FOOD AND DRUG ADMINISTRATION

	CENTER FOR DRUG EVALUATION AND RESEARCH

	ARTHRITIS ADVISORY COMMITTEE

	Open Session

	Tuesday,
	April 11, 2000

	The Ballrooms
	Holiday Inn Gaithersburg
	2 Montgomery Village Avenue
	Gaithersburg, Maryland

IN ATTENDANCE:

STEVEN B. ABRAMSON, M.D., Consultant and Acting Chair
Chairman of Rheumatology and Medicine
Hospital for Joint Diseases
301 East 17th Street
New York, New York  10003

KATHLEEN REEDY, RDH, MS, Executive Secretary
Advisors and Consultants Staff (HFD-21)
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland  20857

KENNETH D. BRANDT, M.D.
Professor of Medicine and Rheumatology
Indiana University School of Medicine
Rheumatology Division
541 Clinical Drive, Room 492
Indianapolis, Indiana  46202-5103

JANET D. ELASHOFF, Ph.D.
Director, Division of Biostatistics
Cedars-Sinai Medical Center
8700 Beverly Boulevard
Los Angeles, California  90048

E. NIGEL HARRIS, M.D.
Dean, Department of Internal Medicine
Office of the Dean
Morehouse School of Medicine
720 Westview Drive S.W.
Atlanta, Georgia  30310-1495

ILDY M. KATONA, M.D., CAPT, MC, USN
Professor of Pediatrics and Medicine
Chair of Department of Pediatrics
Director of Pediatric Rheumatology
Department of Pediatrics
Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, Maryland  20814

LEONA M. MALONE, M.S.W., Consumer Representative
8D Lexington Lane East
Palm Beach Gardens, Florida  33418

IN ATTENDANCE:

FRANK PUCINO, JR., Pharm.D.
Clinical Care Specialist
Pharmacy Department
National Institutes of Health
Building 10, Room 1N-257
9000 Rockville Pike
Bethesda, Maryland  20892

Voting Consultants

DAVID T. FELSON, M.D., M.P.H.
Professor of Medicine and Public Health
Arthritis Health Services/Epidemiology Research Unit, A-203
Boston University School of Medicine
Boston, Massachusetts  02118

LEE S. SIMON, M.D.
Associate Professor of Medicine
Deaconess Hospital
Harvard Medical School
Department of Medicine
110 Francis Street, 5A
Boston, Massachusetts  02215

	C O N T E N T S

	PAGE

Call to Order

Steven B. Abramson, M.D.
Acting Chair	6

Meeting Statement

Kathleen Reedy, RDH, MS
Executive Secretary	6

Introduction of Committee	7

Presentation by the Sponsor, Immunex Corporation,
of BLA 99-0884, Enbrel (etanercept)

Introduction

Dawn Viveash, M.D., MPCP, BPharm
Vice President, Regulatory Affairs	9

Clinical Perspective

Desiree van der Heijde, M.D., Ph.D.
Professor of Rheumatology, University Hospital
Maastricht, the Netherlands	11

ERA Trial

Barbara Finck, M.D., FACR
Medical Director, Rheumatology	16

Summary and Conclusions

Leslie Garrison, M.D., M.P.H.
Vice President, Clinical Development	36

	C O N T E N T S

	PAGE

Presentation by the Center for Biologics
Evaluation and Research Staff

Jeffrey N. Siegel, M.D.
Medical Officer
Division of Clinical Trial Design and Analysis
Office of Therapeutics Research and Review, CBER	46

Questions to the Sponsor and FDA Staff	71

Open Public Hearing

Judith Levinson	87

Norine Walker	92

Gloria Brennan	96

Jack Klippel, M.D.
National Arthritis Foundation	100

Letter from Kara Gregory	102

Discussion and Questions	104

	P R O C E E D I N G S	(8:06 a.m.)
DR. ABRAMSON:  I'm Dr. Abramson.  I'd like to call the meeting to order and begin with a meeting statement by Kathleen Reedy, Executive Secretary.
MS. REEDY:  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 for the meeting and all financial interests reported by the committee participants, it has been determined that all interests in firms regulated by the Center for Drug Evaluation and Research present no potential for an appearance of a conflict of interest at this meeting with the following exception.  Dr. David Yocum is excluded from participating in today's discussion and vote concerning Enbrel.  Further, in accordance with 18 United States Code 208(b)(3), a full waiver has been granted to Dr. David Felson.
A copy of this waiver statement may be obtained by submitting a written request to the agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

In addition, we would like to disclose for the record that Drs. Kenneth Brandt, Steven Abramson, and Lee Simon have interests which do not constitute financial interests within the meaning of 18 United States Code 208(a), but which could create an appearance of a conflict. The agency has determined notwithstanding these interests that the interests of the government in their participation outweighs the concern that the integrity of the agency's programs and operations may be questioned.  Therefore, Drs. Brandt, Abramson, and Simon may participate fully in today's discussion and vote concerning Enbrel.
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.
DR. ABRAMSON:  Thank you.
I'd like now to ask the committee members to introduce themselves.
DR. PUCINO:  Frank Pucino with the Pharmacy Department at the National Institutes of Health.

DR. FELSON:  David Felson, a rheumatologist-epidemiologist at Boston University Medical School.
DR. KATONA:  Ildy Katona, pediatric rheumatologist from the Department of Pediatrics, the Uniformed Services University of the Health Sciences.
DR. SIMON:  Lee Simon, a rheumatologist at Harvard Medical School and Beth Israel Deaconess Medical Center in boston.
MS. MALONE:  Leona Malone, consumer representative.
DR. BRANDT:  Kenneth Brandt, rheumatologist, Indiana University School of Medicine.
DR. ABRAMSON:  Steve Abramson, rheumatologist, NYU and the Hospital for Joint Diseases.
MS. REEDY:  Kathleen Reedy, Food and Drug Administration.
DR. HARRIS:  Nigel Harris, Dean at Morehouse School of Medicine and a rheumatologist.
DR. ELASHOFF:  Janet Elashoff, Biostatistics, Cedar-Sinai Medical Center and UCLA.
DR. MILLS:  George Mills, Center for Biologics.
DR. JEFFREY SIEGEL:  Jeff Siegel, Food and Drug Administration, Center for Biologics.
DR. SCHWIETERMAN:  Bill Schwieterman, Center for Biologics.

DR. JAY SIEGEL:  Jay Siegel, Biologics.
DR. ABRAMSON:  Thank you very much.
We'd like to begin this morning's presentation with that from the Immunex Corporation.
Dr. Viveash?
DR. VIVEASH:  Good morning, members of the committee, FDA colleagues, and visitors.
We appreciate this opportunity to present to the committee comprehensive clinical and radiographic results from a trial of 632 patients with RA as the basis for modification of the current indications for Enbrel in RA.
Dr. van der Heijde will provide background information on structural damage in RA, how it is assessed in clinical trials, and how it's currently taken.  Dr. Finck will present the design and results of the trial, and Dr. Garrison will present the safety profile of Enbrel since the initial approval in 1998 and the risk-benefit profile of Enbrel in RA.
We also have with us today four consultants. Drs. Alarcon and Paulus have extensive experience with trials in RA and treatment of patients with methotrexate.

Dr. Fisher is a consultant statistician who has substantial experience in active control trials and has served on the Cardio-Renal Advisory Committee.
Dr. Sharp served as x-ray image reader and consultant for the Enbrel early rheumatoid arthritis trial.  The modified Sharp method was used to score the x-ray images in the trial.
The development program for Enbrel has followed FDA guidelines.  On the basis of three trials, Enbrel was approved by the FDA in November of 1998 for the reduction of signs and symptoms of moderately- to severely-active RA in patients who have an inadequate response to one or more disease-modifying anti-rheumatic drugs.  Enbrel may be used alone or in combination with methotrexate.
In May of 1999, Enbrel was approved for the same indication in polyarticular course juvenile rheumatoid arthritis.
The FDA guidance for industry spells out the claims that a sponsor may request for the treatment of RA.  These include the two claims that will be addressed today, reduction of signs and symptoms of RA and prevention of structural damage.  The guidance also defines other claims, but these will not be addressed today.

The FDA guidance states that a trial designed for approval for prevention of structural damage must demonstrate slowing of x-ray progression using a validated radiographic index, such as the Larsen or modified Sharp method, or the trial should demonstrate prevention of new x-ray erosions by maintaining an erosion-free state or preventing new erosions.
You'll recall from the earlier slide that the original label for Enbrel was based on studies in patients with RA who had failed DMARDs.  Based on the results of the ERA trial, Immunex proposes that the label for Enbrel be amended to remove the requirement that patients need to fail other DMARDs before Enbrel can be prescribed.
Therefore, Enbrel will become an option for initial DMARD therapy for patients with active RA.
Immunex proposes that the label for Enbrel be amended to "Enbrel is indicated for reduction in signs and symptoms and prevention of structural damage in patients with rheumatoid arthritis."
Now, I would like Dr. van der Heijde to share her clinical perspective on structural damage in RA.
DR. VAN DER HEIJDE:  Thank you, Dr. Viveash.

I would like to discuss with you today aspects of RA that for most of you on the committee will seem very elementary.  However, I hope that the background information I will present will give all of the committee members an understanding of how we assess structural damage in RA in clinical trials and how active RA is currently treated.
I'll briefly discuss the characteristics of joint damage in RA and the scoring method used in this clinical trial.
Next, I will discuss the consequences of disease activity versus disease duration.  Finally, I will touch on the ACR guidelines for the management of RA and the use of methotrexate.
Structural damage in RA has certain characteristics that are unique and are thought to be consequence of ongoing inflammation.  These structural damages include periarticular osteopenia, erosions, usually at the bare areas between the insertion of the joint capsule and the area of the bone protected by thick articular cartilage, joint-space narrowing due to cartilage degradation and loss, joint subluxation and malalignment that are due to tendonlexity, intrinsic muscle wasting and joint damage, and, finally, total joint collapse and ankylosis may occur.  All these abnormalities may occur in both small and large joints.

Slowing of radiographic progression of RA has become an established surrogate marker for overall patient benefit.  Several methods for quantifying the rate of structural damage has been validated and used in clinical trials.  The two most commonly-used methods are those of Larsen and Sharp and their modifications.
The Sharp method designs separate scores for erosion and joint-space narrowing, and these are added to derive the total Sharp score.  This method has been found to be more sensitive to change over time and more reproducible in patients with early RA compared to Larsen.
Originally, the Sharp method was applied to the hands and wrists only.  Our group, as well as others, demonstrated that erosions were frequently present in the feet before they were present in the hands, and that more damage was seen in the feet compared to the hands.
Based on these observations, the Sharp method was modified in 1989 to include the feet as well as the hands and wrists.
The original Sharp method counted the number of erosions and the maximum erosion score for each joint was five, but counting erosions might not represent the degree of damage present.  As illustrated here, one large erosion might represent considerable more damage than a few small erosions.

Over the years, the Sharp method for scoring erosions has been modified to incorporate the magnitude of the erosions as well as the number of erosions.  Both of these modifications, the use of the feet and the magnitude of the erosions, are described in the literature and were included in the modified Sharp method used in the ERA trial.
Which patients are at risk to develop structural damage?  Risk factors for rapid progression of structural damage in RA have been elucidated in several trials, and these were most recently reviewed by Kim and Weisman in this year's March issue of Arthritis and Rheumatism.
These risk factors include the presence of rheumatoid factor and high disease activity which can be expressed as a high number of swollen joints or elevated acute phase reactants, such as CFP or ESR.  Also, the presence of erosions early in the disease course indicates a higher risk of progression of structural damage.  Specific haplotypes, such as the shared epitope, are additional risk factors, and, finally, extra-articular manifestations, such as nodules and vasculitis, although these are not frequently present in early disease.
Patients with one or more of these risk factors are likely to progress at a rapid, steady or linear rate.

The graph shown here is from the longitudinal observational study by Wolfe and Sharp from 1998.  Patients with active early RA within two years of diagnosis were followed over 20 years.  Here, we see the results of the first 10 years.
They received a variety of treatments during that time, and the Sharp erosion and joint-space narrowing scores show a linear progression pattern, and this continues for 20 years.  Although some patients show more progression early and some later, the majority show a linear progression.
Similar findings are reported in other long-term observational studies, such as those by Plant, Kareela, and Graudal.  Progression of structural damage is mainly determined by disease activity, and it's not specific for certain time periods and course of the disease.
The ACR guidelines for management of RA states that active RA may lead to irreversible joint damage, even in the early months of the disease, and that disease-modifying antirheumatic drug therapy should not be delayed for more than three months in patients who, despite treatment with NSAIDs, continue to have joint pain, morning stiffness, active synovitis and persistent elevations of acute phase reactants.

The DMARDs included in the ACR guidelines are listed here.  This list will probably be updated as newer agents that show prevention of structural damage are added to the list.  An example is leflunomide, as it is the only DMARD currently labeled for retardation of structural damage.
Although methotrexate is not currently labeled for prevention of structural damage, it has become the first DMARD used by rheumatologists in the U.S. over the past decade.
Methotrexate has proven to retard structural damage in several studies.  More details on these studies showing this are summarized in the briefing document.
The literature shows that the dose of methotrexate administered to patients in clinical trials has increased during the past 10 years.  The higher dose of methotrexate used in clinical trials may reflect a change in the treatment paradigm for RA from one where DMARDs were avoided in early disease to one that aggressively uses DMARDs in early disease is recommended.  This is in line with recognition that structural damage may occur very early in disease.

In summary, progression of structural damage in RA is a result of disease activity, regardless of disease duration.  Patients with risk factors for progressive disease may demonstrate early rapidly-progressive joint damage.
Early aggressive therapies are recommended by the ACR guidelines for active RA, and rheumatologists in the U.S. are using methotrexate as a standard therapy.
Dr. Finck will now present the ERA trial design and results.
DR. FINCK:  Thank you, Dr. van der Heijde.
I'm pleased to share with you the design and results of the Phase III trial of Enbrel versus methotrexate in patients with active rheumatoid arthritis, the ERA trial.
The presentation will be as follows.  After a brief description of the study design and the patient population, I will present the results for reduction in signs and symptoms and then for prevention of structural damage.  This will be followed by safety.
To conserve time for discussion, I will not be covering the quality-of-life endpoints that were assessed in the ERA trial.  These are in your briefing document, but if you're interested in these, I'll be happy to respond to your questions.

The ERA trial was a randomized multicenter double-blind trial comparing Enbrel to methotrexate in patients with rheumatoid arthritis.  Joint assessors blinded to the treatment and other evaluations were used throughout the study.
An intent-to-treat design was utilized.  Patients who came off of study drug received standard of care prescribed by their primary rheumatologist, but they remained in the study for evaluations.
All visits prior to and after discontinuation of study drug were used in the analysis, and patients were analyzed in the group to which they were initially randomized.
This slide shows the study schema.  There were 632 patients who were randomized and received study drug, 207 in the Enbrel 25 milligram group, 208 in the Enbrel 10 milligram group, and 217 in the methotrexate group.
Now, the dose of oral methotrexate or an equivalent number of placebo tablets was rapidly escalated so that methotrexate would have its best possible performance in comparison to Enbrel.  Patients started at a dose of 7.5 milligrams, and at four weeks, the dose was increased to 15 milligrams, and at eight weeks to 20 milligrams, if patients had any active joints.

Patients were allowed to decrease the dose of oral tablets once by five milligrams or two tablets for adverse events or sustained elevations of liver enzymes.  All patients received folic acid, one milligram daily.
X-rays of the hands, wrists and feet were obtained at baseline, at six months, and at one year or if the patient discontinued study drug or evaluations, they were also obtained at that time.
The primary clinical endpoint was at six months, and the radiographic endpoint was at one year.  The 10 milligram Enbrel group was included in this study at a less-effective dose.  In all of the trials with Enbrel, a dose response to Enbrel has been noted with Enbrel 25 milligrams out-performing Enbrel 10 milligrams on all clinical endpoints, and the presentation today will focus on the 25 milligram Enbrel group.
X-ray images were digitized, and they were presented to the readers on high-resolution monitors.  Each case was read by two of six qualified physicians.  There were five radiologists and one rheumatologist, Dr. Sharp.  All of the readers were trained in the modified Sharp reading method, and the sequence of the films as well as the treatments for the patients was blinded to the readers.

The treatment groups were unblinded after one year when all patients had completed one year of evaluations.  The open label trial is still ongoing, but the x-ray readers remain blinded to the treatment and to the sequence of the x-rays in the second year of the study.
To be eligible for this trial, patients could not have been previously treated with methotrexate, and at study entry, they had to be candidates for methotrexate, and that was defined in that they had to have active disease with no known contraindications for the use of methotrexate.
The 632 patients in this study all had rheumatoid arthritis of a relatively short duration, less than or equal to three years.  Patients were also required to have active disease, and this was defined as at least 10 swollen and 12 tender joints.
Because we wanted to enrich the population in this study with patients who were likely to have erosive disease, they were required to be rheumatoid-factor positive at baseline, and if they were negative, they already had to have erosions present on their baseline x-rays.
With this degree of disease activity, inclusion of a placebo group into this study design did not seem reasonable or justifiable.

There were two co-primary endpoints in this study, reduction of signs and symptoms of rheumatoid arthritis and prevention of structural damage.  In order to preserve the study alpha at the .05 level, both of these endpoints had to be achieved at the .05 level or if only one was achieved, it had to be at the .025 level.
The primary endpoint for prevention of structural damage was initially a superior endpoint that compared the change in Sharp erosion score over one year between all three treatment groups, and if the overall difference between all of the groups was significant, then the pairwise comparison between Enbrel 25 milligrams and methotrexate was to be evaluated.  The study was designed, powered and conducted with the superiority endpoint.
Now, after discussion with the agency and four months before the study was unblinded, the primary endpoint was amended to an equivalence endpoint requiring that Enbrel 25 milligrams not be inferior to methotrexate, based on a change in total Sharp score over one year.

Superiority with respect to erosions was moved to the secondary endpoint.  The primary endpoint was changed because data became available during the trial that showed that methotrexate, when used as an initial DMARD, in patients with early rheumatoid arthritis prevented structural damage, and the magnitude of this response to methotrexate had not previously been reported.
After discussion with the agency, the following definition of non-inferiority or equivalence was agreed upon.  Enbrel must preserve at least 70 percent of the expected methotrexate benefit.
The process of defining equivalence is represented schematically on this slide.  Two assumptions were made based on the literature available at the time.  One, that untreated patients with active rheumatoid arthritis, regardless of their disease duration, would progress at a steady rate of approximately six total Sharp units per year, and, two, that methotrexate-treated patients would progress at a rate of about two total Sharp units per year.
The difference between the expected rates of progression for untreated patients and methotrexate-treated patients is the expected methotrexate benefit, and in this case, that's six minus two which equals four.
To demonstrate non-inferiority or equivalence in the ERA trial, Enbrel 25 milligrams had to preserve at least 70 percent of that expected methotrexate benefit or four.  Enbrel could not be worse than methotrexate by 30 percent of the expected methotrexate benefit or 30 percent of four is 1.2 total Sharp units.

This value, 1.2, was set as the threshold for the upper limit of the 95 percent one-sided confidence interval for the difference between methotrexate and Enbrel that was going to be observed in the trial.
Now I will share with you the results of this trial.  Patient characteristics as shown on this slide.  The majority of patients were Caucasian women, approximately age 50, and approximately 15 percent of the patients were over the age of 65.  Patients in this study had RA for a short time.  In fact, the mean disease duration was less than one year.
To ensure that the groups were balanced, patients were stratified prior to randomization by their disease duration.  Less than 18 months or 18 months to three years.  Three-quarters of the patients were in the very early disease duration strata, less than 18 months.
The groups were well balanced for all other baseline characteristics as well.

Patients had very active disease at baseline.  The mean swollen and tender joint counts were 24 and 30, respectively.  The physician global and patient global assessments as well as the patient's assessment of pain were similar across the treatment groups, and they were approximately five to six units on a scale of zero to 10 for each of those assessments.
The baseline HAQ disability scores were approximately 1.5, indicating moderate disability, even in these patients with early disease.  Acute phase reactants were elevated, and patients reported approximately four hours of morning stiffness.
The groups were balanced at baseline for patients with risk factors for progressive erosive disease.  At least 87 percent of patients were rheumatoid-factor positive, and at least 85 percent already had erosions on their baseline x-rays.
The other predictors of progressive disease included acute phase reactants and swollen joint counts.  These were elevated, and they were equally distributed between the treatment groups.
Compliance with all aspects of the study was excellent.  This is shown on the following slides.
The investigators were compliant with dose-escalating oral tablets, either methotrexate or placebo, as was required by the protocol.  The methotrexate or placebo tablets were increased at four weeks and then again at eight weeks in each of the three treatment groups.

