information shortly.
		Again, we're here this afternoon to discuss NF.  The sponsor has already told you NF is a micronization process, and so we won't spend any time on this right now.
		This is what we tried to show earlier.  This is what you see with Accutane fed, current formulation.  You get very high peaks. 
		Here's a comparison of what happens when you get the current formulation with and without food.  You can see a dramatic food effect, which does cause, as they mentioned, variability between response and in between subjects when meals are taken, meals are skipped, or you change your pattern of taking it.
		This is a table of your Accutane data, looking at the 80 milligram dose, fed and fasted.  What you really see here and the importance of this table is right here.  We're talking about apparent oral clearance.  When you give it with food, you get a clearance of about 8 liters per hour.  When you give it fasted, you go to 25.  There's no metabolic change.  It's the fact that the bioavailability is so much smaller for the fasted dosage form, that what they really have done is decreased the variability in absorption with the new formulation which makes it a more consistent dosage form.  This is what you really see with the old one, this tripling of the clearance because of poor bioavailability. 
		This is combination slide again.  You can see again we have the current formulation fed, the current formulation fasted.  This is the NF fed.  So, you can see it is about half again what you see. 
		Here you can barely see the red line here.  This is NF fasted.  So, from a biopharmaceutics standpoint, we would say there is some food effect with the NF formulation with and without meals.  Technically there is a food effect, but relative to the effect that you see with current Accutane, it's an insignificant change.  We wouldn't consider it one, but there is some degree of food effect there.  
		But clearly, it is a more reproducible dosage form.  You have less variability, and those all cut back to those issues which have been raised previously regarding dosage form and dosing variability.  The fact is that from a biopharmaceutics standpoint, one would judge the micronized formulation as a marked improvement in terms of drug delivery and consistency in drug delivery.
		The NF NDA consists of dose proportionality studies.  It consists of the food effect studies, and also they have a formulation linkage study.  The formulation they used in their clinical safety/clinical efficacy trial differed somewhat from what they're planning on marketing.  They did a study to look at the to-be-marketed and the phase III study material.
		What you basically saw is they were able to demonstrate that at the 15, 30, and 45 milligram dose levels, that the three capsules were bioequivalent, they were dose proportional.  The food effect is there.  However, it is much less and much more consistent than you see with current Accutane and there is no significant difference between the product that is proposed to be marketed and that which was done in their phase III clinical trials.  
		That basically is a very hurried summary of what they did for the pharmacokinetics of this product.  Thank you. 
		DR. BERGFELD:  Thank you. 
		Dr. Kathryn O'Connell?
		DR. O'CONNELL:  Good afternoon.  I'm Kathryn O'Connell, medical reviewer for this NDA in the Division of Dermatologic and Dental Drug Products. 
		I had planned today to actually focus on the design features and study results that specifically inform three issues rather than go over anything anyway.  I'm going to skip over some of these a little more than I planned to for time. 
		But the issues were dose ranging, adverse events, specifically the psychiatric adverse events reported in the trial, and then the problem of the switch-over risk that the sponsor has already addressed.
		The sponsor has already pointed out, as has Dr. Bashaw, that the isotretinoin exposure in the Accutane arm of this trial, the comparison trial, was significantly higher than in the new formulation arm.  So, in my mind if the trial showed equivalent efficacy, then it would suggest that 1 milligram per kilogram per day of Accutane, which is the mid-range of the currently labeled dose, if you give that with food, which is what's labeled, then it's not the minimum effective dose, otherwise they wouldn't be equivalently efficacious. 
		Again, the trial was to compare these two doses, which you've already heard about, so we can skip by that.
		Now, I don't want to get into a big debate about number 1 because it's a little statistical thing and our statistician is here if you want details in the question period.  
		But the bottom line is the second bullet, and the bottom line is the therapeutic equivalence in our view was established.  It's supported by the percent reduction in nodules.  As the sponsor pointed out, it's supported by equivalent global assessments, and it's supported by equivalent short-term need for retreatment in the overall population.  And I'm going to just talk a little bit about that on the next slide. 
		This trial, as Dr. Wilkin just was saying, wasn't really designed to look at relapse rates, which would take a longer time.  But in this trial, the sponsor did look at week 36 to see if the patients needed to be retreated with Accutane.  It was done by phone interviews.  The phone interview is not the same as a physical exam.
		The reason that we were interested in having this looked at in the trial was that the need for retreatment is of particular concern for pediatric patients  and for women.  For pediatric patients, the reason is that they're still growing, and isotretinoin does affect bone.  For women, obviously, if you have to have a second course of therapy, it increases the risk of fetal exposure.  In the literature there's some evidence that pediatric aged patients may actually have higher relapse rates after treatment with this medication. 
		Now, these are the results in the pediatric patients.  As you can see, the proportion of patients that had at least 90 percent reduction in nodules was a little higher in the Accutane arm, and the requirement for retreatment was higher in the new formulation arm.  But again, in a way we're comparing apples to oranges here because, as the sponsor has already pointed out, the exposure to isotretinoin in the Accutane arm was higher than the dose given in the new formulation arm.  So, I don't think this means that there's any inherent efficacy problem with the drug.  It's a dose thing. 
		It's interesting when you look at the women who were using Ortho Tri-Cyclen in the trial, these patients were not included by the sponsor in the per protocol efficacy analysis.  And the numbers are way too small -- you can see down at the bottom what the numbers are -- to draw any statistical analysis from this.  But I only point this out because if future trials are done, this is a medication that has an approved indication for acne.  So, if future trials are done, I think it's important to keep in mind for the design of those trials because there was a difference.  Like I said, the numbers are too small, but the difference was between 84 percent and 57 percent in the proportion of patients who achieved at least a 90 percent reduction in nodules.
		Moving on and I basically already said this, that these subset results may suggest that Accutane may have been slightly more efficacious at the dosage tested, but it's at the dosage tested.  And the overall trial results, in our opinion, do support therapeutic equivalence.
		So, this pretty much will sum up our efficacy conclusions.  Since the exposure in the Accutane arm was higher than in the new formulation arm, we think that equivalence in efficacy would suggest that 1 milligram per kilogram per day of current Accutane may be an unnecessarily high dose for many patients. 
		We think this is important for reasons that have already been pointed out, that the minimum effective dose would help possibly with managing serious adverse events and even nonserious side effects can lead to discontinuation of very effective treatment for severe scarring acne.  So, it's important to minimize, as much as possible, the side effects of Accutane. 