The median dose of methotrexate used in the ERA trial was 20 milligrams per week, and after dose-escalation, the mean dose of methotrexate was 19 milligrams per week.
The yellow line on this graph represents the methotrexate group, and the dose of methotrexate was decreased over the first year of the study for some patients on the protocol.  15 percent of patients on methotrexate had their dose of tablets reduced compared to only three percent of patients in the Enbrel group who had their dose of tablets reduced.  This was per protocol.
Now, the reasons for dose reduction is shown in this slide.  Adverse events and elevated liver function tests were the most common reasons for dose reductions.  The treatment blind was maintained during dose reduction.
As stated earlier, patients could discontinue study drug, but they needed to remain in the study for evaluations.  These patients did receive standard of care treatment, as I said, prescribed by their primary rheumatologist.
A very high proportion of patients, over 90 percent, completed one year of evaluations in the ERA trial, and over 79 percent of patients completed one year on study drug.

Discontinuation of study drug due to adverse events was significantly higher in the methotrexate group compared to the Enbrel treatment groups.
Compliance with x-ray acquisition was also excellent, except for one patient who had no x-rays and was not included in the x-ray analysis.  There were no missing baseline films, and 98 percent of patients had at least two time points for evaluation, and 92 percent of patients had all three x-ray time points for comparison.
Next, I will discuss the results of the co-primary endpoints.  The primary endpoint for reduction in signs and symptoms of rheumatoid arthritis was the area under the curve of the numeric ACR index.
We prospectively defined the area under the curve for the numeric ACR or ACRn as the primary clinical endpoint of the study, in order to follow FDA guidelines that suggested that methods that evaluated response over time were preferable to methods that just looked at the baseline and end of study observations.
The area under the curve for the ACRn allowed us to compare the cumulative response for the active treatment groups over the six months, the primary endpoint.

Now, the ACRn uses the ACR criteria with which rheumatologists have become familiar, and it is assigned a specific value for improvement, such as an ACR21 or an ACR48, in a matter that's analogous to that that's used to define an ACR20.
An example for the calculation of the ACRn is included in your briefing document, on page 34, and if you have questions about this, I can answer these during the question period.
But one can think of the area under the curve as the average percent improvement from baseline on the ACR criteria for each patient over the treatment interval.  The continuous nature of the ACRn allowed us to calculate the area under the curve for each patient and then to compare the mean area under the curves between the two treatment groups.
This graph shows the mean ACRn at each time point for the Enbrel 25 milligram and for the methotrexate groups.  The area under the curve for the ACRn for each group is represented in color.  Blue plus yellow for the Enbrel 25 milligram group and yellow for the methotrexate group.
The difference in the area under the curve for the two groups over six months, the primary endpoint, was significant with a P value of .002, and it remained significant over the entire year of treatment with a P value of .009.  The primary endpoint for reduction in signs and symptoms of rheumatoid arthritis was achieved.

Now, the ACR20 has been used in clinical trials to define responders versus non-responders, and the percent of patients in the Enbrel 25 milligram group, the blue lines, and the methotrexate group, the yellow lines, that achieved ACR20, ACR50 and ACR70 responses is shown.
These results demonstrate that both Enbrel 25 milligrams and methotrexate are effective in reducing the signs and symptoms of rheumatoid arthritis in patients with active RA of a short duration.
A significant percent of patients treated with Enbrel 25 milligrams achieved these responses earlier in their treatment course and at a higher level, and they maintained these responses over the entire year of therapy. At all time points, the Enbrel group was numerically better than the methotrexate group on this landmark analysis.
But one can also calculate an area under the curve for the ACR20, 50 and 70, and when we do that, the Enbrel 25 milligram group is significantly better than the methotrexate group over the treatment interval.
The primary endpoint for prevention of structural damage was equivalence between Enbrel 25 milligrams and methotrexate with respect to the total Sharp score over one year.  This endpoint was also achieved.

This slide shows the equivalent endpoint results.  The mean change in the total Sharp score over one year for methotrexate group was 1.3 total Sharp units, the yellow bar, and for the Enbrel 25 milligram group, it was 0.8, the blue bar.
The change in total Sharp score for both treatment groups is low, considering that the patients in the ERA trial had very active disease and risk factors for rapid progressive erosive damage.  The difference between Enbrel 25 milligrams and methotrexate signified by the Delta sign is a negative 0.5, indicating that Enbrel 25 milligrams was numerically better than methotrexate.
The graph on the right of the slide represents the difference between Enbrel 25 milligrams and methotrexate, again the negative 0.5 units, and it shows the one-sided 95 percent confidence interval for that difference at 0.16.  This is well below that threshold that we set at 1.2 that was necessary for Enbrel 25 milligrams to maintain 70 percent of the expected methotrexate benefit.  In fact, Enbrel 25 milligrams maintained at least 96 percent of the expected methotrexate benefit.

As prospectively defined, the equivalence endpoint for prevention of structural damage was clearly achieved.  Enbrel 25 milligrams slowed radiographic progression in patients with rheumatoid arthritis at least as well as methotrexate.
Now, having demonstrated equivalence, the protocols specify that other endpoints would be evaluated.  First, we evaluated the change in total Sharp score using the mean of the raw change scores adjusted for time on study.  This analysis allowed us to evaluate progression over the first six months of the trial as well as over the entire year.
The rate of progression by total Sharp score was significantly less for the Enbrel 25 milligram group compared to the methotrexate group at six months, and there was a trend towards significance at 12 months.
The secondary endpoint superiority of Enbrel 25 milligrams to methotrexate with respect to change in erosion score over one year was also evaluated.  To achieve this endpoint, a significant difference over all of the treatment groups and pairwise between Enbrel 25 milligrams and methotrexate was required.  This endpoint was achieved.

Change in erosion score over one year for the Enbrel 25 milligram group and methotrexate group is represented on the bar graph here.  Enbrel was superior to methotrexate with respect to preventing erosions.  The overall P value for the three groups was .006, and for the pairwise comparison of Enbrel 25 milligrams to methotrexate, the P value was .002.
For analysis of the change in erosion scores, we also used the mean of a change in the raw scores adjusted for time on study.  Again, this allowed us to look at the change over six months as well as over the entire year, and as can be seen from this graph, Enbrel 25 milligrams was superior to methotrexate at six months, and this difference was maintained over the entire year, and the difference at both time points was highly significant, with a P value equal to .001 at six months and .002 at one year.
We also evaluated the percent of patients in each group who had no progression of erosions over one year.  75 percent of patients in the Enbrel 25 milligram group compared to 57 percent of patients in the methotrexate group had no increase in their erosion score over the full year.  This difference was highly significant with a P value of less than .001.

In summary, the co-primary endpoint for efficacy, reduction in signs and symptoms of rheumatoid arthritis and prevention of structural damage, were both achieved.  Enbrel 25 milligrams was significantly better than methotrexate on the area under the curve for the ACRn, indicating that Enbrel-treated patients had a faster onset of response, a higher magnitude of response and that this was maintained over the entire treatment interval.
Enbrel 25 milligrams was shown to be at least equivalent to methotrexate with respect to change in the total Sharp score and superior to methotrexate in preventing erosions.
Finally, I will present the safety results for the ERA trial.  I will include adverse events, serious adverse events, infections, malignancies and laboratory abnormalities.
Any problem or complaint that occurred while a patient was on study or within 30 days of discontinuation of study drug was recorded as an adverse event.  The adverse events that were statistically associated with any of the treatment groups are shown on this slide.
Injection site reactions occurred in approximately one-third of patients who treated with Enbrel and in 7 percent of the controls.  The injection site reactions were Grade 1 and Grade 2 in intensity.  They occurred once in most patients and usually early in the treatment course, and they resulted in discontinuation of study drug in only one patient.  This pattern and frequency of injection site reactions is similar to that that we've seen in all other controlled trials with Enbrel.

The adverse events that were associated with methotrexate are those that one would expect, nausea, rash, and mouth ulcers.
In comparison, any complaint or event that required hospitalization, such as serious infections or malignancies, were recorded as serious adverse events.  During the first year, 55 adverse events in 42 patients were classified as serious.  23 in the methotrexate group, 14 in the Enbrel 10 milligram group, and 18 in the Enbrel 25 milligram group.
However, the frequency and the rate of serious adverse events were similar in all three treatment groups.  There were three patients who had deep venous thrombosis in the Enbrel treatment group, but all three of these patients had risk factors for DVT.
Of note, there were three patients in the methotrexate group who developed methotrexate lung toxicity during the first year of the study.  This is described as interstitial pneumonitis on this slide.  Methotrexate is an idiosyncratic pulmonary reaction that causes acute shortness of breath and infiltrates on a chest x-ray, and the rate of methotrexate lung toxicity in this study was 1.4 percent, and that's similar to what's reported in the literature for patients receiving methotrexate.

Infections were monitored closely throughout the study.  The rate of all types of infections was higher in the methotrexate group, 1.9 events per patient year versus 1.5.  However, medically-important infections that required hospitalization or intravenous antibiotics occurred in less than 3 percent of patients in each group.
There were no opportunistic infections, and there were no deaths associated with infection in the ERA trial.
In over 600 patients, there was no apparent increase in the frequency of malignancies in any of the treatment groups.  Patients were compared to an age- and sex-matched general population using the National Cancer Institute Surveillance, Epidemiology, and End Results Database, the SEER database.
We would have expected to see based on that database 1.8, 1.9 and two malignancies in the methotrexate, Enbrel 10 milligram, and Enbrel 25 milligram groups.  There were two in the methotrexate group, two in the Enbrel 10 milligram group, and three in the Enbrel 25 milligram group.

The cancers that were reported were primarily those representing the most common cancer types that are seen in the general population, and they occurred at varying lengths of time of exposure to study drugs.
Now, as expected, the majority of laboratory tests were normal throughout this study, and the next two slides will show you the abnormal laboratory values that are associated with any treatment group, and they include the worst value for an abnormal laboratory test for a patient at any time on study drug.
Remember that laboratory evaluations were obtained at each visit, up to nine times per patient, for the first year of the study.
Low lymphocyte counts were more frequent in the methotrexate group, and low absolute neutrophil counts were more common in the Enbrel 25 milligram group.  However, for both low lymphocytes and low neutrophils, the percent of patients with a Grade 3 event was low.
Furthermore, the low lymphocyte counts and the low absolute neutrophil counts were sporadic, and they occurred in most cases at a single visit.  Importantly, transient low neutrophil counts were not associated with serious infections.

Shown on this slide are the liver function test abnormalities, and as expected, they were significantly more frequent in the methotrexate group.  However, Grade 1 and Grade 2 LFT abnormalities occurred in all treatment groups, and most patients in this study were on concomitant NSAID therapy, which may have caused some of these elevated tests.
Seven percent of patients on methotrexate and 1 percent of patients on Enbrel required a dose reduction of their oral tablets as required under the protocol for an elevated liver function test.  There were no Grade 4 laboratory abnormalities in any patient on study drug in the ERA trial.
As shown in previous studies with Enbrel, there were no treatment-emergent laboratory abnormalities in the Enbrel-treated patients that would suggest the need for routine laboratory monitoring.
The objectives of the ERA trial were to demonstrate the efficacy of Enbrel for the reduction of signs and symptoms of RA and prevention of structural damage.  Both of these objectives were achieved.
Enbrel was also well tolerated in the patients with early active rheumatoid arthritis, and the safety profile of Enbrel compared favorably to methotrexate in this controlled trial.  This was the first large head-to-head comparison of a biologic to methotrexate in patients with active disease and risk factors for rapidly-progressive erosive disease.

The data set is very complete with over 90 percent of the patients being evaluable for a full year of study, and the clinical and radiographic results are robust, and they demonstrate the efficacy of Enbrel in patients with active rheumatoid arthritis.
Dr. Garrison will discuss the risk-benefit of Enbrel as an option for initial DMARD therapy for patients with rheumatoid arthritis.
DR. GARRISON:  Thank you, Dr. Finck.
Rheumatoid arthritis is a chronic disease which is associated with significant long-term morbidity.  Although there are good therapies available, a need still exists for new treatment options for patients and physicians.
The ERA trial was designed to address the question of whether Enbrel is another option for initial DMARD therapy.  Specifically, is Enbrel an effective early intervention which will prevent structural damage as well as improve the signs and symptoms of rheumatoid arthritis?
In order to address these efficacy questions, which may expand the use of Enbrel, it is important to look at the entire risk-benefit profile of Enbrel.

The total number of patients treated with Enbrel is shown here.  The Enbrel program has been conducted by Immunex in both the United States and Canada and by Wyeth-Ayerst in Europe, Australia and New Zealand.
I will review the global safety experience.  At this point, over 1,800 patients have been treated in rheumatoid arthritis clinical trials for over 2,600 patient-years' exposure.
Over 700 patients have been treated with Enbrel in studies of other diseases, and since FDA approval in 1998, it is estimated that over 65,000 patients have been treated with commercial Enbrel, with over 38,000 patient-years' exposure.
The length of Enbrel exposure is outlined here as well as the ICH guidelines.  All rheumatoid arthritis patients in global clinical trials have been given the option to continue treatment with Enbrel.  The length of Enbrel exposure decreases with time, not because patients have withdrawn from these studies but because they entered these trials at various time points, depending upon when their initial study ended.
At this time, over 1,400 patients have received Enbrel for 12 months or more, over 400 patients have received Enbrel for 24 months or more, and 53 patients have received three or more years of Enbrel treatment.

The majority of these patients, 82 percent, have been treated with Enbrel twice weekly 25 milligram injections continuously in an uninterrupted fashion for the entire length of time depicted here.
You have just seen safety from the ERA trial presented by Dr. Finck.  In this large 632-patient study, Enbrel was safe and well tolerated, and, importantly, the safety profile from the ERA trial is consistent with all previous studies and with the current package insert.
Turning to safety in all RA studies, including the long-term open-label clinical trials and the United States' post-marketing experience, the same conclusions can be reached.
The safety profile of Enbrel from all these sources remains consistent with that from the controlled clinical trials and the current package insert, specifically regarding adverse events, serious adverse events, serious infections, and malignancies.
One theoretical concern about patients treated with anti-TNF therapies is that they may be more susceptible to infection, and as you know, in May of 1999, the Enbrel package insert was revised in coordination with FDA to ask physicians to be cautious when prescribing Enbrel to patients who have an increased infection risk.

As it is often difficult to interpret data from spontaneous adverse event-reporting systems, I'd like to now review all of our clinical trial data.
On this slide are the rates of serious infections from placebo-control trials from North America and from Europe in patients with longstanding DMARD-failing rheumatoid arthritis.
Serious infections are defined as infections requiring hospitalization or IV antibiotic therapy.  The North American trials were of six-month duration, and the European trial was three months long.  From these controlled trials, the rate of serious infections is similar in the placebo and Enbrel groups.
Here added to the slide is the serious infection rate from the ERA trial, a 12-month trial.  The rate of infections in the methotrexate group and the Enbrel group is similar.  There is no evidence of a higher infection rate with Enbrel treatment from the controlled trials.
And, lastly, added to the far right of the slide is the serious infection rate seen in the post-marketing experience.  It is important to remember that post-marketing events are spontaneously-reported, and unlike the clinical trial data, the true incidence is unknown.

However, the serious infection rate in the post-marketing experience is at a much lower level than that seen in the clinical trials, and the rate has been stable since Enbrel's approval.
Immunex has been working very closely with FDA to understand this information.  As we have not seen any evidence of a higher infection rate in the RA patients enrolled in our controlled trials, a new clinical trial is ongoing, a 1,000-patient controlled trial which will enroll only patients with comorbidities, such as patients with COPD or diabetes, to answer the question of whether there may be a subgroup that may require special caution or if these cases of serious infection are another manifestation of longstanding rheumatoid arthritis and its consequences.
Another question that has been raised is whether patients will have a higher infection rate with longer Enbrel treatment.  Shown here are data from the North American trials on the top and the European long-term open-label treatment trials on the bottom.
Extended treatment of patients with very long-standing DMARD-failing rheumatoid arthritis, the rate of serious infections has remained stable over time and consistent with the rates from the controlled trials, and we are continuing to very carefully monitor these data.

Another theoretical concern about patients treated with anti-TNF therapies is that they may have a higher rate of malignancies.  Generally, it takes five to 10 years to assess an increase in malignancy rates.  In Enbrel clinical trials, there's no increase in malignancies.
Shown here is data from the North American studies, where we can apply the age- and sex-matched cancer rates for the general population from the SEER database.  In over 1,200 patients, we would have expected to see 17.1 malignancies, and we have observed 17.  In Europe, in over 600 patients, six cancers have been reported, also consistent with the cancer rates in the general population.  These malignancies have been of various types, reflecting the most common cancer types in the general population, and of note, only one non-Hodgkin's lymphoma has been seen in the entire program.  We are continuing to very carefully monitor these data.

In one of the questions to be discussed today, the post-approval safety studies are referred to.  This large comprehensive program is outlined here, which will study more than 4,800 patients.  Patients in the North American long-term treatment trials totalling 1,100 will continue to be evaluated for both safety and clinical efficacy for at least five years.
Patients originally in the ERA trial will also be evaluated for at least five years for safety, continued clinical efficacy and prevention of structural damage by yearly radiographs.
600 patients in Europe will continue to be followed in their long-term treatment trial, and the 1,000 patient comorbidity trial previously discussed is ongoing.
A 2,000-patient registry in Europe will begin this year, and in JRA, another registry of 600 patients will be started this year, in addition to studying in a controlled fashion the combination of methotrexate plus Enbrel in the JRA population, and also a safety study in patients with systemic JRA.
We also have a large number of other programs looking at Enbrel in various diseases.  Our largest is a program that's ongoing, evaluating Enbrel in chronic heart failure.  The chronic heart failure trial, which will ultimately study 1,800 patients, has 800 patients enrolled at this point.

A DSMB meets regularly to monitor safety from this trial, and in all of these programs, over 2,000 patients are planned at this point to be studied.  We will add other indications as these indications become more formalized.  This information will add valuable data to our understanding of Enbrel and Enbrel's risk-benefit profile.
As for benefit, responses to Enbrel have occurred quite rapidly within the first weeks to months.  Shown here on the dotted blue line are the swollen joint counts for the 25 milligram group from the ERA trial.
The rapid reduction in swollen joints is similar to the response seen in the long-term treatment trial in patients with many years of rheumatoid arthritis, and our expectation is that this benefit will be maintained for the ERA patients as it has been in patients with longstanding disease.
Not only is the treatment benefit rapid, but it is also very consistent.  Shown here are the ACR20 results for all clinical trials.  On the left-hand column shows the percent of patients achieving an ACR20 response from the Enbrel 25 milligram group from the ERA trial, and to the right are the results from other controlled trials in DMARD-failing adults treated with Enbrel alone or with Enbrel plus methotrexate, and in JRA.  Large numbers of patients achieved ACR20 responses quite consistently.

Similar consistency is seen in the ACR50 responses with Enbrel treatment.  In all patients, regardless of duration of disease, extent of prior therapy or age, the results are remarkably consistent and show substantial benefit.
The continued benefits of Enbrel treatment are also outlined here, where the percent of patients achieving complete improvement, zero tender joints, zero swollen joints, and a zero or normal HAQ are displayed.
The ERA trial results at six and 12 months are on the left, and the responses in patients with longstanding DMARD-failing RA for up to two and a half years are on the right.
In both the ERA trial and in patients with longstanding disease, Enbrel's benefit is clearly maintained with longer treatment, and of note, patients receiving early intervention have more marked improvement in disability, underscoring the benefits of early aggressive treatment.
From the ERA trial, Dr. Finck has shown us that in this large very complete data set, that Enbrel was superior to methotrexate at six months by total Sharp score and at six months and one year by erosion score.

As mentioned by Dr. Finck, the second year of this trial is ongoing.  The data available to date from approximately two-thirds of patients continues to show maintenance of Enbrel's effect on markedly slowing the progression of disease as measured by the total Sharp score.
The last patients have just had their two-year films taken last month, and we expect that the full data set will be analyzed in the next one to two months.  Just as the clinical benefits of Enbrel are sustained, so are benefits on prevention of structural damage.
Here are results at two years on the erosion scores for the methotrexate and 25 milligram Enbrel groups.  The Enbrel group has very little change in the erosion score over two years.  Enbrel's effect on prevention of structural damage is sustained with continued treatment.
Seventy-five percent of Enbrel-treated patients had no progression in erosion score over the entire one year of the trial, compared to 57 percent of patients treated on methotrexate.  These were patients with quite active aggressive disease, predicted to progress at a very rapid rate.  Enbrel is clearly effective in preventing the structural damage associated with this chronic, debilitating disease.