		Now, Dr. McLane has stated that they believe that the .4 milligram per kilogram per day tested in a trial is close to the minimum effective dose.  My feeling from the efficacy data, looking at all of the trials, I think that's probably pretty much right.  It's hovering right around there.  
		But the problem is that even if that's true, we don't really know what range of dosing to recommend to prescribers for patients who require dose escalation.  As you know, dermatologists in practice or anybody who prescribes Accutane now, you try to start with the lowest recommended dose and work your way up if patients don't really respond.  We're not really sure what to recommend.  We don't really know the safety profile for higher doses.  You might want to, when you're thinking about this, refer to, I think it's, page 22 in the sponsor's briefing where there are some of the simulations that refer to changes in dosage of going from .4 to .5 or .66, the different peaks that you would achieve.  So, that's just something that we want to think about. 
		Then on the next slide, I want to just quickly go over adverse events that caught our attention.  The only thing that we need to look at here is that the total exposure that we have for a safety profile for the new formulation essentially is the 300 patients in the clinical equivalence study because the short-term pharmacokinetic studies were not very much exposure.  We did not see and the sponsor did not see any adverse events that have not previously been observed in a safety database.  That's important for currently marketed Accutane.
		We don't really need to go over this because it was essentially the same between arms, early terminations.
		Now, the reasons for withdrawal from the study for safety reasons.  The proportion was the same for both arms.  In other words, it was 16 from each arm.  But the reasons were not.  In the new formulation arm, 4 patients ‑‑ the doctors taking care of them made the decision to discontinue them from the trial for psychiatric symptoms.  None of them were considered serious by the investigators.  There was also an additional patient who was discontinued for a possible pseudotumor cerebri, and that patient also answered yes to all four of the screening questions for the psychiatric symptoms.  In the Accutane arm, there were no discontinuations for psychiatric symptoms. 
		If we go to the next slide, when I looked at this trial, I really don't think that the number of discontinuations is probably a very good comparative measure of safety because it appears that there were some problems with the investigators perhaps understanding what the rules were.  It was very variable.  Some patients that appeared to have mild psychiatric adverse events were discontinued, whereas other patients who, by the scales, appeared to have a greater adverse event were not.  So, I think there were some problems there. 
		But be that as it may, there's no readily apparent reason for the imbalance between arms because those probably should have been balanced.  The trial was very well masked by the sponsor.
		So, that was discontinuations for psychiatric adverse events.  
		Now, if we look at the reported psychiatric adverse events.  So, this isn't people that discontinued.  This is just how many patients had their doctor write down on a case report form that an adverse event occurred.  Again, we have this disproportion.  There were 11 such cases in the new formulation arm and 1 in the current Accutane arm.  Now, this disproportion is statistically significant and it would be cause for concern if it was real. 
		On the next slide, it's important to note here that the reported number refers only to patients who verbally complained of symptoms.  So, in other words, the patients answered this four-question screening tool about whether they had had any significant depression or insomnia since the last visit that "affected their work or ability to perform normal daily activities."  And patients with two or more positive responses went out and filled out the Beck's Depression Inventory again. 
		So, on the next slide, if you add all those patients up -- so, the patients who verbally reported their symptoms, the patients who Dr. Jacobs and Dr. Nelson did in analysis of these cases in retrospect, if you add those cases that did not have a verbal report but were analyzed by the sponsor's consultants, and then you add in some extra patients that did not have a psychiatric adverse event recorded but did answer yes to the self-injurious behavior question or to two out of the four screening questions or had Beck's Depression scores within a few points indicative of severe depression, it comes out pretty even, not exactly equal but the difference isn't anything that would catch your attention. 
		Now, do I know that all those patients had psychiatric adverse events?  Absolutely not.  All I've got is what the investigator checked off on the case report form, and I don't know if they did or not. 
		The bottom line is that if they did or they didn't, there's still no readily apparent reason for the disproportion in the reporting of psychiatric adverse events because the bottom line is we could try to retrospectively analyze this as much as we want, but the fact is that in the doctor's office, the people that were taking care of these patients, something happened that the patient complained of the adverse event and they wrote it down.  If the other patients didn't complain and they had these scores, I tried to add all that up to try to see if perhaps this was just a chance finding and not anything to worry about. 
		So, on the next slide, I just want to say what I said this morning, which is that the trial was really not intended or designed to specifically evaluate this question at all.  We wanted to monitor the safety of the patients in the trial.  And the design and conduct of the trial really preclude I think reliable case ascertainment in retrospect or any estimates of incidence.  There was bias against reporting I think because the patients wanted their acne treated.  They knew that they were getting a drug that works, and if I was in that situation, I would be afraid that I'd be discontinued if I said I was depressed.  I'd probably say I wasn't. 
		Then, like I said, the recording of events and follow-up was variable. 
		If you go to the next slide, a chance finding I think is also consistent with the fact that the reported psychiatric adverse events in the new formulation arm -- really the worst case scenario is they weren't greater than the range that we showed you this morning for those studies where psychiatric adverse events were noted in trials.
		Also, it's consistent with the fact that there were lower serum levels of the drug in the new formulation arm.
		And it's also I think consistent with the fact that the other adverse events that are thought to be dose-related were not more common in the new formulation arm, in fact, were probably less common. 
		Now, this does require some assumptions, though, because even if the association with psychiatric adverse events is causal -- if -- we don't know what the dose threshold is.  So, it could just be that its less than these other events. 
		It also requires the assumption that there's no pharmacokinetic basis for greater central nervous system accumulation of the new formulation relative to currently marketed Accutane.  We have no pharmacokinetic reason to believe that there would be more central nervous system accumulation, but we don't have any direct levels or anything in the central nervous system. 
		So, the bottom line here is that causality between psychiatric disease and isotretinoin use has not been established.  If there is no causal relationship, then the new formulation cannot be less safe than current Accutane in that regard.  If future studies did support a causal relationship, then I think some uncertainty would have to persist simply because we can't explain away the disproportion in the reporting.
		Psychiatric adverse events do not occur in isolation.  You want to ask yourself what's the big picture here.  How did the two formulations compare for other important adverse events?
		We can skip mucocutaneous adverse events. 