In our initial presentation to this committee about a year and a half ago, we demonstrated that Enbrel had a very acceptable safety profile compared with placebo in patients with longstanding disease.  These same conclusions can now be extended to patients with shorter disease duration as compared to methotrexate.
In addition, Enbrel is safe in the elderly, in children, and with chronic use.
Enbrel therapy provides significant clinical benefits, a very rapid effect, substantial, consistent and sustained responses, and now the ERA trial has demonstrated that Enbrel treatment prevents structural damage.
Based on these comprehensive data shown today, we propose that the restriction that patients must fail other DMARDs before Enbrel is prescribed be removed, and that Enbrel be an option for physicians to choose as treatment for their patients who need initial DMARD therapy.
We suggest that the label for Enbrel be revised as follows:  "Enbrel is indicated for the reduction in signs and symptoms and the prevention of structural damage in patients with rheumatoid arthritis."
And we would now like to address any questions that you may have.
DR. ABRAMSON:  Thank you, Dr. Garrison.
I think what we'll do is hold questions for now and ask Dr. Siegel, Jeff Siegel of the FDA, to make a presentation.

DR. JEFFREY SIEGEL:  Good morning.
My name's Jeffrey Siegel.  I served as the clinical reviewer for this biologic license application.  The other people who were members of the review team are shown on this slide.
George Mills reviewed the x-rays.  Boguang Zhen was the biostatistician involved.  Susan Giuliani was the project manager.  Debra Bower was responsible for bioresearch monitoring.  David Green was the pharm-tox reviewer.  Lisa Rider served as consultant.
Currently in the package insert, the indication stated for Enbrel is as follows:  "Enbrel is indicated for reduction in signs and symptoms of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying antirheumatic drugs.  Enbrel can be used in combination with methotrexate in patients who do not respond adequately to methotrexate alone."
The current BLA seeks to extend the label in two ways.  First, it seeks to extend the indication to signs and symptoms in patients with early rheumatoid arthritis.  Second, it seeks a general claim of prevention of structural damage.

In my presentation today, I'll cover five areas.  First, I'll briefly cover the trial design.  Then I'll talk about certain modifications to the protocol which you've already heard somewhat about.  Then I'll talk about some background information on the radiographic endpoints.  Then I'll discuss the efficacy and then, finally, the safety results.
In its presentation, Immunex has already described to you in some detail the design.  I won't go over the design in detail.  Suffice it to say that this was a trial carried out in patients with early highly-active rheumatoid arthritis, patients at risk for x-ray progression.
It was originally designed as a superiority trial, and it involved a head-to-head comparison with an aggressive dose escalation regimen of methotrexate.
There were two co-primary endpoints for this trial.  The first was the clinical signs and symptoms endpoint, based on the ACRn area under the curve for the first six months, which has already been described to you.
The second co-primary endpoint is the radiographic endpoint, and as originally stated, this was based on an improvement in erosion scores at 12 months.

Because there were two co-primary endpoints, the statistical plan called for using the Hochberg method of assessing statistical significance.  Using this method, both endpoints must achieve statistical significance at the .05 level or, if either one does not, the other one must achieve statistical significance at the .025 level to be considered significant.
There were three additional endpoints, disability based on the Health Assessment Questionnaire or HAQ, health-related quality of life based on the SF36 questionnaire, and major clinical response.
Now I'll talk about the modifications to the protocol which took place while the trial was ongoing but before the trial was unblinded.
During the trial, the agency discussed with Immunex evidence from recent reports that many patients with early rheumatoid arthritis who were treated with methotrexate developed few, if any, erosions.  This, of course, raised the possibility that Enbrel may not show superiority in the trial simply because the active control arm had little x-ray progression.
The agency asked Immunex if it would wish to seek an approval based on non-inferiority in the event that the study did not demonstrate superiority to methotrexate.

Furthermore, the agency noted that the basis for a non-inferiority determination should be stated prospectively.
Immunex revised its analytic plan of the radiographic endpoint to a demonstration of non-inferiority.  At the same time, they changed the variable for the x-ray primary endpoint from erosion score to total Sharp score ‑‑ total Sharp score, of course, being a composite of the erosion score and a measure of joint-space narrowing.
The reason for the change in the primary variable was the data were unavailable to establish an effect size for erosion score, but there were data to determine an effect size for methotrexate for the total Sharp score.
I need to talk a little bit about non-inferiority trials and how they differ from the usual trials that we deal with, namely superiority trials.
In some clinical settings, efficacy may be demonstrated for a finding of non-inferiority in an active controlled trial but only certain very specific circumstances.
It's important that reproducible historical experience indicate that in a trial with a given design, that the active control arm will reliably give a result of a given size.

The principles used to evaluate a non-inferiority trial are shown on this slide.  First, based on several historical controlled studies, the effect of the active control is established, and that's shown here with the point estimate and the confidence interval.
Then a margin of the tolerated level of non-inferiority is stated, so that the study can be analyzed statistically.  This is set as generally at least 50 percent to be sure that the effect of the new therapy is at least better than non-treatment, and it may be set at levels greater than 50 percent in many cases, as was done in this trial.
But the point is that the margin is the level of non-inferiority which is to be excluded in the analysis.  In this case, non-inferiority level of 70 percent was set.
Now, to show you how the results are analyzed, look at the various points and confidence intervals shown below.  If the study agent has a greater effect than the active control, then the difference between the new drug and the active control will be negative, as shown here, and if the confidence intervals exclude zero, it can be concluded that the new drug is superior to the active control.

If the difference between the new treatment, the study agent, and the active control is less, then the point estimate will be closer to zero.  If, in this case, the confidence interval, the upper limit of the confidence interval, excludes the margin of non-inferiority, then it can be concluded that the new drug meets the non-inferiority standard.
In contrast, if the effect with the new drug is less than that with the active control, then the difference will be positive, and the confidence intervals may not exclude the stated tolerated margin of non-inferiority.
This slide shows a summary of this, about exactly what steps need to be taken to establish non-inferiority.  First, it's necessary to determine from historical trials that the active control reliably has an effect of at least a certain size.
Next, the planned trial design should be similar to that of prior trials, including the stage of disease, concomitant therapy endpoint and other important variables.

Then a non-inferiority margin is set, which is the margin to be excluded, smaller than the total active control effect, and, finally, it's critical to ensure appropriate trial conduct.  This is particularly important because if the effect size for the active control in the new study is lower than it had been in the historical controlled trials, one may conclude that there is equivalence between the two, but that may not actually reflect a therapeutic benefit of the new agent.
Immunex derived an effect size for the active control arm, namely the methotrexate arm, from several studies.  These included a multiyear observational study of recent onset rheumatoid arthritis published by Wolfe and Sharp in 1998, and a three-arm randomized controlled study which compared placebo, methotrexate and leflunomide.
I need to point out that the first study had neither an untreated arm nor a methotrexate arm.  So it cannot reliably estimate the effect size for the current trial.
I also must point out that the second study used a different patient population than the current study and used a significantly-different methotrexate dosing regimen.
The assumptions for the non-inferiority analysis in this trial were as follows.  It was assumed that the mean yearly progression rate was approximately six units per year based on the total Sharp score in untreated patients.

It assumed the mean progression rate on methotrexate of approximately two units per year, and the margin of non-inferiority to be excluded was 70 percent, namely the Enbrel arm should preserve 70 percent of the methotrexate benefit, meaning ruling out a difference of 1.2 units per year, and Immunex in their presentation went over the calculation of 1.2.
I need to point out that there are some limits to the non-inferiority trial design.  First, historical controls in this case do not provide reproducible data to establish an effect size for the methotrexate arm.
The effect size for methotrexate is based on different patient populations from the current study.  For example, the patients in this study had a shorter duration of disease and, as I mentioned before, a different methotrexate arm was used.
So in conclusion, because it's impossible to formally establish a minimal effect size, non-inferiority cannot per se be taken as evidence of efficacy.  Therefore, interpretation of the trial must be based on the totality of the data, including additional analyses.

In this slide is shown the FDA analysis of the disposition of subjects.  You can see there are approximately just greater than 200 patients randomized, between 207 and 217 of these patients received at least one dose, and this constitutes the modified intent-to-treat population.  No bias was introduced in the people who were randomized but not treated, and, finally, greater than 90 percent of all subjects completed a full 12 months of evaluations.
I will not be describing the baseline demographics since these were covered in detail by Immunex, but we have no major differences with the data presented by Immunex.
I will just mention that we saw no important imbalances in the level of disease activity or in the baseline demographics.
I'll also point out that the prespecified stratification variable of duration of disease had patients distributed with three-quarters in the shorter duration of disease, up to one and a half years, and a quarter of the subjects were in the longer duration of disease, one and a half years to three years, and there were no imbalances, and the patients, as mentioned, had highly-active disease with many active joints.

The radiographic procedures are described on this slide.  Hand and foot films, as you've heard, were obtained at baseline, at six and 12 months.  The radiographics were read by six trained readers in blinded random order.  The correlation coefficient between readers was high, as measured at 0.8.
The agency review of the radiographs showed that the data were complete and of uniformly good quality, and the readings were generally consistent and accurate.
We will not be discussing the reading of the radiographs in any more detail, but if you have any questions, George Mills is here to help answer them.
Now, the primary endpoint analysis specified a mixed model, which estimates a mean annual x-ray progression rate using the zero-, six- and 12-month films as well as baseline covariates.
As I mentioned before, the non-inferiority analysis was designed to exclude a margin of inferiority of 1.2 units per year or greater in the total Sharp score, and the protocol specified a sequential test of first non-inferiority, and then, if that had been demonstrated, then superiority.
The point estimates and 95 percent two-sided confidence intervals are shown on this slide.  The methotrexate arm had a rate of radiographic progression of 1.33 units per year based on the total Sharp score.  The Enbrel 25 milligram arm, the increase in the total Sharp score was less at 0.8.

The difference in the mean progression rate is to determine whether non-inferiority had been demonstrated or shown on this slide.  Above is shown the two-sided 90 percent confidence intervals of the difference between 25 milligrams and methotrexate.
As mentioned before, the difference is minus 0.5, and the upper limit of the 90 percent confidence interval is 0.16.
Using the more stringent two-sided 95 percent confidence interval, shown below, the upper limit of the confidence interval excludes a margin of inferiority of 0.29.
Thus, the test of non-inferiority in this study excluded a margin of greater than 1.2 units per year, with a maximum outer bound of actually less than that, of 0.29.
A test of superiority of Enbrel 25 milligrams to methotrexate, however, does not reach the statistical significance using this analysis with a P value of .21.
Because of the limitations I mentioned before of a non-inferiority analysis in this setting, we must look at additional data to assess efficacy, especially secondary endpoints assessing superiority of Enbrel to the active control arm.

I'll be presenting to you the prespecified stratification by disease duration, using the prespecified radiographic endpoint, and I'll also be discussing the components of the total Sharp score and the erosion scores and joint-space narrowing.  Then I'll discuss differences in the rate of progression in the first six months of the trial compared to the second six months, and, finally, I'll discuss with you the subjects who had no radiographic progression.
Shown here is the rate of radiographic progression using the total Sharp score and the originally prespecified mean mixed model for the two prespecified stratification groups, patients with disease duration of less than 18 months and 18 to 36 months.
There was little difference between Enbrel 25 and methotrexate in the group with disease duration of less than 18 months.  In the group with disease duration greater than 18 months, the rate of radiographic progression was less in the Enbrel arm, Enbrel 25 arm than the methotrexate arm, and the nominal P value for the pairwise comparison here is .03.

As I mentioned before, the total Sharp score is a combination of erosion scores and joint-space narrowing.  When the erosion scores are considered separately in Enbrel versus methotrexate, the point estimate for Enbrel was .4 compared to 0.9 for methotrexate, and the P value was .047.
Again, this is using the mixed model for an estimate of the difference between the means.
However, no difference at all was seen in the degree of joint-space narrowing.  This estimate was 0.4 units per year for both groups, and I should mention to you that the comparison of the erosion scores was the originally-specified primary endpoint for the trial before the analysis was modified.
Next, the agency wanted to look at whether the rate of x-ray progression differed at the beginning of the trial compared to the second half of the trial.  When we examined the data, we saw that there were substantial skewing of the data which actually violated the assumptions of the mixed model.
What I'm talking about here is that if you look at the rate of x-ray progression, most of the patients had very little x-ray progression, approximately zero.  However, there was a small subset who had substantially greater degrees of x-ray progression, hence the skewing.
Therefore, the agency believed that a nonparametric test for differences was more appropriate than using a test of means which requires an assumption of normality.

For its analysis, the agency used the raw data from the last observation and the first observation and adjusted for the time interval.
First, I'll show you the 12-month change in erosion scores using this new method of analysis.  The point estimate for Enbrel 25 milligrams was lower than that for methotrexate, and here the P value was .001.  Again, the differences in the P value here compared to the ones I showed you before have to do with the different method of analysis, the nonparametric analysis, compared to the analysis of comparison of means.
Next, we looked at changes over time.  First, I'll show you the data on erosions.  You can see three things from this figure.  First, Enbrel 25 milligrams shows less of an increase in erosion score in both periods, the zero to six months and the six to 12 months.
However, the differences between arms are more marked in the first period, even though the six-month rate of x-ray progression in the Enbrel arm is less in the last six months of the trial compared to the first six months.
The reason that the differences between the two arms is greater in the first six months is that there is considerably less x-ray progression in the methotrexate arm in the second part of the study.

The differences between the two arms are statistically significant in the first part of the study with a P value of .0006, and they were not significant in the second half of the study.
When this new method of analysis was applied to the total Sharp score for both periods as well as the total 12 months of the trial, similar results were seen.  The point estimate for Enbrel 25 was lower for the zero- to six-month period and for the six- to 12-month period compared to methotrexate.
However, the differences between treatment arms were more marked in the first period, again primarily because the rate of progression for the methotrexate arm was considerably less in the second portion of the trial.  Again, the differences were statistically significant for the first part but not for the second half of the trial.
Next, we looked at the proportion of patients who showed no radiographic progression, and I need to tell you here that the way we defined no radiographic progression was these were patients who had a change in the Sharp score of zero or less over the course of the trial.

You can see that the proportion of patients who had no radiographic progression during the 12 months of the trial in the Enbrel 25 milligram arm was higher than in the methotrexate arm, and this was statistically significant, a P value of .004.  The differences in rate of progression using the total Sharp score were not statistically significant.
We also looked at subsets of patients for the degree of x-ray progression over the 12-month period, looking at the erosion scores.  No important differences were seen based on age, ethnicity, gender or duration of disease.
In addition, we assessed effects on radiographic progression based on baseline prognostic variables, and I'll show you data on patients with increased sed rate and patients with erosions at baseline.
In a group with elevated sed rate at baseline, and this is defined as a sed rate greater than 30 millimeters per hour, the increase in erosion score was less in the Enbrel arm compared to methotrexate in both the patients with elevated sed rate and those who had lower degrees in elevation of sed rate.
When patients were subdivided based on whether they had two erosions on baseline x-rays or less than two erosions, the increase in erosions was less in the Enbrel 25 milligram arm compared to methotrexate in both groups.

So in conclusion, although the trial excluded the prespecified margin for non-inferiority, there are limitations to the interpretation of these data.
Meaningful secondary endpoints did show a difference compared to the active control.  For example, in erosion scores in the six-month data and in the proportion of patients who had no radiographic progression during the trial.
You've seen the clinical endpoint presented already, and I'm not going to be talking about this in detail.  We have no major disagreements with Immunex's interpretation of the data.  I would just say that the primary endpoint of six-month area under the curve for the ACRn showed a statistically-significant difference between the Enbrel 25 milligram arm and methotrexate.
However, the landmark analysis of the proportion of subjects achieving an ACR20 and ACR50 at six and 12 months was not statistically significant.
Next, I'll show you data on the three other clinical endpoints, starting with disability.
The different treatment arms were balanced with the respect to degree of disability at baseline, and there were decreases in the level of disability as measured by changes in the HAQ in all treatment arms.  The differences between arms was not statistically significant.

Quality of life was assessed using the SF36 Questionnaire.  This was analyzed based on two summary scores, the physical summary score and the mental health summary score.
At baseline, the scores on the physical summary score were the same across treatment arms, and these were approximately two standard deviations below U.S. norms.  The physical summary score improved in all treatment arms at 12 months.  However, there was less improvement in the 10 milligram arm compared to the Enbrel 25 milligram arm.
The mental health summary score was similar to U.S. norms at baseline in all treatment arms, and these scores were higher in all treatment arms at 12 months, and the differences were not statistically significant.
Major clinical response was also measured.  The major clinical response was introduced in the Rheumatoid Arthritis Guidance Document.  The rationale for choosing a criterion of the ACR70 is shown here.  The ACR70 represents a degree of improvement which is rarely seen in the placebo arms of controlled studies of disease-modifying agents.

For example, in one study of methotrexate versus placebo, no patients met an ACR70, and another study of cyclosporine A versus placebo in the context of background methotrexate, none of the subjects achieved an ACR70.
A major clinical response is defined as six consecutive months of an ACR70 with no measurement falling below an ACR70 response.
As you can see in this figure, a major clinical response was seen in some subjects in all three arms of the study.  No statistically-significant difference was seen between treatment arms.
I'm going to be turning to the safety portion of the presentation.  First, I'll cover serious adverse events and deaths, patients who dropped out for adverse events, other adverse events, long-term safety, and, finally, the post-marketing reports.
Two deaths were observed during the 12-month study period.  One of these was a subject in the 10 milligram Enbrel arm.  The patient died of lung cancer approximately two months into the study.
The other subject was in the 25 milligram Enbrel arm, and this patient died of non-infectious complications of an aortic aneurysm repair.

The serious adverse events seen in the trial are shown in this slide, and I'll go through each of the first categories in more detail in the coming slides.  The most common serious adverse events seen were infections, malignancies, thromboembolic events, and interstitial pneumonitis, and acute MI.  There were no readily-apparent differences in the overall serious adverse event rates.
In terms of the infectious serious adverse events, pneumonia was seen in three patients in the methotrexate arm, one in the 10 milligram Enbrel, and three in the Enbrel 25 milligram arm, and the other infectious serious events are shown here.
You've heard about the malignancies from the Immunex presentation.  Three malignancies were seen in the Enbrel 25 milligram arm, two in the Enbrel 10 milligram arm, and one during the initial 12 months of the trial in the methotrexate arm.  However, early at the beginning of the second year, an additional methotrexate patient developed bladder cancer.
The thrombotic serious adverse events are shown on this slide.  Four events occurred, all of them in the two Enbrel arms.  Two events were seen in the Enbrel 25 milligram arm.  Both of these were deep vein thrombosis. One subject had a DVT following three months on study.  The risk factor for this patient was taking oral contraceptive pills.  Another subject developed a deep vein thrombosis one week into the study.  They had a risk factor of Baker's cyst.

In the 10 milligram arm, there were two thromboembolic events seen, one DVT two weeks into the study.  This patient had no risk factors, and, finally, one patient had a massive pulmonary embolus associated with the diagnosis of lung cancer.
Thromboembolic events were not seen in the previous randomized clinical trials.  However, thromboembolic events have been reported post-marketing.
This table shows the number of subjects who did not complete 52 weeks of dosing.  As you can see, a higher number of patients dropped out because of adverse events in the methotrexate arm compared to the Enbrel arm, and the other reasons for dropping out are shown here.  Similar numbers dropped out for lack of efficacy in the methotrexate arm and the Enbrel arm, Enbrel 25 milligram arm.
The adverse events leading to drop-out are shown here.  One category is a set of adverse events which are associated with methotrexate use, including alopecia, oral and nasal ulcers and vomiting.  Nine subjects dropped out in the methotrexate arm for these reasons.  None in the two Enbrel arms.

The numbers for patients dropping out due to infection are shown here, 3, 3 and 1, malignancy.  Methotrexate pneumonitis, there were three patients in the methotrexate arm, and none in the Enbrel arms, and this diagnosis was reached before unblinding of the patients.
Regarding laboratory values, the agency saw no significant patterns of abnormalities associated with the use of Enbrel.
In terms of other adverse events, overall, the adverse event rate was somewhat higher in the methotrexate arm compared to Enbrel.  95 percent compared to 90 percent.  The rate of injection site reactions, the rate of bleeding at the injection site, were higher in the Enbrel arm than methotrexate, and these incidence rates were similar to that seen in other trials.  No other pattern of increased adverse events were observed with Enbrel.
I'll turn now to a discussion of long-term safety.  In previous controlled studies, the only adverse event that was seen at a clearly higher rate was the rate of injection site reactions.  However, in the long-term extension studies, some serious infections were seen, and along with the fact that the mechanism of action of Enbrel, namely blocking TNF, may impair an important arm of host offenses, it's very important to look at a number of things which are related to the immune system, including serious infections, over time.

At the time of the initial approval of Enbrel, Immunex agreed to do a Phase IV safety study, Study 16.0018.  This is a three-year open-label study of 1,200 subjects receiving Enbrel, and most of these subjects are patients who were enrolled following completion of other clinical trials.
At the time of this BLA submission, 638 subjects were enrolled in the study, and the goals of this study are to assess long-term safety, including the mortality rate, the incidence of malignancy and autoimmune disease, compared to historical control databases.
The long-term safety data that I will be discussing with you includes 782 patients overall.  Many of these are in the 16.0018 study but some of them are not yet in that study, although they may roll over into this study at a later time.
There are 71 subjects who have been observed for two to three years on Enbrel, and 502 subjects who have been treated for a period of one to two years.
Overall, the adverse event rate showed no adverse events occurring with an incidence higher in the long-term safety study than was seen in the controlled studies, and no adverse event was seen with a pattern of increased incidence with longer duration of exposure.

Overall, the types of infections that were seen in the long-term safety studies were similar to that seen in the controlled studies, and no infection was seen with a higher incidence with longer duration of treatment.
Serious infections are defined here as infections associated with hospitalization or with use of IV antibiotics.  These occurred at a rate of 5.5 cases per 100 patient-years, and the type of infections that were seen were those expected for patients with rheumatoid arthritis in this age group.  No increase in the rate of serious infections was observed with longer durations of exposure to Enbrel.
In the six months following approval of Enbrel in November of 1998, cases of serious infection were reported on Enbrel to the agency.  Of these cases, a number of deaths occurred, approximately six cases of an estimated 25,000 patients who had been prescribed Enbrel.
A number of these cases occurred contemporaneously with beginning Enbrel, and review of the data indicated a pattern of potential risk factors, many of the patients having risk factors which may predispose to infection.

The agency felt that it was difficult to interpret these data.  Of course, the data cannot be dismissed.  However, it's difficult in view of the risk factors many of these patients had to attribute these serious infections with certainty to use of Enbrel.  Therefore, it was thought important to do a number of things, including doing further studies.
So as a result of the review of these data, Immunex issued a Dear Doctor letter with a warning about the use of Enbrel in patients with potential risk factors for infection, namely patients with diabetes, active infections or with a history of chronic infections.
In addition, the agency asked Immunex to initiate a clinical trial to assess the degree of risk for patients who might be at risk of serious infections.
Again, as I said before, since the clinical trials excluded patients at higher risk for infection, it is unknown whether Enbrel may predispose certain subgroups of patients to serious infections since many of these patient groups may not have been studied previously.
Study design is shown here.  It's a 1,000-patient randomized four-month study, double-blinded placebo-controlled study, of Enbrel, and inclusion criteria for the trial is rheumatoid arthritis by ARA criteria, and one of these four potential risk factors for increased infection.

First, diabetes requiring insulin or oral hypoglycemic agents, chronic pulmonary disease, such as COPD or asthma, a history of pneumonia in the past year or a history of recurrent bronchitis, sinusitis or urinary tract infection with at least two episodes in the past year.
Immunex submitted the following sample size calculations.  These sample size calculations assume an event rate of 10 percent in the control arm, and these are estimates since we don't know quite what the event rate will be in this patient population.
Based on these assumptions, the study has a 94 percent power to exclude a twofold relative risk for Enbrel using the 95 percent confidence interval.  However, the power of the study would be lower if the event rate were actually less than 10 percent.
So finally, in conclusion, regarding the x-ray data, the 95 percent confidence interval excluded an inferiority of Enbrel to the active control of 1.2 units per year.  In addition, secondary endpoints suggested superiority of Enbrel in preventing erosions.

The primary signs and symptoms endpoint, the ACRn area under the curve, showed superiority for Enbrel 25 milligrams over the active control.  However, the landmark 6- and 12-month ACR20 and 50 responses were higher for Enbrel 25 milligrams, but the differences were not statistically significant.
And in summary of the safety data, the overall adverse event rate and the serious adverse event rate were not measured to be higher with Enbrel than with methotrexate.
Thank you.
DR. ABRAMSON:  Thank you, Dr. Siegel.
Perhaps if you don't mind staying there, and if a representative from the sponsor could come to the podium, what I'd like to do now is just have questions from the committee, but for this period really first restrict our questions to clarification of the data and the presentations as best we can.
So would someone like to comment?  Janet?
DR. ELASHOFF:  On Slide C-26, it said that an inclusion criteria was that people had to have at least three erosions, but in Table 4.2D on page 43 of the briefing document, it showed a range of Sharp scores for erosions down to zero.
DR. GARRISON:  Dr. Finck will answer that question.

DR. FINCK:  They only had to show erosions on baseline x-rays if they were negative for rheumatoid factor at screening.  So a person who did have a positive rheumatoid factor was not required to have erosions.
DR. ABRAMSON:  Dr. Harris?
DR. HARRIS:  Dr. Siegel, can you remind me about the definition from the FDA's prevention of erosions versus the slowing erosions?  Are there some guidelines with respect to that?
DR. JEFFREY SIEGEL:  Yes.  I hadn't prepared for this, so I'll try my best to answer the question.
In the Rheumatoid Arthritis Guidance Document for making a claim of prevention of structural damage, several different ways of doing it were stated.
One is to show a difference between study drug and control in the rate of radiographic progression, but the other one, as you point out, was to show a difference in the proportion of patients who have new erosions, and I don't think it was spelled out exactly what this means.
One way that this could be shown is to show an increase in the proportion of patients who have no new erosions whatsoever in their survey of joints.
DR. GARRISON:  Jeff, we do have a slide on that that quotes your document.

DR. ABRAMSON:  No.  I'd prefer that we not ‑‑ just crisp answers right now.
Dr. Brandt?
DR. BRANDT:  Yes.  A question, please, with regard to malignancy, and I followed the incidence data that you presented.
Have there in fact been patients who were started on Enbrel who had a prior history of malignancy, and have all of the patients who were diagnosed with malignancy in the trials or post-marketing had Enbrel discontinued or have some patients with malignancy been continued on Enbrel, and what's happened?
DR. GARRISON:  in the clinical trials, patients were excluded from entering the clinical trials if they had had a recent history of malignancy, but they were included if they had had a prior malignancy quite distant.  So there were some patients in our original clinical trials who had treated breast cancer, et cetera.
We have had some patients in our trials who have elected to remain on Enbrel after their malignancy has been treated.
DR. BRANDT:  Any comments on those?  Any information on those?

DR. GARRISON:  For these patients, it was a personal decision between their physician and the patients.  They felt that their quality of life was far better on Enbrel therapy, and after receiving adequate treatment elected to stay on Enbrel, and at this point, I don't have any anecdotes on exactly how those patients are doing.
DR. ABRAMSON:  I have one question regarding the rate of progression, the predicted rate of progression of placebo-treated patients.
The study that you referred to that modified the protocol was, I believe, the Rich study ‑‑ is that correct? ‑‑ that was in our document that showed methotrexate prevented progression compared to placebo?  It was a Journal of Rheumatology article that was referred to.
The question I had in that group, what was the total Sharp score progression in the placebo that methotrexate did better than ‑‑ and I've forgotten the Arava database.  I recall there was a placebo group in there.
So are you hitting this five- to six-unit per year in placebo in those two studies as opposed to the Wolfe study?
DR. JEFFREY SIEGEL:  In the Arava studies that were presented at the time of licensure of Arava, there were two placebo arms in two different trials.

In one of them, I believe the rate of progression was estimated as either 5.5 or 6 units per year.  In the other study, the placebo arm was allowed to cross over into either methotrexate or leflunomide after a certain period of time.  So this was not a purely untreated group, and their rate of progression was 2 units per year, but we don't know how long they were untreated for.
DR. ABRAMSON:  Dr. Felson?
DR. FELSON:  I have a couple of questions.
One relates to how the decision-making occurred in terms of changing the radiographic endpoint.  The way you presented it, Jeff, was that you really initiated this discussion, and it sounded like the discussion was initiated pretty far into the trial, at a point when the company might have been privy to the actual rates they were seeing, and I wondered if you could comment on that, because that would have been a post-op change based on preliminary data, even though it turned out they probably should have held to the same primary endpoint that they started with.
The other question I have relates, I think, to the deep venous thrombosis pulmonary embolism issue, and you commented that in the open-label follow-up experience, there are a number of cases of this.

I guess I would wonder, as the observed and expected rates for cancers were presented here, whether there are any data on the observed versus expected rates of DVT and pulmonary embolism that are available for this, and what they are, and also whether there's a biological mechanism that we can understand that might cause increased coagulation here.
DR. JEFFREY SIEGEL:  Okay.  You've asked a number of questions.  I hope I have them all down.
In terms of the decision about changing the analysis of the radiographic endpoint, it is true, as you stated, that the agency initiated these discussions, and the reason was that the agency was concerned that when the trial was unblinded, that the active control arm, as I mentioned, might show so little radiographic progression, and we wanted to make sure that if Immunex was planning to use an analysis of non-inferiority, that that should be stated prospectively.
In terms of when that was decided, it's my recollection that that was quite early during the trial, although I can't remember exactly how many months in.
I'll need to ask Immunex to comment on the degree to which they were privy to the unblinded x-ray data.

DR. FINCK:  We initiated discussions between the agency and Immunex probably about ‑‑ my best recollection is that it occurred about a year into the trial, when this data became available, and we were actually not privy at all to any x-ray results at that time.
The readers started reading after the patients had been in the study for about a year.  They couldn't read until they had all three time points for a patient, and so although the readers started reading, Immunex was not privy to any kind of database until really just before we unblinded the trial when we started to receive data from bioimaging, but we had no ability to even look at their baseline scores at the time that we started talking about changing the analysis plan.
DR. JEFFREY SIEGEL:  If that was an adequate answer to that question, I'll go on to the DVT.
I don't have incidence data on deep vein thrombosis and pulmonary embolus.  Perhaps Immunex can make some more comments on that based on the historical controlled databases they've been looking at.

However, in terms of a biologic mechanism, these cases of thromboembolic events came as a surprise.  They came initially on review of the post-marketing data that a small number of patients were reported who had deep vein thrombosis a relatively short time following initiation of Enbrel.
Now, of course, when you're talking about 25,000 or 50,000 patients, that could have, of course, occur by chance, but it was noted, and then when it was looked to see whether that was part of this trial as well, we found the results shown here.
In terms of biologic mechanism, none has been proposed.  We would be very interested in any comments from the panel about what parameters they think might be helpful to clarify this.
DR. GARRISON:  If we could have the slide back up?
DR. ABRAMSON:  I think it might be worth looking at ‑‑ urinary prostacyclin could be of interest here.
DR. GARRISON:  We have done a little bit of research here, looking at the rates of DVT and pulmonary emboli in the general population and comparing that to what we've seen in our post-marketing safety surveillance program at this point.  It's, of course, spontaneous adverse event-reporting data.
DR. ABRAMSON:  First, Dr. Simon, then Dr. Pucino.

DR. SIMON:  I have several questions, two of which relate to safety, and one of which relates to efficacy.
The first question is, I was struck by the LFT abnormalities that were noted in the Enbrel-treated groups when previously, at a previous presentation, there was little evidence of LFT abnormalities.
The explanation offered that these patients were on non-steroidal anti-inflammatory drugs is an intriguing one.  However, I presume they were on those drugs when they started the trial, and there must have been some noted baseline laboratory tests, whether they were elevated or not.  So I assume that this was a crude elevation of LFT abnormalities which seems to be quite significant, although it's always minimized when you compare against methotrexate which is certainly more.  I'm more interested in the biologic effect of what LFT abnormalities would be caused by in this circumstance.
My second question about safety is related to the lack of any evidence that you've presented about the generation of autoimmunity, and particularly as it relates to the DVT question.

Previously, there had been some evidence that there were spontaneous antibodies to various different things.  You mentioned nothing in this data set about either measuring them or not, and there is a lot of perhaps rumor in the community, in the rheumatology community, about the incidence of anticardiolipin antibodies, antinuclear antibodies and anti-DNA antibodies, and I wonder if you can comment on that, and then, after that, if I can ask the efficacy question.
DR. ABRAMSON:  Okay.  So there are two questions here at least.  One is what do people think about the twofold elevations of the transonomisis in about the 20 percent of the patients, and the other is anticardiolipin antibody profiles, or antinuclear antibody profiles in these patients.
DR. GARRISON:  We can put this slide up.  This just is one that you saw in the presentation, which reviews the grade of laboratory abnormalities.  These patients did have multiple laboratory tests over the entire year.  This is the worst value that was ever observed, and these were primarily transient LFT abnormalities.
DR. ABRAMSON:  And any new data on the auto-antibodies?
DR. GARRISON:  The autoantibodies, Barbara.

DR. SILVER:  In this trial, we not only measured autoantibodies, including antidouble-stranded DNA antibodies and anticardiolipin antibodies, at baseline, six months and 12 months, we did see fluctuations in the auto-antibodies in all of the autoantibodies, but we did not see sustained elevations over multiple time period when we measured these.
The three patients who had DVT did not have anticardiolipin antibody present before or after those events.
We also in this trial looked at an autoimmune features checklist.  It was special for this protocol.  We were trying to evaluate whether there were treatment-emergent new autoimmune features, and if I could have that slide, please, the autoimmune features checklist did specifically try to look at signs and symptoms of lupus or overlaps, and there was no difference between the treatment groups, any of the treatment groups, with respect to the new occurrence of autoantibody feature or new autoimmune features, except for oral ulcers.
If we took out the term "oral ulcers," which, of course, are more frequent on patients with methotrexate, there was absolutely no difference, and there were no treatment-emergent autoimmune features.
DR. ABRAMSON:  So just a clarification.

In the course of all the testing, the percentage of patients who ever had a positive auto-antibody comes into what range?
DR. FINCK:  It's hard when you say any auto-antibody, but ‑‑
DR. ABRAMSON:  Let's say anti-DNA antibodies.
DR. FINCK:  Yes.  Could I show this slide?
This is a baseline.  It was not at any time, but as you can see, there were patients, about 1.5 to 2 percent of patients, who were antidouble-stranded DNA positive at baseline, and although the tests varied over each time we tested them, there were never times when patients had very high levels of the antidouble-stranded DNA.  Most of the times, these were transient, and again you can see that there's variability, a little bit higher and a little bit lower, in the methotrexate groups but really not of very much significance.
DR. ABRAMSON:  Dr. Pucino, and then Dr. Grant.
DR. PUCINO:  Along the same line, in the open-label long-term follow-up studies, do we know anything more about autoimmune diseases occurring on Enbrel, and, also, what is the percentage of positive antibodies in that population?

DR. GARRISON:  In the open-label long-term treatment trials, we've seen no cases of SLE.  We have banked serum from these patients, and we have not retested them for the development of autoantibodies.
We did all of that very careful work using the controlled trials, looking specifically at the placebo groups, here with the methotrexate group, and we have that sera available in case there does appear to be developing clinical symptoms, but at this point, there's no clinical symptomatology at all and no cases of SLE.
DR. ABRAMSON:  We'll have one question from Dr. Simon, and then a final comment from Dr. Elashoff.

DR. SIMON:  I just found it interesting that the ACR20, even the pictured area under the curve, and as compared to the ACRn, I was wondering if someone could explain to me exactly what was done.  By doing the ACRn, why did it change the numbers the way it did, in that I understand the ACRn minimizes the various different measurements, and thus one can't do a cut on these various different measurements as you can with the traditional ACR area under the curve, and thus it might change the data in a spin way, thus perhaps giving us a better improvement than would be measured with the more traditional measurement, and since much of these data are turning on this particular measurement of the ACRn, a particular measurement that's not entirely well accepted by everyone in the rheumatologic community, and since I'm not a statistician, I was wondering if somebody with more experience in this area could comment on that.
DR. ABRAMSON:  Right.  May I suggest that it's an important issue?  It actually is one of our major questions in the discussion period.  So I think we'll get into that in a lot of detail.
Dr. Elashoff is going to address some statistical issues that she thinks have an impact.
So thank you very much, and we'll have this presentation here.
DR. ELASHOFF:  Is there a way to have the microphone and to point at my slides at the same time?
PARTICIPANT:  Use the wireless microphone.
DR. ELASHOFF:  Okay.  Well, I'll just go ahead.
The comments I want to make are not so much ones that I think influence how we regard the results of this particular trial but I think, to the extent that it's setting policy for what we might do in future, this kind of definition of superiority and of not inferior can lead to extremely inconsistent kinds of results.

The top line there shows that if a benefit of new drug is positive or to the right, so that if that benefit as compared to the standard, the confidence interval excludes zero, then the drug would be called superior, and it doesn't have to exclude it by anything more than a fraction.
If you define, like in this case, a non-inferior cut point which is far away from zero, like 70 percent of the effect, you could have a confidence interval that satisfies the not-inferior criteria but still would be markedly statistically inferior, and so I object to this kind of definition of using superiority one way and not inferior the other.
The second comment I wanted to make is there were talk about guessing what the progression rate would be for placebo or methotrexate, but there's no talk about where the 70 percent rule came from.  Most equivalence or bioequivalence is done with 80 percent, and even then, I think those are frequently broader than one would like to have.
Also in this particular trial, and I guess mainly for historical reasons, we're in the situation of looking for non-inferiority for the sum of two scores, erosions plus joint-space narrowing, and looking for superiority on one of those two.  So they're not really two different measurements.  One is the sum of two measurements, and the other is that particular measurement.

So I would like to say that in terms of setting a precedent, I wouldn't like to see these particular definitions set a precedent.
Thank you.
DR. ABRAMSON:  Thank you.
Yes?
DR. JAY SIEGEL:  Just as a matter of clarification, I think many of us in the agency would not like to see this set a precedent, and I thank you for your comments.
I do want to comment a little bit on this issue you raised of non-inferiority.  It is in fact a poor choice of terms.  It is in the International Harmonization literature and in the statistical literature, and we use it.  Some of us prefer not to, but in that an inferior drug can meet a non-inferiority standard, but it's important to note that there are two different goals of an equivalence trial or a non-inferiority trial, and they differ importantly from a regulatory perspective.

One goal is to prove that drugs are interchangeable, that the new drug is as good as, as useful as, the other one, and for that you may want to set a very high standard that it retains at least 70 percent, 80 percent, whatever number you choose, there's no magic well-accepted number, and in thrombolytics for mortality trials, 50 percent has been used.
But that involves a lot of pragmatic decisions as well as clinical decisions, but the other reason you can use a non-inferiority design is simply to prove that the new drug is effective, and by law and regulation, we do not require ‑‑ and I'm sure many members of this committee have observed this in the NSAIDs ‑‑ you do not necessarily require a new drug to be as good or almost as good as other drugs.  What you require of a new drug is that it be effective.  So arguably, as long as you prove that you retain some of the benefit of another drug, even though you may be inferior, as Dr. Elashoff showed, you may well be effective, and we would not use a study of this design to allow a claim of equivalence or non-inferiority just to support a claim of efficacy.  So that's a distinction I want to raise there.
I think one can argue a lot about whether 70 or 80 percent or 50 percent or what's the right number.  I actually have more concerns about the number that we took that percent of before, but just so you understand, though, that we're not so much talking about using this to establish that it's non-inferior but, rather, to establish that it has activity, that it has efficacy.

DR. ABRAMSON:  Thank you very much.
I think that's a good point to end this morning's session on.
We'll take a 15-minute break and reconvene at about 10:30.
(Recess.)
DR. ABRAMSON:  We're now going to begin the open public hearing, and first hear from Judith Levinson.
MS. LEVINSON:  Good morning, Mr. Chairman and Members of the Food and Drug Administration advisory committee.
My name is Judith Levinson, and I appreciate this opportunity to address you today.  Not being a professional speaker, please excuse me if I appear somewhat nervous.
I am 55 years old and have crippling rheumatoid arthritis for the past 15 years.  I have undergone six surgeries on my feet, resulting in one inch bone loss to the length of each foot.  Both my hands have also undergone six surgeries, including knuckle replacements, tendon transfers to my thumbs.  My wrist bones were removed, and six inch rods were inserted making them stationary.

I'm sharing this information with you to give you background on my condition, and to tell you how Enbrel has given me back a quality of life that I did not think ever would be possible for me again.
I am a wife, a mother, a daughter, and a sister, a published poet, and have designed and worked with stained glass.  My artisan name is Wounded Dove.  Although rheumatoid arthritis has affected my physical condition, it has not taken control of my creative spirit.
If Enbrel had been available when I was first diagnosed, perhaps I would have been spared some or all the painful surgeries I have endured, and I would not have lost years of an active and productive life.
For the past 15 years, I have had to overcome enormous obstacles, becoming so disabled that I had to retire on disability in 1991.  I was forced to give up many activities that I loved because of constant pain and swelling in my joints.
I was trapped in a body that could no longer bike-ride, ice-skate, play tennis or horseback ride.  Holding a fork or using a knife to cut my food was almost impossible.  Every day was a bad hair day because I was unable to raise my arms to comb my hair.

I needed help dressing because I could not pull a top over my head or button a button.  These were the darkest days for me.  I feared I would ultimately be confined to a wheelchair.
Rheumatoid arthritis attacks joints causing constant pain and swelling that can result in crippling and disfigurement.  My hands are so misshapen, I am often stopped by total strangers and asked what is wrong with them.
A little over a year ago, my life was dramatically changed for the better.  On January 7th, 1999, I came home from an appointment with Dr. Howard Levine, who is affiliated with the Center for Rheumatic Disease and has been in practice for over 30 years and for whom I have great respect and trust.
That day will forever be stamped in my memory because that is the day my life was returned to me.  Enbrel became my miracle drug.  I started my injections that day and to date, I have given myself a 132 shots.  Enbrel can now prevent future destruction of my joints, although nothing can repair the damage that has already occurred.
Over the years, I have tried a gamut of drugs, many of which caused severe side effects, including fatigue, swollen joints, incredible pain and extreme depression.