		Headache you would think we should look at that because we're talking about the central nervous system.  Is there any signal here?  I don't really think so.  The frequency of headache in the two arms was approximately equal, but the duration was a little bit longer in the new formulation arm.  Both cases, characterized as migraine, occurred in the new formulation arm, and there was one possible case of pseudotumor in that arm.  The Accutane arm had three discontinuations for headache, and the new formulation arm only had one.  So, I'm not really concerned about this.  I think it's probably the same. 
		Pregnancy is another issue, as the sponsor pointed out yesterday.  One patient did become pregnant while taking the new formulation.  The stated facts of the case that I've seen don't suggest to me that the patient was noncompliant with her contraceptive measures, which included oral contraceptives.  But I don't know that.  There's no way to really know that.  Everybody I think would agree that 1 pregnancy among 244 female patients in the controlled setting of a trial for a known teratogen is of great concern. 
		The next slide.  We can skip over this essentially.  Dr. McLane already covered that.
		The risks associated with switch-over.  There are two issues here really.  That's if one product replaces the other or if both are on the market at the same time, some of these issues would apply either way and some would maybe be exacerbated by having both on the market.  I think Dr. McLane covered what would happen if people on the new formulation took it twice a day or whatever.  But I think one thing that we need to think about is what happens if the physician calculates the dosage. 
		In other words, if the patient is just given the right amount for its formulation and they happen to take it twice a day instead of once a day, I think that's what Dr. McLane was referring to.  But what I'm thinking about is, what happens if the physician calculates the dosage based on the old formulation and it's really the new formulation?  
		So, again, maybe in the discussion, if you look on page 24 of the sponsor's briefing document where there's some data about higher doses of the new formulation, I think up to .66 milligram per kilogram. 
		The other issue with switch-over has kind of been alluded to.  But our feeling is that whatever trade name we settle on, it should ideally retain the 18 years of name recognition that we have for this potent teratogen.  It should at the same time clearly distinguish the two products if both are to be marketed.  So, it's kind of a catch-22 there how to work that out.  So, that's another consideration. 
		So, we can get to the bottom line here and close.  It's our view that there's no apparent pharmacokinetic basis that we can come up with to suspect that the new formulation would be any less safe than current Accutane, and that applies to the issue of a possible interaction with hormonal contraceptives and to the psychiatric adverse events.
		But the real question here is given the unknowns and the switch-over risks, basically you want to ask what does the new formulation offer to patients. 
		The sponsor's stated goal is that enhanced convenience improves patient compliance and that reduced intra- and inter-patient variability, while retaining the efficacy and safety profiles of currently marketed Accutane is achievable because of the pharmacokinetics with the new formulation.
		Our view is that because the food effect with Accutane is so large, the new formulation does reduce variability in serum levels of isotretinoin, but the benefit for patients would be dependent on equivalent or better safety and efficacy since the impact of the convenience factor is likely to be small.  The reason I say that is that in my experience in the clinic, it seems to me that taking medicine on an empty stomach is more challenging than taking it on a full stomach.  I think that in the case of this age group, which consists of a lot of teenagers, it's probably hard to find one sometimes with an empty stomach, as anybody knows who has one and tries to feed them. 
		(Laughter.)
		DR. O'CONNELL:  So, basically this is our take on it.  Thank you. 
		DR. BERGFELD:  Thank you very much. 
		It is now 4:30.  We are due to retire at 5:30, and what I'd like to do is to limit the discussion period to about 20 minutes and then go the questions, which are two.  So, right now if there are any of the committee members that would like to discuss any point of the presentation or clarification. 
		Dr. Rosenberg.
		DR. ROSENBERG:  Yes.  Of course, like most people of my generation in dermatology who remember before there was Accutane, if it weren't for Accutane, we'd still be giving them x-ray.  Accutane made all the difference in the world for the practice of dermatology, and we've come to love it, albeit with its problems. 
		The idea of changing brings up all the anxieties of change, but whether we vote to approve it or not, based on what I saw, I'm not about to start writing the prescription.  I don't think 36 weeks is any time to talk about retreatment.  And retreatment is not the same as being perfect.  I'm very suspicious of something that causes less mucocutaneous dryness.  When my patients tell me they're too dry, I tell them that's what they're paying for, that's what they're buying.  They're buying this reaming out of the follicles so that after they've put up with it for 20 weeks, they're never going to have acne again at a high percentage.  
		And if they tell me that they can make their acne go away at a half dose, I tell them Dr. Cunliffe has written that paper and others have written that paper.  You can make acne go away with a half dose, but you don't have the same percentage of permanent cure.  It's never going to be a 100 percent permanent cure.
		But if you go through the whole rigmarole for 20 weeks and put up with the symptoms, and so forth and so forth -- and, of course, don't get pregnant -- that there's a good likelihood you're never going to have acne again.  And that's why we're doing it.  That's why we're spending all this money and going through all this.
		Statistically it might not be worse, but it certainly wasn't any better.  Actually it wasn't as good.  As I say, the finding of less scaliness makes me suspicious.  And I don't see any reason to change any of my patients to this until we've seen some papers come out that at the end of 2 years how many are going to not be perfect.
		DR. BERGFELD:  Any other committee members wish to discuss?  Dr. Branch?
		DR. BRANCH:  I'm just curious as to why a trial that obviously took a huge amount of effort to launch was set up with non-dosage equivalence between the two arms when you have pharmacokinetic profiles that look -- you've stabilized your availability within an individual, but the rest of the profile looks pretty much the same to me.  So, I just find that it's hard to be asked to draw a conclusion in terms of efficacy when you've got a dose-ranging study.
		DR. BERGFELD:  Dr. Abel, then Roche.
		DR. ABEL:  I think we need to know the minimum effective dose of Accutane. 
		As far as questions of efficacy, I'm not convinced how much the NF formulation has to offer.  There is a convenience factor and certainly there would be more consistency in bioavailability of the drug.  I think there are a lot of questions that I have.
		DR. BERGFELD:  Dr. Miller, Dr. King, Dr. Epps?
		DR. EPPS:  From the presentations, I have concerns I guess about the psychiatric findings, 11 I believe and 1 in the other, in the Accutane that there are more problems, we'll say, or symptoms in the NF group.  Certainly we would need more data in that regard. 
		The other issue is the convenience.  Certainly you can tell people to take it with food or put a sticker on the bottle that says take it with food.  There are other medications that we take with food.  And if someone isn't compliant enough to take Accutane twice a day, I'm not going to give them Accutane to take once a day.