Since I started injecting Enbrel, my strength and energy level has been restored.  No side effects, only positive results.
I'm asking you to make Enbrel available to all who suffer from this debilitating and crippling disease, whether mild or severe.  Do not let another person, young or old, suffer unnecessarily.  You have the power to see that this does not have to happen to future generations by approving Enbrel for people facing a diagnosis of active rheumatoid arthritis.
I also want to take this opportunity to thank the Immunex Corporation family of scientists and employees who have spent the last 10 years researching and developing drugs like Enbrel.
You are my champions in the fight for a disease-free world.  There is a light now at the end of a very dark tunnel for me and for many other people.  Your dedication to the science of providing drugs for medical treatment benefits all mankind and allows people to have a better quality of life.
Also, I'd like to thank the committee for approving Enbrel and changing lives of thousands of patients like myself.
Before Enbrel entered my life, I wrote the following poem, called "Wounded Dove's Final Song," which has been published, and I would like to share it with you.

"Many seasons and sunrise have come to pass, my soul grows tired and cold lasts.  My song voice weak and low, I can no longer go this alone.  The other songbirds come and watch as I try to stay upon my perch in the tree, which can no longer shield me from past injuries.
"When the final day has come, I pray some kind soul will find and bury me under my favorite poplar tree, so I can hear the songs of the other birds in the trees as they watch over my soul and remember me."
Thank you.
DR. ABRAMSON:  Thank you, Ms. Levinson.  We appreciate your comments.  We are all very impressed by the courage of people like yourself with rheumatoid arthritis.
Norine Walker?
MS. WALKER:  Good morning, ladies and gentlemen.
I'm an individual with rheumatoid arthritis, and I don't have any financial interests in Immunex Corporation.

I was here a couple of years ago when the panel was considering the approval of Enbrel and was moved by the speakers prior to my own presentation that had been involved in the clinical trials, I had not, and particularly moved by one of the women that said that prior to having met Enbrel, she had not been able to raise her hand to brush or comb her hair.  We've all been there.
And also remembering how fortunate I had been that I had been diagnosed early with the onset of the disease only four months after the symptoms had started and had been treated in a team approach by physicians and other care-givers.
When I was diagnosed by a rheumatologist locally in a teaching institution, the first thing that he told me was that in five years, typically, people with rheumatoid arthritis are disabled, not something that someone who's 18 years old wants to hear, when they're ready to start their college career and set the world on fire.

But I started with the treatments for rheumatoid arthritis, and as I moved from my college days at the University of Maryland up to my professional career in Baltimore was treated by a Hopkins-trained rheumatologist, but not only the medicines that she scripted for me, but she also scripted treatment with physical therapists, with hand specialists, with foot specialists, and over time, as the disease progressed, the interaction of the drugs continued to progress, led me to my team of cardiologists, psychologists, internists, gastroenterologists, et cetera, et cetera, as many of us that have rheumatoid arthritis have to travel with this disease.
One of the things that I have found through meeting some of the other people with rheumatoid arthritis is the great impact that Enbrel has had on some of them.  Of the 43 million Americans, I fortunately have met a handful of them.  Some of them are young adults similar to myself that have had such terrific benefits from being on Enbrel as I have.  Something simple as being able to participate in athletic sports, not competitively maybe but being able to have a regular exercise program, being able to downhill ski after not having had that chance for many years.
Even my friend that's able to lift her hands above her head and reach the back of her head, which she hadn't been able to do for years and years because, as a three-year old diagnosed with rheumatoid arthritis, she had severe limitations.

We've suffered with side effects of medicines.  We've suffered with doctors' visits, with lab tests, with contraindications, with complications, as I've mentioned, with the rheumatoid arthritis drugs, triggering other maladies, but we've gone through these travails with our arsenal of medicines, and as we've started to be treated by Enbrel, we've seen opportunities to reduce that arsenal.
Fortunately, my epiphany came earlier this year when, after having done my morning routine of range of motion exercises, I was able to sit on the end of my bed before I got ready for work and say I have no pain, I have no pain.  There is no pain.
For somebody that's had this for 20 years, to have that epiphany, that light bulb go on, is quite astounding.  Now, I don't have those days every day, but they're increasing in number, and I've been able to start tapering off some of the other medicines that I'm on.
My hope is that in the future, that I may be on only one or two of these medicines rather than my full grouping, and that is encouraging.
However, there are people out there that are not yet at the moderate to severe rheumatoid arthritis that I and some of my young adult friends are, who need to not go through 20 years of medicine, side effects, complications, surgeries, visits to labs, visits to physical therapists.

For early intervention, and I feel as if I had early intervention because I had a team of professionals that were looking out for me.  I think that that's very, very valuable.
My quality of life having had the early intervention was improved remarkably.  I've been successful professionally and have contributed to society, and that's what I could see from Enbrel being used for early treatment in persons with arthritis.  They won't have to suffer through the things that we have and won't have to be debilitated or be on the disability rolls.
The impact of having reduced the disability rolls by people with rheumatoid arthritis is something to be thought about.
My remarks a couple of years ago also included the encouragement to continue with trials of individuals such as myself that have other complications beyond simply rheumatoid arthritis, and I think that comment was obviously taken to heart to a certain extent because we are looking at it for early treatment, but there are still cases where the research needs to continue, so that the medicines that we are providing are safe and have minimal side effects.
Thank you.
DR. ABRAMSON:  Thank you.
Gloria Brennan?
MS. BRENNAN:  Good morning, everyone.

Like Judith and Norine, I, too, have rheumatoid arthritis, and this morning, I feel extremely grateful, extremely blessed and really humbled by the fact that I was diagnosed in May of 1997, and Judith and Norine had a lot more pain, a lot more stiffness, and if anyone has been there, you just want to cry for them because my experience with it was so short when compared to theirs.
Anyway, I want to tell you I'm very spontaneous the way I speak.  I try to be organized, but it never works out.  So forgive me for that.
I took a bath this morning, and I was thinking of all the things that I so took for granted before rheumatoid arthritis ripped my life apart.  I took a bath, and I watched myself taking a bath and watched myself lift my body off the tub with my wrists, and I thought that was pretty good, you know, when I think about the other way I was.

I played tennis the other day, very poorly, but I bought myself a new racket.  I always wanted one, and I'm a bad player, but I played, and I ran with my dog and walked with my dog Ginger, my Australian shepherd that I found a couple of years ago.  She's a big dog.  I don't like big dogs, but I'm stuck with her.  She can run and knock me down, but now I have the freedom and the energy to do lots of things.
I live in Owings Mills, Maryland.  I have a full service salon and a day spa at the Hilton in Pikesville.  I'm from Colombia, South America.  My mother is here with me, and when I first got diagnosed with rheumatoid arthritis, all I could envision was twisted fingers and pain because a girl in my chorus in church at the time had it, and she always wore slippers, and she always walked real slow.
So when I first got it, I went into an immediate denial about it because I didn't have any real pain.  I just had inflamed joints in my wrists only.  I mean right here, the telephone finger joints.
I went to the library. In fact, I didn't tell my mother about it.  I didn't want to upset her.  I went to the library and got all the books on rheumatoid arthritis, so that I could read about what was in store for me, and at this point, I had not had any flare-ups.  I didn't know what was going to come, but what I read was very, very negative.  It was like, okay, you have it, here's what you can expect the first six months and the next six months, and within two years, it will be possibly total joint destruction.

I'm single, I have my own business, and I'm in the business of making people feel and look good, and therefore I did not like what was going to be in store for me.
I remember calling my ‑‑ I didn't even know a rheumatologist.  Since then, by the way, I did date one, but our joints didn't connect.
(Laughter.)
MS. BRENNAN:  And I learned about Arava, too, in that dating process.
(Laughter.)
MS. BRENNAN:  And at an Arava meeting, I stood up.  I didn't know it was an Arava meeting because I didn't know what Arava was, but it was like 350 rheumatologists, and I was so excited about Enbrel, I just had to share it, and I did, and the rheumatologist that I was with, he said, "That was not politically correct," and then somebody from Arava said, "You'll have to pay for your own dinner."
(Laughter.)
MS. BRENNAN:  So you know, needless to say, we didn't last very long.

So the rheumatologists at Sinai Hospital in Baltimore recommended some drastic aggressive measures.  My mother went with me because I had to wait three weeks for that meeting, and it came on, the flares came on, slowing walking, no heels, I have heels today, flat shoes until my study, and nothing really worked.  That's the thing that really upset me because I would get upset stomachs, but nothing seemed to work.
I remember going to Ocean City one time in Maryland to just relax, and I had a flare-up, and I really love swimming.  I wanted to go into the ocean, and I couldn't.  I had to ask people to help me walk into the ocean, knee length, knee deep, and I couldn't bend.
So I agree that Enbrel should be a drug recommended for an early diagnostic of rheumatoid arthritis simply because from what I've seen today, it stops the progression and the destruction of the joints, and we all need our joints to stay mobile and to have a full quality of life.
Thank you, Immunex.  You gave me back my life.  Thank you, FDA.  Go for it.
DR. ABRAMSON:  Thank you very much.
It is our hope that we develop drugs that can make people better, everyone better, who takes them.
Dr. Klippel from the National Arthritis Foundation.

DR. KLIPPEL:  Good morning.  My name is Jack Klippel.  I'm a rheumatologist and medical director of the Arthritis Foundation.
It's indeed a privilege and a bit of a humbling experience to follow patients to the microphone, particularly those who have benefitted from such a major advance, and I should say on a personal level, that in two of the instances, for Judy Levinson, who more than a decade ago I saw in the first year of her illness, and neither of us had a clue what was in store for her, and I've lived through years where she suffered greatly and am particularly gratified that she's happy and doing well, and I have the privilege of working with Norine Walker, who is in fact a leader in the Arthritis Foundation and whose leadership is actually responsible for many of the things that occur within the Foundation.
I speak today as a representative of the Foundation, to comment on the major advances in the treatment of rheumatoid arthritis that have occurred over the past decade.
A longstanding era of empirical therapy has given way to scientifically-based treatments that in a short period of time has resulted in dramatic improvements in the lives of people affected by this chronic, disabling disease.

I would like to specifically recognize important and significant developments that have contributed to this achievement.  First, the advances have only been possible through a steadfast investment in basic and clinical biomedical research.  These have provided insights into the pathogenesis of rheumatoid arthritis, and the conduct of rigorous clinical trials that have documented the effects of treatment on the disease course.
The Arthritis Foundation has been particularly pleased to play a small part in supporting this research.
Second, the biotechnology and pharmaceutical industry has successfully built on this science base and has developed effective products that modify biologic pathways important in this disease.
The development of targeted drugs specifically for use in rheumatoid arthritis is a new and important direction for industry, and, finally, we would like to recognize the agency for review and revision of labeling indications of drugs used in the treatment of this disease.
Clear statements as to whether a drug improves symptoms or prevents joint damage and destruction is a major step forward in allowing prescribing physicians to make more intelligent decisions and informing patients as to realistic expectations from drug treatment.

We consider studies that look at a more primary role of aggressive treatment early in the course of rheumatoid arthritis as a logical next step, as a way of better control of this disease, and hopefully to minimize the long-term consequences of this chronic disease.
Early diagnosis and early treatment are key strategies of the Foundation's National Arthritis Action Plan as we work towards Healthy People 2010.
We indeed look forward to the next decade with hopes that scientific research will uncover additional mysteries of this disease and will not only allow for better control but ultimately methods to cure and prevent it.
Thank you very much.
DR. ABRAMSON:  Thank you, Dr. Klippel.
Finally, we have a letter to be read to the record by Ms. Reedy.
MS. REEDY:  From Kara Gregory in Darien, Connecticut.
"I send you the perspective of a mother of a young child, seven years now, who was diagnosed at age four with systemic onset JRA.  Enbrel has been the only drug that has worked for us, and I wish the drug had been available to us three years ago.

"My son was on numerous drugs with many adverse reactions, and his swelling and pain persisted to the point where he was unable to walk, eat, move his head during his sleepless nights due to pain, even had to be physically turned over.  He was unable to do anything himself.
"We tried methotrexate, too, which is what rheumatologists usually prescribe first now, and it had adverse reaction in the liver and horrible mood swings with prednisone and some of the NSAIDs.
"Rheumatologists told us our son would probably never get better, and he would probably never respond to any drug.  That is when we went the natural route which helped a little, and then Enbrel was approved, and we noticed the difference immediately, and within four months, he was running, climbing, and his swelling is now almost undetectable.
"I believe Enbrel to be so much safer than the current preferred treatment by rheumatologists, and when a child develops RA and does not respond to other products, then I truly believe they should be given Enbrel before any of the other DMARDs and other drugs out there.

"My son has been on Enbrel for 18 months, and the difference is incredible.  Everyone, including his rheumatologist and pediatricians, are amazed at the difference because they never thought it would happen.  So the plea is to please approve that Enbrel be the first drug used and not only after other DMARDs."
DR. ABRAMSON:  Okay.  Thank you very much.
We're now going to move to a series of discussion questions that address the risk-benefit ratio of Enbrel and its proper place in these requested changes to the labeling.  There are 12 questions, and we will try and spend about 10 minutes on each question.
The first is in the area of safety, and I'll just read the preamble.  "In this trial and the original licensure trials, for patients with advanced RA, no differences were observed between Enbrel-treated and control patients with regard to serious infection.  The occurrence of serious infections and deaths from infections among patients who received Enbrel in the post-marketing period resulted in additional language in the product label and the initiation of a randomized trial of Enbrel in patients with RA to assess infectious complications in a population at risk for potential risk factors.  In addition, randomized controlled trials of Enbrel are underway to assess safety and efficacy and other indications."

The first question in the safety database category to the panel is, "Please comment on the adequacy of the completed and planned studies to assess the safety of Enbrel for long-term use in patients with early rheumatoid arthritis."
So would someone on the panel like to comment?
DR. HARRIS:  May I?
DR. ABRAMSON:  Yes, Dr. Harris.
DR. HARRIS:  As I understand it, the study will be utilizing a thousand patients with comorbid conditions for four months.  My issue is whether or not four months is an adequate period of time in which to do a study such as this, whether or not the risks might not exist for a longer period than four months.
DR. ABRAMSON:  Dr. Siegel?
DR. JEFFREY SIEGEL:  Yes.  We also feel that four months may not be adequate to fully ascertain the risk of increased infections.  This was a practical decision that was reached because it was felt that it would be very difficult to keep patients in the control arm of the trial longer than four months.
DR. ABRAMSON:  Dr. Schwieterman?
DR. SCHWIETERMAN:  Yes.  Let me just add to Dr. Siegel's comments.

It's very difficult to know, of course, what an adequate length of trial is when you're reviewing the anecdotal post-marketing data, but of those events that we reviewed, a large majority of them, if there was a causal relationship, occurred relatively soon after the initiation of Enbrel, that is, within the four-month period, and so based upon those observations and based upon Jeff's comments, that's how that study length was chosen.
DR. ABRAMSON:  But given ‑‑ just to pick up on this ‑‑ given the denominator of post-marketing reporting, and if one assumes that the drug may not induce the infection but in someone who otherwise develops an infection prevents normal handling, one would then, in picking up Dr. Harris's point, want to know what the likelihood of events of infection would be in this population over four months, presuming it's not the drug that induces it but the natural history of the incidence of the event.
So how do you think about that?  If you take a thousand diabetic patients and others, what's the likelihood that you're going to get a sepsis or some other event that gets complicated by therapy?

DR. JEFFREY SIEGEL:  Unfortunately, we didn't have firm data to base these on.  Some of the data that was used was data from congestive heart failure studies where the rate of infections has been quite high in some of the controlled studies.
DR. SCHWIETERMAN:  I think your point is well taken.  It's difficult to know with any certainty about how the study is powered or whether it's sensitive enough for these particular changes, and suffice it to say that discussions occurred over actually the course of many months as to what kind of trial design, including much larger studies of a non-enriched population, enrichment studies and so forth, and based upon the analyses we did of the post-marketing data, albeit, you know, with full knowledge that those analyses would only give us a guess, a best guess as to what was going on, we felt that an enrichment study of these particular patients was the way to go, given the incidence of the events in these particular patients, and as to the power of the study, we could only do again a best guess as to what kind of signal we'd see with these groups.
DR. ABRAMSON:  And Dr. Simon first.
DR. SIMON:  In the context of doing an enrichment study, was thought given for such a short trial to be done only during those times of years where these individuals who are at risk are truly at risk for URI exposures, such as winter as opposed to summer?

One would have seen differences of infection rates, and are we concerned only with sepsis or are we concerned with upper respiratory tract infections that then are worsened while the patient is on an inhibitor of TNF-alpha, and then the other question, which I'm concerned about, relates to the LFT abnormalities, and the usage of this type of therapy in patients with known hep C disease.
There was an allusion to a study in hep C patients, hep C-infected patients, and could you comment on how you're looking at those kinds of chronic infections as relates to incidence of problems with superimposed TNF-alpha inhibitor therapy?
DR. SCHWIETERMAN:  Well, let me comment on your first question first.
What drove our considerations for the trial design in the study was less the upper respiratory tract infections but more the serious AEs, including systemic inflammatory response syndrome relatively soon after the initiation of Enbrel, including hospitalization with serious infections, including quite dramatic Grade 4 infections from there, and consideration was given to all the kinds of adverse events that might be seen in those who would be collected.

But, principally, the study is designed to address the issue of catastrophic or very serious AEs. Undoubtedly, there are many, many questions remaining that could have been asked in this particular study, but given the gravity of our concerns about this, albeit with post-marketing data and a fair amount of uncertainty as to what to make of it all, we focused our attention on that.
DR. ABRAMSON:  Okay.  Dr. Katona?
DR. KATONA:  Dr. Simon also asked about hepatitis C.  hepatitis C-positive patients are excluded from the trial.  The hepatitis C population, that's a separate trial.
DR. GARRISON:  I have one clarification about the hepatitis C population.
DR. ABRAMSON:  Okay.
DR. GARRISON:  There are seven patients in our clinical trials who have had hepatitis C and have been treated concurrently with Enbrel, very small numbers.  None of those patients has had any problems with reaction or exacerbation of their hepatitis C.
DR. ABRAMSON:  Okay.  Thank you.
Dr. Katona, then Dr. Felson.

DR. KATONA:  I think this is the other side of the coin for serious infections.  I think the study getting the particular high-risk individuals for four months is going to tell us the short-term complications, but I would like to ask all the studies, what you presented for post-approval, have those all, including the European studies, are those all going to systematically be looking at all the complication rates?  Because I believe that's the ‑‑ we really don't know how many years patients are going to be on Enbrel, and I think that's really the key for long-term, and we probably don't know all the data there is.
DR. GARRISON:  When we were here last, we did commit to following these patients in our long-term treatment trials for at least three years.
We have extended that to at least five years, and as long as sufficient numbers of patients stay in, we will continue to follow those patients.  This is a very valuable source of data for us.
So yes, we're going to be following them for primarily significant events.  Any hospitalization, malignancies.  In the later portions of the studies, the more nuisance events are more difficult to collect.  Patients get tired of reporting every cold that they've had, and I think that we have some pretty good data in our control trials that really very clearly shows the difference or no difference in rates of those kinds of infections, statistically-significant events, and we're following these patients for a very long time.

DR. ABRAMSON:  Okay.  I have a question about the European Registry.  It was on one of your slides.  Can you describe that?
DR. GARRISON:  The European Registry is in almost its finalization form, and it's being conducted by Wyeth-Ayerst, and I don't have the particular details, but these patients again are going to be followed specifically for significant events, hospitalizations, serious infections, malignancies, autoimmune diseases, SLE, et cetera.
DR. ABRAMSON:  Is that via the licensing agency in Europe or is it ‑‑
DR. GARRISON:  Yes.
DR. ABRAMSON:  Okay.  Other questions?
I have a question.  I guess a lot of the difficulty that we have is in the potential for Type 2 errors that we're getting with follow-up, but how does one judge the three sepses in a septic joint in the study that we heard this morning with no sepses or bacteremias in the methotrexate?  Is it a signal or not a signal?

I don't know that we can make a judgment, but can we assume that there is no difference in those groups?  Can we make any statement, except that we need more follow-up or not?  I'm just curious what other people think about that.
DR. JAY SIEGEL:  Well, you know, what wasn't presented in any of the presentations that may bear somewhat on this, I think some of you may be aware of this, with Enbrel, the first indication that was studied, although not on the list of other studies, was in patients with full-blown active sepsis, and there was a significantly-higher mortality in the Enbrel arm than the other arm, and that underlies some of the ongoing concerns.
So we're looking at a database that is not large enough to exclude effects and probably never will be, certainly in terms of long-term effects.  We're probably going to, as with many drugs, you know, carry into the future some level of uncertainty as to the effects on things like malignancies or late infections, but I just wanted to point that out as a background for one of the reasons why these small trends that you're talking about are something that we've at least looked at carefully.
DR. ABRAMSON:  Dr. Simon?
DR. SIMON:  I think we all grapple with that particular problem, particularly when asked to look at a new therapy to be used first line, when we don't understand a lot of the long-term toxicities.