		DR. BERGFELD:  Dr. McLane, did you want to address any of the discussants?
		DR. McLANE:  Yes.  Specifically on the efficacy, I didn't present my table, but it is in the brochure that the people at the table do have on there.  On efficacy, we did reach the statistical requirement. 
		On the retreatment issue, that was actually agreed upon with the FDA on the time frame.  It's the time frame that is twice the time frame that we recommend for the initiation of retreatment, and it was felt to be the minimum time in order to have an assessment of the retreatment.  
		I think those were the main points I wanted to make. 
		DR. BERGFELD:  Dr. Wilkin, did you want to in any way respond? 
		DR. WILKIN:  Yes.  That's what Roche proposed.  I think somewhat after they proposed that, we noticed in a Roche brochure, Systemic Isotretinoin, Active Ingredient of Roaccutane.  It's published by Roche, Basel, Switzerland, 1994.  This was actually where I took the diagram that showed the dots that represented the studies.  I don't know that we had actually seen this compelling information on the difference between a dose that would reduce the number of nodules and how that might be different from the dose that ultimately would reduce the need for retreatment. 
		DR. BERGFELD:  Dr. King?
		DR. KING:  I come back to the same issue.  Again being somewhat of the older Windows generation, every time they say new and improved, '95, '98, 2000 window, it oftentimes is not improved.  I'm not sure. 
		Again, I know we've been voted down on the registry, but now there are going to be two different kinds of Accutane from Roche and particularly those competitors.  So, how are we going to distinguish which one is there and which one is not?  
		So, in the State of Tennessee, they had four people prescribing 80 percent of all the chloramphenicol causing all the adverse effects.  So, the reverse side of registry is also identifying physicians who are inappropriately prescribing or monitoring it.  
		So, given a new formulation, I'm not sure how you're going to figure out psychiatric side effects and all that when half the population is missing and you have two or three different combinations.  So, I think we're going to be back here about three years from now debating this once again.  So, I'd just like to think that the FDA and Roche have a real thing to deal with.  I'm not sure.  I'm with Dr. Rosenberg that unless you make them peel and all that, it's not been my experience that people stay cleared.
		DR. BERGFELD:  Dr. Anderson?
		DR. JENNIFER ANDERSON:  I'm just unsure.  Are we going to be voting on approval of this new formulation?
		DR. BERGFELD:  No.  We're going to answer the questions which relate to dose-ranging studies, are they needed.
		DR. JENNIFER ANDERSON:  But this drug hasn't been approved yet.
		DR. BERGFELD:  Dr. Wilkin, do you want to respond to that?
		DR. WILKIN:  Well, we're talking about two pieces:  the Accutane that's on the market and the new formulation, which is currently under review and has not yet been approved.
		DR. BERGFELD:  Dr. Malone?
		DR. MALONE:  I would just think that you would need more studies because you have two different dosage equivalents and you'd want to compare the same dosages in one study I would think.
		DR. BERGFELD:  Any other discussants?  Yes, Dr. Rosenberg. 
		DR. ROSENBERG:  Could we be told what happened to the young woman who became pregnant? 
		DR. McLANE:  This woman was given basically all of the components of the pregnancy prevention program with the exception of enrollment into the Slone Survey because they do not accept enrollments of clinical trials.  The patient had two serum pregnancy tests 1 day before she started the Accutane and one 10 days before she started the first dose of Accutane.
		There's personal information on this.  Her father was her gynecologist that referred her for the medication for oral contraceptives.
		DR. BERGFELD:  Dr. Greene?
		DR. GREENE:  I'd just point out that from my look at it, 1 in 244 is not statistically significantly different from 3 in 1,000 which is the rate that we heard about all day yesterday.
		DR. ELLISON:  That's exactly correct.  That was the table we put up with the Slone rate, the rate from the pilot study of UHC, and the rate from this clinical trial.
		DR. BERGFELD:  Any other committee members that wish to clarify something?  Dr. Tan?
		DR. TAN:  Yes.  I think it seems to me that the rate for retreatment needs to be considered as one of the endpoints for approving their equivalence. 
		DR. BERGFELD:  Thank you. 
		Anyone else?
		(No response.)
		DR. BERGFELD:  I'd like to ask Roche, because I asked you to shorten your presentation, if you think that there's something that you need to include at this point or to expand upon, I'd give you the time to do that.
		DR. YOUNG:  We're talking about really the dose of NF.  You have been treating everybody with doses of Accutane.  You're comfortable with those doses of Accutane.  I think what we're talking about in NF is what is the equivalent dose of NF to the Accutane.  
		So, if we take a patient and you're normally dosing this patient -- I'll just pick a weird number -- 1.2 milligrams per kilogram b.i.d. in that patient, that would be your normal therapy as a physician.  We easily, based on the pharmacokinetics and the linear pharmacokinetics and everything we've seen, can tell you what would be the equivalent exposure of NF for that 1.2.  So, I want to make sure everybody understands, given the relationship and all the pharmacokinetics we've done with parents and metabolite, we're able to kind of equate exposures between NF and Accutane.  That's just for information purposes.
		DR. BERGFELD:  Thank you. 
		DR. ELLISON:  Yes.  I'd like to add further to that and one other point. 
		One of the major issues with respect to the current trade formulation is how many people are not getting the advice, at least from their physician, to take it with food.  I think you saw that if you were on .5 milligram per kilogram, what the result would be if you didn't take it with food.  This may be in not necessarily a teenage person, but it may be more likely in someone who is in their 20s.  The consequence of that will, indeed, be -- I think nobody would deny it -- that there would certainly be a much higher likelihood of relapse and the need for retreatment.  That was of concern to us, the survey we did showing this very large group of patients that weren't getting these instructions on the script.
		The second is that if you're going to do this kind of study and you're going to look for one dose versus the other, we thought that we would take the minimum effective dose because of the point that we can model up to equivalent higher doses and to an exposure level where you know you've got the same exposure as that other dose in the trade formulation.  So, at least you know you're in those exposure bounds.  The efficacy of that may not necessarily translate or may not be entirely known.  That was a decision we made because the idea of going down would have been much more problematic.  We wouldn't know if your safety would have improved.  So, that's why we chose that dose, knowing that you could go up on a modeling basis. 