Yet at the same time, we as rheumatologists have spent our lives using drugs that we don't really understand very much about their long-term toxicity, some of which have been very helpful, some of which have fallen by the wayside.
It is an iterative experience.  Unfortunately, the regulatory environment doesn't appear to be able to help us with that too much at this point in time.  Maybe perhaps the longer-term trials, the European Registry, will help us understand this better, although I'm a little concerned that the numbers may not be large enough to really give us the answer.
I'm particularly interested also in the malignancy issue as well as the sepsis issue, but I think that that should not preclude us from feeling very positive about this particular therapeutic intervention.
DR. JAY SIEGEL:  Could I get a clarification?  Because you made a note something about the regulatory environment isn't able to help us with this question.
Our question to you is, you know, what can or should be done?  It may be that there are things that ‑‑ I'm not sure what you're presuming about the regulatory environment, but we would like to know what you all think should be done, so we could figure out what role we and Immunex and others can play in trying to get it done.

DR. ABRAMSON:  Dr. Simon?
DR. SIMON:  Well, since I've been on this committee, I've had the opportunity to participate in discussions that are very similar to this.
We've heard ways that this committee has actually required other sponsors to actually create relatively small registries.  I think that fundamentally, what we've learned is that we really need to move towards a way to study large groups of patients over a long period of time and to have large cohorts that are studied that way.
We have the opportunity to do that with governmental support if we could convene enough of it to get it supported over time, so that we would have real registries, where all the patients with rheumatoid arthritis are followed or a great majority of them are followed for 10-20 years, and we can understand those kinds of implications.
I think the agency should take a leadership role in encouraging groups to do that.  Recently, the American College of Rheumatology Board of Directors actually reiterated their belief that that's a very important thing for the government to support, the NIH to support, and it would be good that the agency saw its way towards thinking in that regard as well.

DR. ABRAMSON:  Dr. Felson?
DR. FELSON:  Yes.  I'm going to reiterate a lot of what Lee just said, but I think it's especially an acute issue here where this is a compound where, unlike methotrexate or other drugs that were released or used in rheumatoid arthritis, we don't have any experience from other diseases and really don't have any sense of what its long-term effects are going to be, and I think the notion that this might be like other drugs recently approved by the FDA that had to be withdrawn later from the market because of an unanticipated but uncommon very severe problem is not unreasonable, and I think it would be nice to have real large-scale long-term ‑‑ the notion that the company's going to follow these people for five years is very reassuring.
Frankly, the data presented here provide no reassurance that there's not an increased malignancy rate because the number of people followed is not sufficient to see an increased malignancy rate.  The person-years analysis is misleading here.  That event doesn't occur till three to five to 10 years later, and I think, you know, long-term large-scale observational data is absolutely critical.

I'm not sure it necessarily needs to be controlled data.  I think sometimes, you know, controls that are already in the literature or controls that are created from other settings sometimes can help us figure it out, but I think there's a genuine concern here.
This is obviously, you know, something that's new and very helpful to patients.  There's no question about that.  But it's new, and its long-term biological effects are unknown, and I think that's real concerning.
DR. ABRAMSON:  I think, just to add to this discussion, it is not just another drug that's been approved, and I think we need to come back to the hearing a year ago, because it is the first biological in this field.
There were relatively few patients studied at the time of approval, and that's, I think, important to keep in mind compared to traditional pharmaceutical agents.  So it's not just the numbers of patients, but it's the numbers and the time.
So this drug, because it's a very impressive drug and does all the dramatic things in many but not all patients, has a very important role, but we should keep in mind that it's the first of its kind that has a different level of numbers of people to follow.

I am concerned.  I don't like data presented as patient-years when you only have small cohorts followed for a year or two.  I think I agree with David.  It's a bit misleading, and as Dr. Garrison said, you need four or five years to follow people if you're looking for a malignancy in this area, and so we don't have enough numbers and length of time, and that's the discomfort that I think is still there.
Dr. Simon?
DR. SIMON:  And even when even a few malignant events are noted early on in an early RA trial, that makes me even more nervous.
We think of rheumatoid arthritis as a disease that has associated with a risk of lymphoproliferative disease over 30 years, not over three years, and although there is one Hodgkin's patient, and that certainly can happen spontaneously in all circumstances in anybody, it just makes me a little concerned when I see data in patient-year, and I actually feel very uncomfortable that the sponsor has not acknowledged that at the get-go, that by expressing the data, it is almost the implication that in all of their trial data sets, that a patient-year expression is appropriate for this particular problem.

I do recognize that they have achieved ICH guidelines as of this present presentation, and I think that's wonderful, but at the same time, in this context of this kind of therapy, it may be 10 years before we can understand the implications of malignancy associated with chronic use of this agent or agents like it.
DR. ABRAMSON:  So I think it's an appropriate time now to move to the second part, because I think we're also all impressed with the discovery and the bench-to-bedside work, and now the surveillance that the sponsor is providing, working with the FDA.  So I think everybody's moving along in a very, you know, exemplary way.
The issue then becomes the second question here.  "Should the sponsor conduct additional studies beyond the usual post-marketing surveillance to further assess the safety of Enbrel in patients with early RA?  If so, please comment on the kinds of studies that would be informative."
Dr. Pucino?
DR. PUCINO:  Yes.  I think it would be helpful not to just know numbers but the pathogenesis behind why people are getting DVT, why are people seroconverting to positive antidouble-stranded DNAs, and why are people developing malignancies, and to try and focus on the why and not just that it occurs.
DR. ABRAMSON:  Right.  Assuming these are validated observations.

Dr. Katona?
DR. KATONA:  This is a question for Immunex, and I'm just kind of looking forward to the future of five-10 years from now, if there are patients with malignancies or some unforeseen events, and at that point, we might come to the conclusion that we completely have to abandon our treatment which was very useful for very many patients.
Has any thought gone into using Enbrel as an inductive therapy, like for a half a year or a year or a year and a half, and follow those patients along, switching them to another therapy at that point when the disease is well-controlled and collecting long-term data maybe on those patients along with patients long-term on Enbrel?
DR. GARRISON:  We have not conducted a study of that design.  It's something that has been suggested to us.
We have a large number of studies that we're trying to conduct, and I think that it is one that will be done, whether it's by Immunex or by the rheumatology community.

One other point, if I may make one point, about the malignancies, is that we have looked very carefully at each of these cases, and although patients in this trial had RA of short duration, many of them were not young people.  Many of them had multiple years of smoking history, et cetera, et cetera, other risk factors that would make you not dismiss their malignancy, and I'm not saying that at all, but at least not make you think, well, this is something very odd that's happening in this person.
DR. ABRAMSON:  Dr. Simon?
DR. SIMON:  I also wondered, taking Frank's lead here, we've not really talked a lot about the observation about the absolute neutrophil count, and that didn't come up in the discussion of the sepsis issue.
But I'm not entirely sure I understand the biology of that at all, and obviously it's a very important issue in the question of sepsis and response both to minor infections as well as serious ones.  That's clearly an area that we need to further understand since it really stands out as something unique to this kind of therapy, and why that would happen is unclear.
DR. ABRAMSON:  Right.  Were there other cell lines, like platelets, or any other ‑‑ in terms of the sponsor?  In people who were neutropenic, was there a drop even in the normal range ‑‑
DR. GARRISON:  No.
DR. ABRAMSON:  ‑‑ of the platelet count or something?

DR. GARRISON:  No.  There was no thrombopenia at all.
Can I show a slide?
DR. ABRAMSON:  Sure.
DR. GARRISON:  Okay.  Slide up.
This does go into a little bit greater detail about the ANCs that were seen in the trial.  You know, we did measure these cell counts very frequently during the study, and we've just shown any grade as well as the specific grades that are associated.
As you can see, most of these were Grade 1, which is at a level of 1,500 to 1,999 cells per cubic millimeter, which I think may occur in the setting of RA transiently in and of itself.  Not to dismiss that, but again looking again at more severe levels of neutropenia, there were no significant differences.  I mean, 1, 3 and 3 Grade 2, and 1, 1 and 1 3 in this trial.
If we looked at our placebo-control trial, just one more, the differences were not seen there in Year 2 in the ERA trial.  There were no differences among the groups.
If we look at the Phase III placebo-control trial, where we did have a placebo, we did not see anything reflecting this pattern at all.
DR. ABRAMSON:  Thank you.
Dr. Brandt?

DR. BRANDT:  You pointed out earlier that the cases of thrombosis were not associated with the presence of anticardiolipin antibodies.
Can we say the same thing about the episodes of sepsis not being associated with cytopenias?  Do you have that information?
DR. SILVER:  In the ERA patient, the one patient with sepsis, was in the setting of a pneumonia.  That patient did not have a low neutrophil count.  The bacteriemia is different from sepsis, and the patient was not hypotensive, had a positive blood culture after someone needled a cyst, and the patient was septic arthritis.  I don't know for sure, but I think that patient also did not have a low neutrophil count.
When we looked at these patients with low neutrophil counts, we looked at over their whole time had they had any serious infection, and none of them had.
DR. ABRAMSON:  Dr. Harris, and then Dr. Simon, and then I'm going to go around and ask each panel member if there's one area that they'd like to see in response to this question that needs further study.
Dr. Harris?

DR. HARRIS:  I'll ask a question.  There's no reason a priori, of course, if the thrombosis story is indeed something that pans out, that it need be antibody-related, and certainly the molecule itself could perhaps activate endothelial cells or platelets in some way and be itself prothrombotic, and I was wondering whether or not there's any in vitro or other data to suggest that.
DR. FINCK:  I don't know of a lot of data, but there was some data that looked at ‑‑ I think the author was Seffarini ‑‑ the presence of TNF actually in increasing coagulation parameters.  So that would be opposite, and that's the only data that I'm aware of.
DR. ABRAMSON:  Dr. Simon?

DR. SIMON:  Not to beat a dead horse about this absolute neutrophil count problem, but I'm a little uncomfortable with the explanation that's just been presented in that we do know of patients that have particular syndromes associated with rheumatoid arthritis who develop very profound neutropenia, but these were not these patients, and this was a longer trial than the Phase III trial, and therefore I'm a little concerned that perhaps we're beginning to see a long-term event taking place on exposure, and because Dr. Garrison presented some two-year data, I wondered in the two-year data set whether there was any incidence of absolute neutrophil counts as well or whether that incidence increased in that circumstance.
DR. GARRISON:  In the long-term open-label trials, we've evaluated these people hematologically, serially, and we haven't had any neutropenia that's been associated of this pattern at all.
DR. ABRAMSON:  Thank you.
So in terms of this question, now we've heard that there's a high-risk four-month study, people at high risk for infection.  There's a European Registry being planned.  There's going to be follow-up of your clinical trials for three to five years, and I guess what I'd like to do is just ask the panel members if there's one or two things in the context of those things or additional things they'd recommend that they want to have tracked or have some concern about.
Dr. Siegel?
DR. JAY SIEGEL:  Could I also supplement that question?

Since I've heard a number of panelists emphasize the importance of long-term data, and at least one laud five-year follow-up and another says we need more than five-year follow-up, I think Immunex ‑‑ I remember although they've presented patient-year data, they noted that first, as well, that you really need longer data to look at that.
So the question is, you know, five years is better than three, but where should we get ‑‑
DR. ABRAMSON:  I don't know.  You need people who are maybe more expert in latency and things like that.
We as rheumatologists who are old enough have had the experience with Wegener's granulomatosis ‑‑ I guess it was in the mid-1970s, whatever ‑‑ an incurable disease was made better by Cytoxan, and at the five-year follow-up, there was, what, 20 percent lymphomas, lymphoproliferative disease, et cetera, as well as bladder cancer.
You know, for us older people, that's in the back of our minds.  I don't know that they're two different drugs, but there is this little bit of a signal, and I think that's the concern, in terms of being more aggressive in its use as a question.
It's obviously a terrific drug for many, many people, but that's the anecdote.
So Frank?

DR. PUCINO:  Again, more information on pathogenesis of these things if they are proven valid.  Also being a little bit more proactive instead of waiting till someone develops lupus as we know with other anti-TNF therapy has developed, to be serially monitoring these things.
DR. FELSON:  I'll dredge up another example that's in the opposite direction actually with methotrexate and liver problems, and I think we're all worried about long-term liver complications from methotrexate, and it really wasn't until 10-year follow-up studies came out from Mike Weinblatt and Joel Kremer that our concerns were generally assuaged.
They weren't huge studies, but they had enough follow-up that they basically excluded the possibility of frequent cirrhosis and that was very helpful, and I would think that these are rare events.  So small numbers of patients followed up for 10 years is not going to be all that helpful.  We need bigger numbers, but I would ask the company to begin to project that.
I mean, this is a very popular treatment.  It's going to be used by thousands of patients for long periods of time, assuming, you know, a lot of things that we've heard in evidence today, and I don't think it's so far-fetched to think that they could continue following these patients to figure out whether they develop malignancies, and what the rates of that are.

DR. KATONA:  I think at this point, it's very difficult to say too many new things, but I would like to look at this from the patient's perspective and more like asking the regulatory agency just we really have to make sure that the patients understand that we really do not know exactly what is going to happen five-10-15-20-25 years from now, and especially speaking from the pediatric community, maybe 70 years from now.
So I think until we're honest about it, and both Immunex, other companies, as well as we, the rheumatology community, collecting the data, that's all I could think of.
DR. SIMON:  I'd like to actually generate my comments more to the agency than to the individual companies.
I don't think it's fair to ask the company to invest in what really is required, which I believe that the agency can take a leadership role and a bully pulpit role in getting the community to develop long-term observational trials, outcome trials, of the use of not only TNF-alpha inhibitors but other drugs as well in the context of the treatment of rheumatoid arthritis.

As David had alluded to, the positive aspects of understanding the liver toxicity of methotrexate also led to a far better understanding of the incidence of lymphoproliferative disease in the treatment of patients with methotrexate, and only by doing those kinds of 10- to 20-year studies will we really understand the incidence of that and its effect, and I believe the agency has a major opportunity here to play a very major leadership role in getting the government to truly sponsor and support so that the rheumatology community and others can study the incidence of problems in these patients.
MS. MALONE:  I agree with both what Lee and Ildy have said.  I think there is the need for large-scale long-term follow-up.
Also, I think in this follow-up, we need to take into consideration that rheumatoid arthritis is not happening in isolation, that as these people age, other things are happening to them, and, you know, what the interplay is with this drug.
It all sounds almost too good to be true, you know, and I personally know people who are on the drug, and it's been miraculous, miraculous, but I think, like Ildy said, that there has to be the education on the part of the pharmaceutical with the doctors and the doctors to the patient that the future is unknown.

DR. BRANDT:  Yes.  I think we've seen some very impressive positive results here, and I can certainly understand the enthusiasm, but as I think everybody has said, we just don't have data that permit conclusions over long-term usage, and we need those both from the standpoint of infection and the standpoint of malignancy in sufficient numbers of people to be able to answer these questions.
It takes time, and it's going to take money, but I think it's essential.
DR. ABRAMSON:  So I would agree.  I think the good news is we're not discussing licensing this drug or not.  It's already licensed, and so the issues are different, and if we can educate doctors and get access to patients of good care, what we're really talking about is delaying three months the use of methotrexate, for example, until this drug were available for patients.  So the issue of safety given its numbers and experience, I think, is still out there.
What we saw this morning was encouraging, and I still think we need more data as we're saying on sepsis and tumors.  I think the LFTs have to be tracked a little more closely.  As Lee brought up early this morning, I don't know whether that 20 percent AST or ALT ‑‑
DR. SIMON:  ALT.
DR. ABRAMSON:  ALT elevation was a real signal or not, but I think it should be kind of looked at in these studies.

I think the use in hepatitis C, a lot of our patients are carriers of hepatitis C, and that's an unknown area.  I don't say that's a new study, but I think at some point, we ought to start looking at opening up the use of this drug because those people are treated with interferon which can exacerbate their arthritis.  So they're a real difficult patient population to treat for the clinicians, and if this drug were good, I think that's a useful area.
I share Dr. Harris's concern that the four-month high-risk trial may not be apparent to really see signal of infections that are going to happen in these patients that then get worsened by being on drug.
So those are my comments.
Dr. Harris?
DR. HARRIS:  Well, my comments are, again, just urging careful monitoring, and I feel that the burden is on the FDA to do exactly that, which is to monitor carefully.  I'm sure you do that anyway, but I think that is the important thing, and then the other point that was made is that patients themselves, at least there should be some sort of warning about not knowing the long-term effects, and indeed, I am going to add one other story, of course, corticoid steroids in the early '50s.

Of course, rheumatoid arthritis was the disease in which this was the miracle that didn't work 10 years later.  Hopefully that won't be the case here.
DR. JAY SIEGEL:  Just to be clear on that issue, we monitor in the sense that we monitor reports that come in from the community which are, as we've seen in this case, extremely difficult to make determinations about regarding incidents relative to background in areas such as we're talking about, infections and malignancy, except when there are very strong signals.
So if there is a need for a more reliable source of data, then that would need to come from the planned either controlled trials or cohort studies, and what we're discussing now in fact is which of those we should be asking the sponsor to conduct at this point in time.
DR. ABRAMSON:  Janet?

DR. ELASHOFF:  It definitely seems clear that one needs long-term studies which are better than post-marketing surveillance studies.  Whether you actually need a control or whether you just need careful follow-up of, I think, generally multiple people treated under multiple conditions because then at least you can compare within the data set itself.  Although you don't necessarily have a great comparison, at least you have some comparison, whereas post-marketing surveillance, you typically don't really even know the denominator, let alone what would go on in other circumstances.
DR. ABRAMSON:  And an additional thought in terms of who should bear the burden of this, I think the NIH could play a role here, too.
I know they're looking at targeted studies that are hard to fund and some surveillance, I think, would be worth talking to them as well.
Kent?
DR. JOHNSON:  Let me just interrupt for two seconds.
Just to expand the discussion a little bit, there are international thoughts on this, too, as a lot of people in this room know.  I think it's quite obvious to everybody here that our post-marketing system is incredibly limited, as are post-marketing systems for most other countries in the world.
Whether the EU is going to start some formal requirement, I would love to see that happen.  I would love to see the FDA kick in, also.  There's a group called OMERACT, which is just a very ad hoc organization, that's been thinking about long-term databases in rheumatoid arthritis for exactly this sort of thing.

The big conceptual challenge is even if you do a 10-year study, and you find, you know, a handful of lymphomas, what does that mean compared to background?  How do you make a rigorous comparison?  Do you need a control?  Do you need matched controls?
We're never going to get 20 randomization studies, but you could deal with the control problem, although it's very tricky, you know, from a complexity point of view in cohort studies.
But I think the greater issue is how to get this organizationally going.  There's three centers right now, the Stanford Center, Manchester and Sweden, who have at least on a preliminary basis thought about at least establishing a common database which is the beginning for something like this.
The whole other dimension, and nobody's mentioned it, although the patients, you know, would be interested in this, what happens to efficacy long term, because really you want to make a risk-benefit judgment for a 10-year proposition, and you need some efficacy data which is tricky to ask the companies to collect, although it hasn't hesitated me from doing that.
DR. ABRAMSON:  Dr. Brandt?
DR. BRANDT:  I'm going to save mine for later.

DR. ABRAMSON:  Dr. Paulus, would you like to make a comment?
DR. PAULUS:  Obviously, there's a lot of intellectual and emotional interest and support for truly long-term collection of data in an observational cohort-type study over a generation or longer, but to do that, you really need sustained long-term commitment and money, and I think that one model for funding something like this is the Orphan Drug Program, which is really very successful and is a collaborative effort between industry and the agency that has legal authorization to go on for as long as necessary and that may be the way to go with this.
DR. ABRAMSON:  I think that's a very key point, that this shouldn't be the burden of the individual sponsor of an individual drug at some point, because we're going to keep seeing new drugs come out between the industry, the FDA and the NIH.
Perhaps there ought to be some way to designate certain of these new products for long-term follow-up.
Okay.  So on Questions A and B, in terms of the agency, are there other issues that you want addressed there?
DR. SCHWIETERMAN:  I just want to be clear.  This has been a valuable discussion.