		I guess our whole issue around this formulation again, I think the idea of convenience is less important to us than that concern that we have about variability with food, particularly in populations that for them it may be more difficult to take this with food. 
		Thank you. 
		DR. BERGFELD:  Thank you. 
		Dr. Rosenberg, then Dr. Abel.
		DR. ROSENBERG:  My problem is I took from reading the material that at comparable blood levels, there was a suggestion of less mucocutaneous side effect.  I just don't think that mucocutaneous side effect is a side effect.  I think it's the effect of dedifferentiating epidermal cells.  I just wonder if we are really getting, at comparable blood levels, the same efficacy that we're used to.
		DR. McLANE:  Well, I had pointed out the mucocutaneous side effects for one of the main reasons.  It is one of the criteria that has been shown to have a dose relationship.  In fact, what I have in the document that you have -- but we had additional information within the NDA -- 99 percent of the patients all had chapped lips on both formulations.  So, the mucocutaneous events that I was referring to were the quality of life issues of a bleeding nose or having to not wear their contact lenses in which we had a difference between the patients. 
		DR. BERGFELD:  Thank you. 
		I have Dr. Abel and then Dr. Malone.
		DR. ABEL:  The point about taking Accutane with food seems to be a simple physician education issue that could be addressed with publication of studies showing effects of food and efficacy with and without taking it with food. 
		Second, if in the Roche trials the lower level of efficacy dose was selected, well, then wouldn't there be greater concern if you go up from there regarding side effects, adverse effects, psychiatric, other?
		DR. BERGFELD:  Dr. Ellison, are you going to respond? 
		DR. ELLISON:  Yes, just very briefly.  I think the concerns would be what we don't know.  What we do know is we can model this up so that you can anticipate the same exposures at a given dose calculation of trade, which is what David was talking about.  So, the concern would be that drug given from the new formulation or some very subtle differences in the kinetic curve would cause more side effects than not, but overall your AUC, you can calculate what that exposure would be.  This is particularly important with respect to the decreased inter- and intra-patient variability with this formulation.  So, you can really model the boundary conditions, if you will, for adverse events.
		DR. BERGFELD:  Thank you. 
		Dr. Malone and then Dr. Winokur. 
		DR. MALONE:  Because there are so many safety concerns about the medicine, I would think you would want to compare the same dose of the two drugs rather than relying upon models if you're trying to look at a new formulation.
		DR. BERGFELD:  Thank you. 
		DR. WINOKUR:  Just an observation or maybe a question.  All of the compliance literature that I am familiar with always makes a big point of fewer numbers of doses is always associated with better compliance.  Now, this population may be so motivated that it's a different story than any clinical population that I'm familiar with, but I just wanted to not lose sight of that aspect.
		DR. BERGFELD:  Could I ask Roche if you have any compliance information?
		DR. McLANE:  We did not measure compliance directly on this trial, but we did measure it by the number of packages of medications that we received back and the number of capsules in these packages.  It was quite comparable between the two formulations.  It was over 85 percent compliance on the patients that completed the therapy.
		However, we do know from our prescriber survey that 22 percent of the patients that are prescribed to get it twice per day don't take it that way.  They take it once per day.  We know that there's that wide number of patients that when they're prescribed to take it with food don't.  What happens then is that you really do get this under-dosing.  When you looked at some of the curves that David had presented, you do see this under-dosing of the patients.  That means that their treatments might be longer.  
		And what happens if you do that with the new formulation, you wouldn't get that type of effect.  You would have much more predictable exposure and so your 20 weeks period of treatment would be efficacious.
		One of the things that we had in your package is that over 80 percent of our patients had an excellent response when we looked at this criteria, an excellent or cleared response.  So, with this new formulation, we are efficacious and we're getting a significant amount of clearance.  We're going down to two nodules or lesions in these patients.  So, it is efficacious.  But with this more predictability, you really get the benefit. 
		DR. BERGFELD:  Thank you. 
		I think at this point we've moved past our 20 minutes, unless there's a question that must be asked or a clarification that must happen.  
		Seeing none, I think we'll move ahead with the questions.  Dr. Bull?
		DR. BULL:  FDA questions to the committee.  Again, given the data presented, does the committee feel that further dose-ranging studies are needed for isotretinoin?  If so, please discuss possible study designs.
		Question 2.  Does the committee believe that there may be possible consequences associated with the simultaneous marketing of Accutane and the new formulation for both prescribers and patients?  If yes, please comment on appropriate strategies to alleviate them.
		DR. BERGFELD:  Thank you. 
		I'm going to set the first question back on the table and ask for comments and even a motion, if that's in your mind.  Given the data presented, does the committee feel further dose-ranging studies are needed for Accutane?
		Dr. Wilkin?
		DR. WILKIN:  Actually it's a clarification.  The question has been changed from Accutane to isotretinoin so that it's inclusive.
		DR. BERGFELD:  Thank you. 
		Anyone?
		(No response.)
		DR. BERGFELD:  Let me put a motion on the table then.  All those in -- Dr. Abel?
		DR. ABEL:  I just had a question.  Wasn't it stated that we don't know the minimum effective dose of Accutane?
		DR. BERGFELD:  Dr. McLane?
		DR. McLANE:  Yes.  What we observed in this trial is that we do know the minimum effective therapeutic range for isotretinoin.  This is the range at the .5 milligram.  It's also the range that was shown on the table that Dr. Wilkin presented, and that is the range that the new formulation falls in.  In fact, we're slightly above the .5 milligram per kg.  So, we are at the minimum therapeutic range for dosing of isotretinoin, and we know it for the new formulation and we know it for the current marketed formulation.
		DR. BERGFELD:  Does that clarify the position on dose ranging for you?
		DR. ABEL:  So, it is known then.
		DR. BERGFELD:  Yes. 
		DR. ABEL:  All right.  Thank you. 
		DR. BERGFELD:  Dr. Wilkin, then Dr. Greenhill.
		DR. WILKIN:  Yes.  If I could just ask Dr. McLane for a clarification.  The table that I showed wasn't clear in the booklet that I abstracted that from.  Is that all the same formulation, all of those studies?  And is that the current formulation?
		DR. McLANE:  To tell the truth, I'm not familiar with that book.  It was published in Basel.  It was never circulated in the United States.  I do know that it was based on some earlier studies that were conducted in France where they actually have different dosing regimes and some of the dosing that is available throughout the world. 
		I believe it's based on some of the published material in which dosing has been looked at in retrospective studies where patients have been evaluated for how much accumulated dose they had received during therapy and, consequently then, what was their efficacious range and the need for retreatment based on the retrospective analysis of these patients or patient databases.
		DR. BERGFELD:  So, the bottom line is it's not applicable to this discussion?
		DR. McLANE:  No.  Exactly.
		DR. BERGFELD:  Dr. Greenhill.
		DR. GREENHILL:  In the past, there had been some question about one of the proofs for the presence of a causal relationship between any of the isotretinoins and psychiatric symptoms.  I have wondered if part of this question might address the possibility of looking for a study of the kind that had been suggested of following patients for a period of time, perhaps following them on different doses and extending the dose-ranging study so that it would be possible to address maybe two questions.  One is the different dosage levels provide not only successful, immediate treatment but prevent relapse, and secondly, are the higher dosage levels associated, within a period of follow-up, with any psychiatric symptoms at all because prospectively you might have a better chance.
		Adverse events are theoretically effects of medication just as the disappearance of acne.  And there might be a dose relationship, there might not be.  I think it might be useful to try to address this.  We're not going to ever be able to rule out the possibility of a type 2 error, but at least any more information we can get would be helpful in addressing it.  So, I wondered if this question is the place where such a suggestion might be raised.
		DR. BERGFELD:  Well, I want to ask the FDA specifically.  The question deals with the efficacy or does it deal with the efficacy and the adverse events, or all of it?
		DR. WILKIN:  Again, the dose ranging is really the minimum effective dose that gives you the least amount of side effects. 
		DR. BERGFELD:  So, the answer to you, Dr. Greenhill, is that there needs to be another study that was proposed to look at those specific adverse events.
		Dr. Branch?
		DR. BRANCH:  It seems to me that there are two new factors that are coming on the table.  One is that the endpoint is changing.  It's going from early nodule reduction, which is what this clinical trial did, and the focus is now going on recurrence after a full course of treatment.  
		The other is there has been no discussion on the dose relationship of the adverse event profile.  Yet, there is a body of data from the past.  Would it be reasonable that before another study is proposed, there's actually a look at the data that's available to look at those two particular aspects?  Because it may be that you've already got your answer.
		DR. BERGFELD:  Dr. Wilkin, Dr. Bull, do you want to respond to that?  Dr. Murphy?  Dr. O'Connell?
		DR. O'CONNELL:  Can I just ask for a clarification?  Which two aspects specifically? 
		DR. BRANCH:  The need for recurrence or at least the need for a further course of treatment due to recurrence, which seems now to be a key endpoint measure, and the second is there really has been very little discussion on evidence for a dose-response relationship in the adverse event profile, apart from chapped lips.
		DR. BERGFELD:  Any FDA response? 
		DR. WILKIN:  I think we're always happy to look at data that has already been collected that can answer a question rather than setting out to just simply reproduce that.  If the sponsor has that, we certainly would look at it.
		DR. BERGFELD:  Dr. Rosenberg?
		DR. ROSENBERG:  I really didn't hear what the final outcome was of that young woman who became pregnant?  Did she have a baby at term or what?
		DR. McLANE:  She had a termination.
		DR. ROSENBERG:  She had a termination.
		DR. McLANE:  Yes.
		Could I answer just quickly on the question on the trial design and mucocutaneous events?
		DR. BERGFELD:  Sure.
		DR. McLANE:  There are some mucocutaneous events and the triglycerides is one that you can measure.  The triglycerides is a measurement that, because of a systemic effect and there's a mechanism that has been proposed that is a dose relationship.  So, the triglyceride level is a very good marker for a dose response for the adverse event profile.  With that, we do see the differences in elevations.   
		If I could have the slide on the triglycerides, the one that's in my presentation.  Within there, you do see differences between the two formulations, and that's proportional with any other adverse event that is dose-related.
		Secondly, I want to talk for one second on the design of a trial that would have to look at retreatment.  Currently you would expect about 20 percent of the patients to have a retreatment, and that's similar to the information that's in the literature and similar to the information we obtained within the trial.  So, consequently, in order to have enough patients to evaluate properly on retreatment, you would need a very large trial design in order to address all of the safety issues on the retreatment, and it would take an extensive period of time to have that type of trial.
		Thank you. 
		DR. ROSENBERG:  Just back to that pregnancy.  3 per 1,000 is more than get lung cancer from smoking cigarettes, just so we have it in perspective.
		DR. BERGFELD:  Thank you. 
		Dr. Branch?
		DR. BRANCH:  Given the point that you made, I agree with that.  I'm not sure that there is a lot of merit in going down on the dose-response curve unless you've got fairly clear evidence that the adverse event profile also improves.  You're clearly close to a peak of your acute response rate.  You've got 95 or some very, very high proportion of acute response rate.  Clearly there's room to go down there, but if that doesn't meet the criteria you need for sustained benefit, then it seems to me that the key endpoint measure is still your long-term recurrence rate.
		DR. BERGFELD:  Dr. King, will you make that statement publicly? 
		DR. KING:  I guess listening to all this, I have something simple.  I agree with going down on the dose-response curve doesn't add much, so I agree with Dr. Branch for today that the only thing to look at is adverse events.  If there is any suggestion.  I don't know how to do that.  That was originally in my proposal for the registry.  So, I don't want to beat that dog anymore, but adverse events is the only thing you can go after.
		DR. BERGFELD:  Any other discussion?  Because I'm going to propose the question.  
		(No response.)
		DR. BERGFELD:  I'm going to say, given the data presented, does the committee feel further dose-ranging studies are needed for isotretinoin?  I'm going to call the question as yes.  I'll call the question as those in favor of a yes answer, please indicate by raising your hand.  That would suggest that other studies need to be done.  All those in favor?
		(A show of hands.)
		DR. BERGFELD:  5.
		Those opposed?
		(A show of hands.)
		DR. BERGFELD:  The vote is 5 and 10.
		Any abstaining?
		(No response.)
		DR. BERGFELD:  The answer is no, and so we need not to discuss anything else.  The discussion regarding possible further studies regarding adverse events have all been recorded and can be reflected on by the FDA. 
		Moving then to question 2, does the committee believe that there may be possible consequences associated with the simultaneous marketing of Accutane and the new formulation for both prescribers and patients? 