But are there any specific studies that might be needed, and perhaps before we answer that question, Dr. Abramson, you may want to delay that until we get done with the efficacy discussion, but since obviously this is an issue related to the overall risk-benefit.
DR. JAY SIEGEL:  And am I correct in understanding ‑‑ maybe I got heard wrong.  But the sense of this committee is that we should not require this company to address the long-term needs; rather, we should spend our efforts urging the NIH to do it?
DR. ABRAMSON:  No, no.
DR. JAY SIEGEL:  That's what I thought I heard lots of people say.
DR. ABRAMSON:  No.  I think you were hearing options.  I think I'll take a crack at it.
What you heard from the committee is that we need more long-term data, that you're doing with the company a lot of very important things to address that.
I think there's a sense that it may not be coming up to the necessary level perhaps, the four-month issue and the infection we talked about, that maybe that needs to be extended, just as an example.

But I think in the bigger picture, the long-term, big picture is that the agency and the corporations and NIH have to look at this as a generic problem.
I think for this particular issue, beefing up what already sounds like it's being done, it sounds like we're very much on the right track here with the European Registry, the five-year clinical trial follow-up, and this high-risk group, and then backing away from being able to make any comment about tumors just yet, based on the one- or two-year period.
I don't think it's fair to make a presentation that there's no increased risk of tumor because we have 25,000 patient-years of experience.  We have one year of experience in 25,000 people.  That's all we have.
DR. SCHWIETERMAN:  Let me just add, if there are no more comments,  I think it's sound advice we're hearing, and the agency has actually heard this before from this committee, and without getting into the policy that we're having for the development of rheumatological agents, given that this is a rapidly-developing field, and obviously the standard of care and the needs of the patient are changing, our requirements simultaneously are changing, and so I just want to reassure the committee that this is not a static thing, that we recognize the points being made and have actually begun to engage sponsors in high number of patient trials and so forth.

DR. ABRAMSON:  And remember, we're not talking about withdrawing this drug or approving this drug.
Any other comments?
(No response.)
DR. ABRAMSON:  Okay.  So let's go on to Clinical Measures.  "Rheumatoid arthritis is a chronic disease with symptoms that wax and wane over time.  Drug effect can be assessed in different ways.  The measurement that captures the entire experience over the duration of the trial, and that potentially discriminates small degrees of improvement, such as the integrated ACRn, has the advantage that it incorporates all the trial data.
Alternatively, measures, such as ACR20, may better reflect a meaningful clinical response, and there is more experience validating this as a measure of clinical benefit compared to the ACRn.
Finally, endpoints that are measures of response status at the end of the trial may better reflect the likelihood of a durable response and thus be more clinically meaningful.
In this trial, Enbrel effects on ACR were detected earlier than methotrexate, but the differences at the end of the study were less marked."

I'm going to ask David Felson to first comment on the Question A here.
"Please comment on the use of ACRn area under the curve as the primary measure of clinical benefit."
DR. FELSON:  I think this was a well-designed and well-thought-out trial.  Let me start off by saying that.  I was personally very impressed at how the data were presented and how they were planned.
I got the sense that there are two ways of evaluating the outcome in the efficacy of the analysis that were used here, and I think we need to separate them.

One is ACRn, and the other is area under the curve, and what generated the power that was seen was primarily area under the curve, which can be used also for ACR20.  It almost always generates more power to average effects over time in people than it does to take one landmark point in time, and symptomatic of that was the comment I think Jeff or someone else made that when ACR20 area under the curve was looked at, it also showed highly-significant differences between Enbrel and methotrexate, suggesting to me that that was the reason that there was more discriminate validity here, was because the area under the curve analysis was used, which is a thoughtful and appropriate way of analyzing data which may not show as much precision and power at any given point in time.  So I think the notion that ACR20 might not be as good as ACRn is ‑‑ I don't know that this trial speaks to that.
I should just comment that ACRn turns out to revolve around one measure, if you think about it.  So what happens is a patient improves by five out of seven measures, and then the ACRn is defined as the measure among those in which the patient improves the least.
Okay.  So it's dependent on one single measure, not on a panoply of measures, although to get there, the patient actually has to improve on a panoply of measures, and that is not as statistically powerful as developing, say, an index measure, and therefore it would be expected that if you wanted to maximize discriminate validity, you wouldn't use ACR20, you wouldn't use ACRn, you'd just use an index measure, and that's actually in the ACR Committee development work that the FDA was involved in, and that's what the statisticians all wanted to do, because they knew it would maximize power.

The trouble with an index measure, and somewhat the trouble with ACRn, is mentioned here in this paragraph, which is that there are a lot of other elements to the process that we went through.  One was to try to figure out what's a minimal clinically-meaningful improvement, and that was done with surveys of rheumatologists testing out patient improvement, and that threshold of greater or equal to ACR20 in multiple different outcome measures was arrived at after that other element was decided upon, okay, meaning that that greater or equal to 20 percent isn't just chosen because it provides the best discriminate validity.  It turns out its discriminate validity is quite good, but it's also there because it sort of represents a minimum threshold level above which patients seem to have improved, clinically improved.
And the other big advantage right now of ACR20, and it's not necessarily a reason to continue to use it, but it turns out to be a big advantage, is that it's being reported by everybody.  So if you look at the presentation that the Immunex folks made and the FDA made, there were explicit comparisons right off the bat with ACR20 rates in other trials, other drugs, methotrexate and other ‑‑ I mean, I can tell you there are lots of such comparisons.
It's a very valuable benchmark now because it's being widely reported.  So I would think that ‑‑ you know, could other ways of evaluating efficacy be used, might they work better in terms of discriminating between active treatment and control?  Yes, you bet they might work better.

Does this work pretty well?  Yes, it works pretty well, based on a lot of different analyses of different data from different data sets.
I would suggest that it's a very reasonable way of testing efficacy, and that it provides a nice standard that we can all go to a lot.
One other comment about the results presented, and this paragraph also comments on it, I think, very perceptively, which is that in my reading of the ACRn analysis and the area under the curve analysis that was done in this trial, that the difference in AUCs is generated by the fact that the Enbrel patients respond earlier than methotrexate patients.
It's not necessarily based on the fact that there's any important difference in the ultimate response rates of Enbrel and methotrexate, and I think that's a distinction that we need to keep in our mind's eye as we look at this trial.
DR. ABRAMSON:  Dr. Simon?

DR. SIMON:  I also agree this is a very well-designed trial, and for those who don't know, I'm not a fan of methotrexate, but I take a little issue about the earlier response issue, because, in fact, when you think about it, they were patients who were underdosed at the beginning with methotrexate, based on safety and other issues, and they may have been overdosed with methotrexate later on in the trial, showing equivalency or lack of difference in response between the two, until you did an ACRn.
So I'm a little bothered by some of the claims that you would get rapid response which may be seen with methotrexate as well, although the incidence of three patients with interstitial pneumonitis augurs poorly for the use of high-dose methotrexate.
On the other hand, we've all seen that more methotrexate is used all the time, and it's not uncommon in my practice to start off patients well above the 7.5 milligram point and then us putting patients at greater risk.
Thus, I still am confused in the discussion that David just gave, in that we saw improvement with the ACRn across all parameters at all time points, but yet when you look at the ACR20, there was no difference after six months to a year between the two.
Which one do we put more weight on?

DR. FELSON:  I'm not sure.  I guess I'd defer to the company or to Jeff or someone who's analyzed these data.  I didn't see them do an analysis of efficacy parameters between six and 12 months.  It looked like the radiographic parameter changes weren't different between the two groups, but, I mean, the differences were generated by that early zero- to six-month curve primarily, I mean, in almost every one of those outcomes.
DR. ABRAMSON:  Can someone from Immunex address that?
DR. JAY SIEGEL:  It is somewhat comforting to note, I guess, in our analyses that if you look at the various ACR curves or the various radiographic curves that on almost any endpoint, Enbrel at 12 months had a point estimate that was somewhat better than methotrexate, but I think it would be correct to generalize across them, although there may be some exceptions that, if you look at specific points in time in general, you see significant differences in the first several months, and then in the last half year, you see still a separation but no significant difference.
DR. FINCK:  I'd just like to add that the endpoint of area under the curve for ACRn was the prospectively-defined endpoint.  It wasn't used after the fact to make the two drugs look different.

We did prospectively define it as the prospective endpoint because we did want to try and follow FDA guidelines that recommended that area under the curve might be a better way or at least over time might be a preferable.
I don't think we really had seen a lot of area under the curve or over time analyses except in the European data, which is very impressive.  They use the disease activity score over time.
We agree that there is not a significant difference at a single time point at the end of six months or 12 months, but the rapidity of response with Enbrel is an important feature of Enbrel and needs to be taken into consideration, and we did give methotrexate a reasonably fast onset, so that it could have its best performance.

Actually, in clinical practice, it may have a much slower onset, and the difference would be even greater, but I would like to show one slide because I think that it shows you how powerful the ACRn under the curve was, and that is, if you look at weeks at ACR20, weeks at ACR50, weeks at ACR70, which have been used in other trials, there's statistical difference, in fact very impressive statistical difference, between Enbrel 25 milligrams and methotrexate, and also, if you look at the DAS, which is a validated index that's used as area under the curve or has been reported as area under the curve, it also shows a very high statistical performance between 25 and methotrexate, and when we did a correlation coefficient between the area under the curve for the DAS and the ACRn, the correlation coefficient was .8.
So these two measures correlate very, very well, and you can also do area under the curve for any of the individual ACR criteria, and Enbrel 25 milligrams performs better than methotrexate with the exception of tender joint count which approached significance but did  not go over significance.
So I think you have a choice, but we did prospectively define, and again I'd like to remind the committee we're asking for efficacy, not superiority, over methotrexate.
DR. ABRAMSON:  Right.  While you have that slide up, and picking up on Dr. Felson's point, how much could that be attributed to the earlier response?
If you're dose escalating methotrexate, so the first month or so, you're lagging behind in getting a therapeutic effect, how much ‑‑ it's just understanding how the data is presented.

DR. FINCK:  We also want to show that the responses ‑‑ we're looking for a slide comparing the Phase III results in placebo-controlled trials to what we saw with Enbrel in this trial, in the early RA trial, compared to methotrexate, and I don't know if we're able to find that.
But many of you do remember these, that in our earlier trials, we saw similar ACR response rates at the prospectively-defined endpoints of the trial that we saw in the ERA trial.
So we didn't feel that we in this trial had to actually show that Enbrel was effective against placebo.  We had shown that, and that it was important to show that it was effective and at least as effective as ‑‑
DR. ABRAMSON:  But that wasn't my question, though.
DR. GARRISON:  And we do have everything.
DR. ABRAMSON:  Dr. Brandt has a question.
DR. BRANDT:  You have about one out of three patients who doesn't hit ACR20.
What have you done to compare the responders with the non-responders, and what have you learned about the differences between people who respond and people who don't?
DR. FINCK:  We've actually looked at this.

Can I have the slide up?  We've looked at ACR responders and non-responders using the ACR20 criteria as a landmark analysis and looked at not only total Sharp score but with erosion score and clinical response, but in this case, if you look at the radiographic results, you can see that there's really not a clear pattern.
There are responders and non-responders who  have very little change on their total Sharp score and on their erosion scores, and although the Sharp scores tend to go up in the methotrexate and in the lower Enbrel group, they go down, there's really not a correlation per se.
Can I have the one ‑‑ I think it's 4.  That's it.  If I could have this up, we did find a correlation between patients who had the best clinical response with patients who had the least radiographic progression but not when we looked with ia landmark analysis.
When we looked at it over time, the best correlation was with area under the curve for improvement in CRP with a correlation of .45, which is similar to what's been reported in the literature, and every other measurement that we looked at as an area over time or improvement over time, we saw that those patients, the better their response, the least their x-ray progression.
DR. BRANDT:  I was wondering about predictors at the outset.
DR. FINCK:  Right.  We didn't find ‑‑ you mean in terms of the out ‑‑ I'm sorry.

DR. BRANDT:  Are there any differences at baseline that you might use to predict responders and differentiate them from non-responders?
DR. FINCK:  No, we didn't find any baseline predictors that would have suggested we could have sorted them out.
DR. ABRAMSON:  Dr. Katona?
DR. KATONA:  A follow-up question on the very same issue.
In the briefing document, there was one figure that the age 60 and less than 60 and more was compared, and these were looking at erosion scores, and that was really the only figure in which Enbrel performed worse than methotrexate.
So the question is, was the group which was about, if I remember, 25 percent of the patients, more than 60 years of age, different in any way response rate or complication rate different from the others?
DR. FINCK:  First, I'd like to show the odds ratio for the age less than 60, greater than 60, if I have that up.

As you can see, to the right of the blue bar ‑‑ for this, it would be that if it's to the right of the blue bar, it means that they had better response on Enbrel, and to the left of the bar means that the response was better on methotrexate.
Most of the patients were under the age of 60.  So we get into talking about very small numbers here, but you'll also see that those confidence intervals overlap that bar or that blue line.  So I don't think you can make a statement that anyone over the age of 60 would not have an effect from Enbrel.
DR. ELASHOFF:  I have a brief comment on this.
Looking quickly to the FDA analyses, from what it looks like is that for the Enbrel group, you can't do much by any of the baseline predictors that they looked at, although perhaps some of them worked for the methotrexate group as predicting more or less response.
DR. ABRAMSON:  First, Dr. Simon, and then Ms. Malone.
DR. SIMON:  I just want to go back one more second to the minimally clinically-important differences because both of those issues seem to be growing in importance as we're looking more and more at this data.

I'd like to reiterate that again this is a very good study, and it has very good data in it, but a little bit of a problem is, is that we don't even know yet whether these measurable differences in x-ray change are important clinically.
We think they might be.  We still don't know, but, more importantly, I wonder if again I could ask David to comment.  Since the ACR20 has built in kind of a minimally clinically-important implication in its measurement, the ACRn does not.  How does then one interpret the change as being between methotrexate and Enbrel as being important or not important, although statistically important?
DR. FELSON:  Well, you can't make a judgment about whether it's clinically important if you use the ACRn because there's no guideline as to what particular ACRn difference might be characterized as clinically important.
I mean, the potential advantage of this is that it might be able, because it's data-based and data-driven, to have a little more discriminate capability, although because it's derived from one measure rather than all seven measures, it's not very likely to be.  But clinically-important improvement is not determinable here from this measure.

DR. SIMON:  Can I just make one more comment about that?  Sometimes things get brought up at this committee and to the agency, and then other companies in the audience or elsewhere then jump on to the bandwagon because they see a successful measure that gets then approved or voted on in certain ways.
I would like to reiterate that that's a very important point, that if you don't have any defined minimally-important issue that you can then apply to the measurement, it becomes very difficult to understand how to think about that in the care of a patient, and I'd like to urge people before they start to use the ACRn regularly, that they remember that we don't know what it means and what the changes might or might not mean as it relates to the progression of disease or how the patient functions over time.
DR. JAY SIEGEL:  I have no problem with that advice, but I would like to point out that there's a difference, and when you talk about what's minimally-clinically important, there's a difference when you're talking about an individual patient level and a study level.

One of the factors that goes into a determination that 20 percent improvement is meaningful is how much improvement it is to make a life difference in the patient, but another factor that goes in often, and I'm not a rheumatologist, that often goes into these cut points is, well, you know from experience that if somebody is 10 or 15 percent better, then the next time you see them, they'll be maybe 10 or 15 percent worse, and so you don't know if that's a real change.
If that's a factor, that's not the same when you're looking at a 10 or 15 percent improvement over a large number of people that's statistically significant.  So that's just something to bear in mind.
DR. ABRAMSON:  Leona, please.
MS. MALONE:  This is sort of a basic question from the patient's viewpoint.
If you're not showing that the Enbrel is superior to methotrexate, why would a patient new to the disease go ahead and take Enbrel as opposed to methotrexate?  I mean, that's basic.  It's why.  Methotrexate's been around a little bit.  There's a little more data on it.
What would be a deciding factor?  I'm a patient.  I don't know what to do.
DR. JAY SIEGEL:  Let me answer that question first because I don't want to answer it from the marketing perspective but from the legal perspective and just to mention two things.

One is that our law requires that a drug be safe and effective.  There's nothing in our law that requires that it be as effective as other drugs that are out there.  So a lot of hypertensive medications, antibiotics, whatever they are, get approvals that haven't shown themselves to be superior to other drugs.
Just from the regulatory point of view, it's important to note that.
From a drug development point of view, it's important to note that there are many reasons why a drug which is equivalent in efficacy may be preferable.  It may have a better safety profile.  It may cause cost competition.  It may be more effective in some subsets of patients.  It may be more effective in patients who fail the other one or it offers different therapeutic strategies and regimens.
So there are reasons behind the regulatory approach that allows additional effective drugs to be approved, but that's not addressing your question as to why one would choose the product.
MS. MALONE:  No.
DR. ABRAMSON:  Let me address that.
MS. MALONE:  I understand that.  I understand that, and I know that the need for, you know, a lot of different medications in the same class is because sometimes one will work, one will not.

But what would make me want to take this initially?
DR. ABRAMSON:  In fairness, there are, as we've heard during the public hearing, people who have very dramatic and extraordinary responses in the short term to this drug.  So that it's hard even to do a double-blind study sometimes because people get so much better, and I think that is the issue.
Now, the data over time then you see, over six and 12 months, the differences tend to become closer, and so that that immediate dramatic effect arguably tends to diminish.
Now, there may be many people, and I'm sure the patients here today will tell you that this effect can be sustained and extraordinary.  So I think that's what we're talking about, but really what's on the table today is does waiting three months for methotrexate to work compromise you from getting that effect?
It's not like you can wait 20 years with rheumatoid arthritis before you can get to this drug as some of the people we heard from today had to do.  The drug's terrific.  It's on the market.

The question that we're discussing today, if many people just come together at three months, and we don't have enough safety data yet perhaps, that's the question.
Now, the other thing is that when you look at the ACR50s and 70s and don't talk about individual anecdotal experiences, you know, you tend to see curves that are very comparable with many of our drugs.
So it's not as if a 100 percent are getting better on this drug and only 50 percent on our other drugs.
Lee?
DR. SIMON:  Well, that extension really leads to what's minimally clinically important, and what are the differences, and that's why this is such a difficult question, and your point about individual responses versus group responses is really critical.
Unfortunately, clinical trials are group responses, and they're designed and done for a regulatory issue, of approval, based on the law that you so eloquently described.

The problem, of course, is that doesn't answer the questions that we need, which goes back to the original discussion, and the problem is, is that often what gets done in this business of regulatory discussion is not the same thing as determining what is minimally clinically useful or important, but that's what Dr. Abramson is referring to, and that's what goes into the different decision of which drug to choose at which point in time.
DR. ABRAMSON:  Okay.  We'll do one last comment, and then we'll go down through the questions.
David?
DR. FELSON:  I actually wanted to make a comment that was derived from looking at some of the slides and thinking about this a little.
We've published data suggesting that especially for methotrexate, that response rates diminish with disease duration quite dramatically, so that if you start drug early in disease, you get a very high response rate.  If you start drug later in disease, probably later patients also represent patients who haven't necessarily done well with earlier treatments, you respond less.
In C-83 of the sponsor's presentation, there's a histogram of ACR response rates across their different studies, and I think their original studies wee salvage patients, like all RA studies start with, patients with quite long disease duration, and what you notice here is not that curve, okay, meaning that response rates don't vary by disease duration.

The DMARD failures, Phase II-Phase III, failures methotrexate and Enbrel, and please, company, correct me if I'm wrong here, were all studies done in patients whose mean disease duration at baseline was something like nine to 10 years.  In one of the cases, I think it was five years.
DR. GARRISON:  Eleven years.
DR. FELSON:  Eleven years.  Fair enough.
Now, the distinction is that methotrexate, which is depicted also on one of these histograms, has a dramatically-better effect early in disease than in later disease.
So the response rates to methotrexate in this trial was 65 percent.  In the other big early disease duration trial, which is a comparative trial of methotrexate and auranofin that Mike Weinblatt did, it was 68 percent, okay, as opposed to methotrexate treatment later in disease, which has much lower response rates, 35 to 40 percent.
So one of the arguments ‑‑ and to bring this up, we're sort of talking about ‑‑ it gets at the comment you made, Steve, of are we really holding back something that's helping patients?

Frankly, the data suggest that people with early disease respond to just about everything, and that it's only in later disease that the response rates for other things start to tail off, and this really assumes ‑‑ so, you notice that in order for them to demonstrate a statistical significance between measures which have been easily able to detect significance between Enbrel and other drugs and other studies, they had to come up with an area under the curve special analysis.  The ACR20 repeated measure didn't necessarily do it, and that's because the differences were really small, okay, and that's because methotrexate works well in early disease.
Okay.  This treatment has its greatest marginal effect on efficacy and greatest help for patients later in disease, not earlier in disease.
DR. ABRAMSON:  But not to be denied early.
Just want to know if Drs. Garrison or Finck want to comment on what Dr. Felson said.
DR. GARRISON:  Well, I think you're right, that we have very good consistency of our results in multiple disease durations, kids, adults, elderly.
We tried very hard in this trial to design it so that methotrexate would work very well, and we did do sort of a look at most of the physicians who were involved in this trial, and they were marginally uncomfortable with how aggressively we were dosing methotrexate three years ago.