		Any discussion here?  Dr. Greene, Dr. Greenhill, and Dr. Lammer.
		DR. GREENE:  One thing that's not clear to me is, is the sponsor proposing that these two formulations be available on the market in perpetuity, or are you going to change over from one to the other?  That's not clear to me.
		DR. ELLISON:  Absolutely in the beginning they must both be on the market.  You certainly can't expect people to switch from one to the other.  
		After that, we were interested in what you thought about this, as we're interested in your ideas about this as I think FDA is, what this is going to look like in practice, what you see the risks are, and so on. 
		So, the way this usually goes is we need to see how it looks in that first year of conversion.  We intend to be very active in conversion.  We're going to be out there with double the frequency of contact because we're rolling out the targeted pregnancy prevention office system, and I'm not sure what else after our discussions yesterday.  So, assuming this drug is approved, we will be doing a lot of conversion.  So, the question will be how much needs to remain out there totally on the market or compassionate use and so on.  So, we're not entirely sure.  Your discussion of this will be very helpful to us.
		DR. GREENE:  Well, if I could ask a follow-up question then before you leave the podium.  What would be the advantage to maintaining the old formulation as opposed to the new?  Why would you want to keep the old one?
		DR. ELLISON:  What we've heard -- and these have been anecdotal -- is that some people want to keep it.  Some people around the table are agreeing with that, and there's that reason and that's a meaningful reason I suppose.
		The other thing is certain patients or certain physicians feel very comfortable with this.  It's not a medical reason. 
		I think very often in the early days, particularly physicians who have an office system like the dermatologists here who take this very seriously really want to see that in their hands and their clinic they are getting the effect that they anticipate getting.  So, there's always a transit period.  
		That's really it.  Normally you would probably, in the course of time, remove the old formulation if there was complete conversion.
		DR. GREENE:  Well, just one more follow-up.  It seems to me that the only issue really remaining on the table is that you've got two different outcome measures.  One is acute resolution of symptoms that you've studied with the new formulation, and the other is acute and also durable remission that has been studied with the old formulation.  Once you have data indicating a durable remission with the new formulation, I'm hard pressed to see the advantage to keeping the old.
		DR. ELLISON:  That would be correct.  The problem will be is that it's the one-year relapse-free period that I think for Dr. Rosenberg and others who have been in practice and really understand the value of a permanent approach to severe nodular acne.  You'd really have to study people for at least a year.  That's, as Jack pointed out, a very long and very arduous study. 
		You could, if one was doing the progressive cohort program that Dr. Mills suggested earlier for psychiatric disease, maybe obtain more data from that kind of situation and that might be a possibility.  But the classical clinical trial design would take a very long time.  So, it's really going to have to be, I think, one of those situations.  
		Normally speaking, if you can remove the trade formulation, you'd rather do it.  It depends if the practitioners really are going to be okay with that.  Sometimes you can reserve it for compassionate use only and not really market it to pharmacies, and if people have a special need for it, you can supply it.  So, that's really the situation. 
		There is no necessarily rational -- that you can study and provide data for -- reason to keep the old formulation on the market except for the natural transition that people have.
		DR. GREENE:  Well, one year is not that long a study.  Certainly there's no cancer therapy that's studied for only one year or less than one year.
		DR. ELLISON:  It's a question of accumulating cases and trying to see a difference because if you were to compare the formulations to see a difference in relapse rate, you'd need a very large sample size.  So, it took 14 months to recruit the 600 patients.  We are known as one of the faster development organizations in the industry, and it took us 14 months to do this.  So, that's what I mean not about length of treatment in the trial, but length of recruitment and that kind of thing.  It takes a very long time.
		DR. BERGFELD:  You are looking at a three-year outcome then.  Your recruitment, the study, and then interpretation.
		DR. ELLISON:  Essentially that's right.
		DR. BERGFELD:  Dr. Greenhill.
		DR. GREENHILL:  Just a simple question.  Is the cost of a once-a-day use with NF comparable with twice-a-day use of Accutane?  That's going to have some effect on prescribing and consumer acceptance. 
		DR. BERGFELD:  Can you address the cost issue, Dr. Ellison?
		DR. ELLISON:  We don't know what the price will be right now.  We don't have an approval. 
		But there is one answer to that, and I think it's a very important question.  About 90-something percent of prescriptions are reimbursed:  1.4 percent by Medicare and the rest are from managed care organizations and third-party payers.  So, at this point cost is not a barrier to treatment.  Certainly we don't anticipate price, in this particular case, compromising that situation.
		DR. BERGFELD:  Dr. Lammer?
		DR. LAMMER:  I work at a hospital where 60 percent of the patients are on Medical.  Cost is an issue every single day for almost all the patients there. 
		But my comment really here is to reiterate what Dr. O'Connell said earlier that I think if there is a new formulation that comes out, the brand name should be very, very similar to build on the educational activities that have already gone on to make the public and women aware of their need to avoid pregnancy while using the drug.  So, I want to just agree with and emphasize that recommendation that was made earlier.
		DR. BERGFELD:  Thank you. 
		Dr. Abel?
		DR. ABEL:  A point of information.  What is the situation with regard to generics?  Will we have to be concerned that there will be different formulations out there when the patent runs out and we'll have to deal with two different kinds of isotretinoin anyway?
		DR. BERGFELD:  Dr. Bull, Dr. Wilkin, someone, FDA?  Dr. Woodcock?
		DR. WOODCOCK:  Any generic drug that would be approved has to have the same rate and extent absorption to the reference listed drug.  They have to be identical in their Cmax and area under the curve.  The formulations don't have to be exactly the same for a generic drug.  They can have very minor differences. 
		DR. BERGFELD:  But their efficacy and safety profiles and adverse event profiles have to be somewhat comparable, don't they?
		DR. WOODCOCK:  Are not tested.  That's the difference with a generic.  That's why part of this discussion is interesting because we make an assumption when a generic drug is approved that if the blood levels are identical of the active ingredient and the shape of the curve, the Cmax and the area under the curve, the absorption, then the effect of the drug, as sort of a basic biological principle, is going to be the same.
		DR. BERGFELD:  Could I ask another question that follows that?  The activities that we concurred on yesterday regarding mandating some educational activity in a registry and a pregnancy test, would that not apply to the generics?
		DR. WOODCOCK:  Absolutely.  We have faced this already with generic drugs where the innovator has had various voluntary restrictions on them or other programs associated with them, and we have successfully maintained that any generic copies would have to have an equivalent program.  It may not be identical, but it would have to have the equivalent effect because that is intrinsic to the safety and effectiveness of the product. 
		DR. BERGFELD:  Thank you. 
		Dr. Epps and then Dr. Miller.
		DR. EPPS:  My only suggestion would be for the company to get on the formularies of the HMOs, insurance companies as quickly as possible.  Lately we've been hassled more and more about getting approval for Accutane.  We have to fax notes.  We have to talk to somebody on the phone to get approval.  Sometimes it's denied, and for a patient who really needs it, it's very expensive, as you know.  It can easily be over $1,000 by the time you deal with the tests and the medication, and if they need another course, then it's very expensive.  We're starting to get more and more denials.  Certainly if it's going to be once a day, it could cost a little bit less.  We know you want to recoup your investment, but we are having problems lately getting approval for it. 
		DR. ELLISON:  Point taken. 
		I just want to comment to Dr. Lammer.  When I said 1.4 scripts were covered, that doesn't mean that Medicare doesn't cover it.  It means that of all the prescriptions written, 1.4 percent were paid for by Medicare.  So, it's not that it's not covered.  It's that's the population that's getting it.
		As to your point, yes, that's obviously part of the process, so we will be doing that.  I take your point.  I also take your point about the additional paperwork for prior authorization, and maybe there's something we can do with the databases and so on that can maybe kill two birds -- or what did you say, Dr. King?  Put everything in a boat?
		DR. KING:  Yes, load all of your changes in one boat and float them all there because actually at registration, you could actually get the approval and the whole thing at one time.  I still say you can't sell the product if you can't get the dermatologist to write it, and he won't write it or she won't write if it's not easy.
		DR. BERGFELD:  Dr. Miller and then Dr. Anderson.
		DR. MILLER:  This is a question for the FDA.  Given the restrictions for this drug, what is the anticipated activity with generics?
		DR. WOODCOCK:  Generic competition, of course, is encouraged once the drug goes off patent and when it's at a point where it does not have exclusivity protections.  We can't, of course, talk about whether there are any folks in the pipeline or whatever, but generally it depends on the sales of the drug and how profitable it would be, if it's intended to have generic copies.  Certainly I would imagine that restrictions on the product would be factored in to the price equation for any generics.
		DR. BERGFELD:  Thank you. 
		Dr. Jennifer Anderson?
		DR. JENNIFER ANDERSON:  I just had a question.  If the sponsor were to withdraw Accutane before the patent ran out, would it be possible for generics to enter the field, or would that be precluded?
		DR. WOODCOCK:  You can't use a drug as a reference listed drug if it's been removed for reasons of safety or other problems.  If it's simply been removed for other reasons, it still could exist as a reference listed drug, which is the standard to which the generic is compared.
		DR. BERGFELD:  Thank you.  
		Any other discussion?  We have 15 minutes. 
		(No response.)
		DR. BERGFELD:  I'd like to call this question because it has a second part if the vote is yes.  Again, does the committee believe that there may be possible consequences associated with the simultaneous marketing of Accutane and the new formulation for both prescribers and patients?  
		The first vote will be for yes.  All of those in favor of a yes response, please indicate by raising your hand. 
		(A show of hands.)
		DR. BERGFELD:  14.
		Negative, please raise your hand?
		(A show of hands.)
		DR. BERGFELD:  1.
		Abstaining?
		(No response.)
		DR. BERGFELD:  None. 
		If the answer is yes, then we must continue.  If yes, please comment on the appropriate strategies to alleviate them.
		Yes, Dr. Holmboe?
		DR. HOLMBOE:  I think one area is going to need to be again at the level of the pharmacist when they pick up the drug.  It may be an area where a medication guide could be specific to the type of formulation with a warning that this is a once-a-day versus a twice-a-day drug.  You can actually put them in front of it. 
		DR. BERGFELD:  So, you're recommending a recommendation of a medication guide for this.
		Dr. King and then Dr. Greene?
		DR. KING:  I think it's going to be a whole lot like Classic Coke whether it sells or doesn't sell.
		(laughter.)
		DR. KING:  I think it's going to be actually a period of three years in which Hoffmann-LaRoche and the FDA are going to have a period in which they're going to phase it in and phase it out based on the economics, et cetera.
		That's why I proposed the original study.  If you're going to float a boat, you might as well put all of it there.  So, if you're going to take about a three-year study to show equivalence, you might as well say we're going to change in three years.  That's always subject to if it doesn't sell.  You can't sell it if nobody is going to buy it.  
		So, I think that would be a prime window to make the phase-out and it would leave Hoffmann-LaRoche and FDA to deal with issues of whether or not the generics are going to be, A, major competitors or, B, if they're going to come up with the same kind of safety profile.
		DR. BERGFELD:  Dr. Greene?
		DR. GREENE:  I would just like to echo what Ed Lammer said a couple of minutes ago, and that is I don't want all the effort that has gone into the education, marketing, et cetera of Accutane to date with respect to its potential problems to be lost on the new formulation.  I don't want somehow there to be some confusion that this is the safe alternative which doesn't have teratogenic risks or some other confusion.  That would be a serious problem. 
		DR. BERGFELD:  Any other suggestions that haven't been voiced today?
		Dr. Ellison, do you want to respond in any way?
		DR. ELLISON:  I would ask if there are any other ideas.  I think putting the thing in the medication guide, if we're going to have one, is really a great idea actually because the patient has to get it.
		DR. BERGFELD:  I'm going to venture that you need to visit in some kind of way your dermatologists to figure out how they're going to handle these two different boxes.  And I suspect some kind of study group would be helpful to focus on the best way to deliver that information to both the physician and patient. 
		DR. ELLISON:  Thanks.
		DR. BERGFELD:  Is there any closure for the FDA?  Dr. Murphy?
		DR. MURPHY:  Have you been here long enough?
		(Laughter.)
		DR. BERGFELD:  I want to thank this opportunity to thank the committee very, very much, as well as those who prepared for this meeting from the FDA and Roche.  It has been a wonderfully informative meeting, and I think that we really gleaned a lot of information out of the committee members which were of diverse backgrounds.  So, thank you all, and goodbye.  It's over.
		(Whereupon, at 5:20 p.m., the committee was adjourned.)