So they would not have wanted to start methotrexate at the levels that you're starting at in your practice, Lee, and I think that the rapidity of response is important to people who have chronic pain, and what we're asking for here is not that all physicians use Enbrel first in treating every RA patient.
What we're asking is that you be allowed to have the option to use this first in a patient that you think that Enbrel is the treatment you think is best for that person.
DR. ABRAMSON:  Why don't we move on to B and C together, and I'm going to read it but ask again Dr. Felson, who has the most experience in this, to make the first comment.
So "if approved for the proposed indication, to what extent should the label for Enbrel reflect other measures of clinical benefit, including landmark analyses of ACR20 at six and 12 months, and to what extent should the label emphasize higher degrees of response, including ACR50 or 70?"

DR. FELSON:  I think that the label ought to have as much information that's clinically useful as possible, and I think those are useful pieces of clinical information, so I would think that both B and C, the answer, I think, is yes.
DR. ABRAMSON:  So the question, when I read this, is it just the data for Enbrel or is it comparative data, such as we were presented today?
DR. SCHWIETERMAN:  Admittedly, this is a question that we don't normally ask because I completely agree with Dr. Felson.  The label ought to reflect what the data show and in a way that is helpful to both the physicians and patients alike.
Behind this question is a general recognition that the ACR20 has been questioned, both in meetings and actually in print, as a clinically-relevant endpoint, and while we don't have the time to get into that here, and I don't mean for this meeting to be a discussion of that, I wanted to get the committee's general sense of what they felt about these endpoints.
I think it's been helpful today.  Clearly, there's a lot of things to measure in rheumatoid arthritis, whether it's early versus late response, whether it's radiographic endpoints, whether it's quality of life, and the relationship of all those together, and to the extent that we can present the data so that physicians and patients can make choices, I think it's helpful.

I was trying to get a feel for what the committee felt about, as much as anything else, to be honest with you, future trials and how we prioritize these particular things.
DR. ABRAMSON:  I think it's a very useful thing to doctors, because this is where a lot of these very excellent drugs begin to separate from less good drugs, so that a nonsteroidal will give you an ACR20 in a significant number of patients, but when you're looking for 50s and 70s, you begin to see the impact of these new drugs.
So it's sort of like sunscreens.  It's sort of like SPF30/15, and I think it's a very useful way to compare drugs.
The reason I asked about should it just be one drug versus the comparative, I would like to see it, in my own view, because you're not always looking at many drugs.  The drug that's been tested should have its ACR50 and 70 response and allows you to cross in your own mind to other drugs that may not have been head-to-head with those, but to get some standard of how to compare Drug A with B.
So I would favor having ‑‑ if further people have comments?  No.  I'm sorry.  Now it's just for the committee and the agency.
All right.  On B and C, anything else you want to hear from us?

DR. SCHWIETERMAN:  No.  That's fine.  Thank you.
DR. ABRAMSON:  On D, actually we were asked to vote on D, which I guess was one of the specific requests for the day in terms of label change.
"Do these data combined with the safety experience support expanding the current indication for Enbrel to include a signs and symptoms claim for patients with early RA who have not yet received a DMARD?"
Dr. Simon?
DR. SIMON:  Well, I think this question really is an extension of what Ms. Malone just asked, and I think that in thinking about it some more, what would I do as a clinician in that with the data we've now accrued, it does appear that with the speed of onset of response, that given the safety profile of comparative between methotrexate and Enbrel, that Enbrel's probably more tolerable, and under those circumstances, with at least as good a response, perhaps faster onset, you would need more methotrexate to get the same response.
I think that it is an unreasonable issue to allow to be used without failure of a DMARD.

DR. ABRAMSON:  So you would be willing to catch up, let a month of improvement, without the 15 years of safety data that we have in methotrexate and a 25-year disease, make you evaluate this question a particular way?
DR. SIMON:  Well, as everyone has heard me over and over again, and I was one of the few people to vote against Enbrel's approval originally because of its issue of safety, lack of a safety database that was long-term, I do believe we are iteratively accruing more and more evidence.
I think methotrexate is also a dangerous drug, and yet everybody thinks it's the gold standard, which I think it should fall from because of its lack of safety and its risks.
So on the context of unsafe drugs, we don't know whether or not Enbrel is or is not because we have not had enough time.  Given the information that we have, this is how I see it.
DR. ABRAMSON:  And we'll get the data more quickly.
Any other comments?  Dr. Pucino?
DR. PUCINO:  I think from what we know so far, it looks pretty good for early onset for management.  So I think as it's stated that this drug probably should be allowed a chance to be used.
DR. ABRAMSON:  This is not a vote now.

DR. PUCINO:  Oh, okay.
DR. ABRAMSON:  It's just comments.  I'm sorry.  Go ahead.
Dr. Felson, do you want to comment?
DR. FELSON:  No.
DR. ABRAMSON:  Dr. Harris?
PARTICIPANT:  Would you entertain a comment from the floor on this?
DR. ABRAMSON:  I think not.  Well, you know, David, if you want to address the pediatric issue specifically ‑‑ your term expired on this committee.
(Laughter.)
DR. ABRAMSON:  So let me just speak to the other side that Lee raised.
I have a concern that because it is so effective in the short-term, that it will become a drug of first choice in the community.  I'm still concerned about some of the signals of sepsis, and it's not fair to bear the burden of tumor on this drug, but I just don't think we have enough data available.

So I still share those issues.  I think there is still a need to gather more information on this drug, again remembering that this drug did not come to market with the numbers of patients studied that we see with other drugs.
When we did Arava, for example, there were thousands of patients who were treated.  There were 200 people treated for a year when this drug was approved and about 5 or 600 for six months, and now we're a year or two into this process with many patients treated, but many of them for relatively short periods of time, without good capture of adverse events necessarily.
So I would still wait another year in my own view.
DR. FELSON:  I didn't have the courage to say what you said.  I've sort of been leaning on the fence in terms of thinking about this problem because I think there's wonderful efficacy data here, and the safety data is genuinely reassuring, I think, despite all the concerns we all had.
But the truth is I wouldn't want to give a patient with early rheumatoid arthritis this treatment without some better data on long-term safety.  I wouldn't want to sentence them to potentially having a really dangerous long-term side effect without knowing more, especially since there's nothing keeping them from ultimately getting it.

This is approved.  It will be straightforward for them to get a later point, and let them go ahead and, you know, try and get treated initially with something that's got proven efficacy and where the safety issues are better appreciated than this.
I think that that remains my concern.  I'm still not sure, though.  I think I could be convinced either way.
DR. ABRAMSON:  Yes?  Dr. Harris?
DR. HARRIS:  You know, listening to all of this, my own view is probably more like Lee's view.
I feel that Enbrel is being used anyway, I mean, even, you know, if we say in terms of its current use.  So indeed, if there is risk that we don't know, the risk will exist and occur anyway.
You know, really what we are saying is let us do it earlier.  You know, let us approve it as a first line ‑‑ not first line but as a first stage.

If there's trouble down the road, you're going to get it anyway.  We've approved it, and the trouble will occur.  So really, I think that, one way or another, the concerns about safety really are not important in terms of what we are considering today, and certainly if anybody employs large numbers of people, you know that if they're out of work two or three months ‑‑ admittedly, it's a long disease and so on, but that difference does make a difference in terms of people's productivity, and certainly given that the safety data looks relatively good at this time early, my view is it's reasonable to get this ‑‑
DR. ABRAMSON:  Let me just ask a question.  Are you satisfied with the studies that are ongoing, that will capture infections sufficiently, or should there still be a little holding back, which creates an incentive to collect more data?
Suppose, for example, the four-month study, that was all there was going to be, and it was closed out, is that an issue to talk about?  Once this is out, what's the incentive to ‑‑ Dr. Simon?
DR. SIMON:  I recognize that we're always tending towards public policy whenever we sit and discuss these particular questions, but in fact, that kind of answer will come out rather rapidly as we have seen over and over again as drugs get pulled from the market based on observational experience.

I really am troubled by our professional group, our rheumatology group's weddedness to the idea that methotrexate's a wonderful drug.  I have found personally, as a clinician and looking at a lot of data sets over time and watching presentations here, that I don't believe it's as wonderful a drug for my patients as some other possibilities.
Having the opportunity to have such an agent as this I think is very important.  Because of the lack of
‑‑ which is really represented by the health assessment quality of life issues, the fact that whenever anyone goes against methotrexate, most of the newer drugs look much better because there isn't the nausea, there isn't the other problems that methotrexate conveys even early on in therapy.
So therefore, yes, there are some significant lack of information.  I'm very concerned about the long-term follow-up.  I'm very concerned about the idea of understanding sepsis.
I would hope that they would study this in winter, not in summer, for only a four-month period of time, if they're trying to answer a question of infection, when we all know when we admit our patients, hospitals are empty in the summer.  They're full in the winter with people who are infected.  So yes, I'm still very concerned about that.
DR. ABRAMSON:  Dr. Paulus?

DR. PAULUS:  I think we're discussing the question of whether we should force people to take drugs that we know are not safe before we allow them to take something that may or may not be unsafe, which we know is effective for the reasons that Lee has eloquently stated, and it's preferable to a lot of people.
The idea that this is already available on the market, therefore if a physician or patient wants to take it first, they can go ahead and take it might be true if it weren't for the control that reimbursement companies have.
So that if we say that you have to take methotrexate first, you're going to be darn hard to get anybody able to take it before methotrexate.  So I think that what we're talking about is whether we as physicians and patients should have the option to make a decision which isn't going to be impeded by some bureaucracy.
The other issue that I'd like to bring up is the question of pregnancy or somebody who wants to get pregnant.  We don't know whether Enbrel is safe for somebody who wants to get pregnant, but we do know that methotrexate is not, and that leflunomide is not, and some of the other things that we use regularly and routinely are not.

So if you had a patient who wanted to start a family, who had recent onset of rheumatoid arthritis, it's conceivable that you might consider this to be your first choice drug.
DR. ABRAMSON:  Okay.  Dr. Brandt?
DR. BRANDT:  The safety data that we heard presented are reassuring with all of the limitations that we discussed, I think, adequately, and we're not going to get long-term data soon.  Long-term data are long term.  They take a long time.
(Laughter.)
DR. BRANDT:  I think that we've heard the advantages articulated to making this available as an option early on, and the issue of putting reins on it, if we do that, we're not going to be able to free up those reins up very soon.
If there are adverse effects that become apparent with the monitoring that's proposed, they will become apparent as they emerge in less than five years perhaps, and then we have to deal with those at that time, but I think that there are advantages with regard to efficacy, and as far as we can see at this point, safety issues are in fact more reassuring to me than they were a year or year and a half ago.
DR. ABRAMSON:  Yes?

PARTICIPANT:  The point about choosing between methotrexate as the first drug versus Enbrel, I think, goes back to how much we know about methotrexate, and the fact that we feel confident about it.
I think we feel confident about using a drug that has a potential for producing significant side effects.  The only thing we have is the experience to manage those complications, but actually if you talk to patients, they actually come with a list of potential things that they don't want to have when you start them on methotrexate.
So really and truly, we're dealing with that.  There's the uncertainty what's going to happen in the long term, and like Dr. Brandt very clearly said, we don't know, and we will not know because it's a long-term effect.
So we are asking for the option, I think.
DR. ABRAMSON:  Okay.  That's a good point.
All right.  I think we're probably ready to vote on this D, unless someone has a final pressing comment.
So we'll ask for a show of hands.  "Do these data support expanding the current indication for Enbrel to include signs and symptoms with early RA who have not yet received a DMARD?"
So who would answer yes to that?  Just a show of hands.

(Show of hands.)
DR. ABRAMSON:  And no?  I'm sorry.  No is ‑‑ okay.
(Show of hands.)
DR. ABRAMSON:  All right.  So the answer is yes.
MS. REEDY:  Seven, two.
DR. ABRAMSON:  Seven, two.  Thank you.
Yes, sir?
DR. SIMON:  Just to see if I can just sway you one more time, if the ‑‑
DR. ABRAMSON:  I was already swayed.  I didn't want to be like a wimp and be inconsistent.
DR. SIMON:  If the original presentation a year and a half ago had included the data that we now have that they achieve ICH guidelines, I think we would have had a much more difficult time restricting the utility of this agent to only DMARD-failure patients.
DR. ABRAMSON:  I would agree.  The numbers last year were of great concern.

I guess the only comment, again, this shouldn't be a vote to say, you know, let the academics kind of figure out next who's, you know, and then let's ‑‑ I think we still need this issue of registry.  Everything that we talked about that's being done has to be really tightened up and be more of a policy because I don't think there should be a sense that people said there's not concerns.  I think it's just a ‑‑
DR. JAY SIEGEL:  I want to clear up one point and also get some clarification from the committee on another before we move on.  I hope I'll do this fast.
First of all, the numbers you saw at the time of approval did meet ICH standards.  Now, ICH standards take into account that they may not be right for all diseases, and I won't argue that they were adequate, but we should be clear on that point.
The numbers of patients exposed and exposed for six months and 12 months were standards, and in fact, getting those numbers did in fact delay the application for several months, delayed the availability of this drug for several months, and getting larger numbers would have delayed that further, which isn't to say it shouldn't be done, but it is to say that, you know, this is the sort of trade-off that we face with drugs always.

The clarification I'd like is on 1-B, which is what study should be done, because although you've mentioned leverage, there is, assuming we do move ahead and approve this new indication, there is still leverage.  We discuss with companies commitments to do studies.  We don't have a lot of leverage to make it happen, but now they publish the updates of how they're doing on those commitments on a web site, and obviously the community can exert a certain amount of leverage, and this company has done a good job as far as we know in conducting all the studies that they've committed to do.
You've mentioned a couple of times the concern about the four-month randomized study.  Now, we understand, of course, long-term follow-up in a cohort study, but what we've heard from Immunex and what we're inclined to believe is that asking people who are eligible for this drug to be on placebo for periods extending four months would severely impact the ability to recruit.
So if you can design an ideal study with longer periods and then not be able to recruit into it, are you suggesting maybe that that isn't right, that it should be possible to do longer ‑‑ because the other way to get power is larger numbers.  Then you don't see long-term effects, and you've made the issue that long-term effects are an issue in malignancy, but malignancy has many years of latency to present.  Infections don't, and maybe large numbers of four months is more realistic than trying to get a longer period of randomization.

DR. ABRAMSON:  Well, that may be the answer.  The point that we were addressing before is are there enough spontaneous infections over four months in this number of people to see that their outcome was worse, and as in the sepsis study that you referred to, it wasn't that the drug necessarily was causing sepsis, but in the context of sepsis, do you do less well, and so it's an analysis of how this study is powered for the background incidence of infections that you're likely to see, and what happens if you're on the drug?
DR. FELSON:  Just to respond to a tangential issue raised by Dr. Siegel and relevant to this trial and how it was designed, I think the perception, and I think the reality is that it is very hard and probably not very ethical to recruit a lot of patients to placebo-controlled trials in rheumatoid arthritis at this point, and I think the design of the current trial and even the ultimate equivalence design of the radiologic outcome was really thoughtful and forward-thinking.

I think if I could suggest to the FDA that they ought to adopt that model, I mean, I think this is a disease that ‑‑ it's no longer really acceptable to mount large placebo-controlled trials in which placebo-assigned patients receive no DMARD.  I mean, that's just not reasonable, and you won't be able to recruit patients into a trial like that because physicians won't put their patients on those.
DR. JAY SIEGEL:  Obviously, you're talking about trials such as this for a year.  Are you also suggesting that four months is ‑‑
DR. FELSON:  Well, I think four months is sort of the outer limit at which you could allow people, because after that time you begin to see irreversible radiographic change in placebo ‑‑ I mean, it's not really ethical to keep people on placebo, especially if they're in early progressive RA-type stage, and I think this is a real genuine concern, and I think the rheumatology community is not going to be willing to recruit patients like this into these kind of trials anyway.
DR. ABRAMSON:  Dr. Garrison?
DR. GARRISON:  I just wanted to reassure the committee that we have been working very closely with FDA on these issues, and we've used the best available data, which comes from some randomized trials that you've seen recently, as well as from the ARAMIS database, to try to come up with assumptions on what kind of serious infection rate we're going to see in this trial.

But we are also going to be looking at the infection rates.  We're going to have a DSMB.  People are going to be evaluating these patients very carefully, and if we find that the infection rate is not where we're assuming, we will make adjustments to the trial, so that it will be a meaningful study.
DR. ABRAMSON:  Dr. Simon?
DR. SIMON:  Just as an extension to what David just mentioned, the problem with the four-month data set, it's based on the idea that imaging as we know it today by x-ray, that the changes aren't necessarily so obvious in that first four-month period.
The problem, of course, is when you begin to image with MRI and other newer technologies, you begin to see damage much, much earlier, and you begin to measure much greater amounts of damage, if in fact that's what we're measuring.
So I'm only urging you to recognize that as in other things that have been iterative, this is also going to be an iterative event, and therefore whatever we decide today may be totally different tomorrow.  So perhaps maybe four months is okay, but I actually doubt that.

Now, there have been multiple published reports now of even six weeks of disease having dramatic changes by MRI.  If those are and turn out to be true erosions, and they are adjudicated as such, then that would suggest that even any time on placebo is entirely unacceptable, if that's real.
DR. ABRAMSON:  Okay.  Janet, and then Kent.
DR. ELASHOFF:  I'm just wondering why this four-month trial, which seems to be basically looking at infections, has to be placebo-controlled versus some other control, because if the infections are the issue, why do you need the placebo control versus another control?
DR. JAY SIEGEL:  I think the background rate of infections in this population exists and it would be very hard to precisely determine.  I don't think we could generate meaningful data otherwise.
DR. ABRAMSON:  Kent?  This will be the final comment for this.
DR. JOHNSON:  A quick comment from Drugs.
I must say in some sense, I agree with the comment about taking an equivalence, making it from an efficacy point of view an equivalence design and having it be a safety trial.  We're doing that with some big ulcer trials that have efficacy equivalence and also endpoints.

The other thing about using placebo period obviously is problematic, and the presumption is you've got background therapy, and DMARDs are going to be a part of that background therapy, and there's already a whole lot of trials that have been done with background methotrexate, including one by this sponsor.
And the third thing is you can imbalance your randomization, and you can imbalance your time on drug, and you may just need a few months of placebo to validate your assay in essence which is what you want if you had the two other arms that are going after an equivalence comparison.
DR. JAY SIEGEL:  So you were suggesting not an external control, which I responded to, but potentially like a methotrexate control or another active control or something?
DR. ELASHOFF:  Like this trial we felt shed some light on whether infections were increased or not, and it didn't have a totally placebo control.
DR. ABRAMSON:  Okay.
DR. SCHWIETERMAN:  Just one point.
The study is not designed to deny patients standard of care.  It's to deny patients the add-on of additional therapies to what they have been taking already.  So many of the patients can be on methotrexate, for example, in this study, and they will be randomized to placebo.

An important point any time we discuss placebo-controlled trials, since clearly the issue is less placebo than what's being denied as standard of care and safe and efficacious therapy.
DR. ABRAMSON:  So this study just needs to be examined for power and Type II error.
In terms of that, are you comfortable with where we are in this?
DR. SCHWIETERMAN:  Yes, we are.
DR. ABRAMSON:  I think I should just comment that this is a big issue, and I think that what we're seeing is really an outstanding collaboration between the corporation and the agency to try and grapple with a, you know, major problem, and I think everyone's doing as responsible, you know, as a model really.
I think the committee just wanted some perfection, but it sounds like you're ‑‑ some of us.
DR. SCHWIETERMAN:  Thank you.  The committee's advice has been very helpful here, and as time goes on, I think these questions are not going to go away but actually get more complex as there are more agents on the market.
So I appreciate the advice.

DR. ABRAMSON:  Yes.  Okay.  So now, to the question in Number 3, "Radiographic measures.  The design of this trial was changed from one to establish the superiority of Enbrel over methotrexate to one to establish non-inferiority of the equivalence of Enbrel to methotrexate with regard to radiographic outcomes.  However, the absence of an adequate historical trial database establishing the degree of efficacy of methotrexate on radiographic changes in early RA precludes drawing definitive conclusions from the latter analyses."
So "Please discuss whether there is a basis for concluding that the methotrexate effect in the population studied is large enough that the non-inferiority data suggest that Enbrel also has an effect which surpasses that of placebo."
DR. JAY SIEGEL:  Let me put that in plain language.

We could argue probably forever as to whether the methotrexate effect is four units and whether we should exclude 70 or 80 percent or whatever, but nuts and bolts, coming down to brass tacks or whatever the right metaphor is, if you compare the two, the outer limit of the confidence interval is .3 or .2.  I think .29 and .16 were the numbers we saw.  I don't like excessive precision in these measures, but depending on whether you use a 90 or 95 percent confidence interval, what this question really boils down to is, if you assume ‑‑ you know, the natural progression of the disease here is four or six units, and we don't have a direct ‑‑ four to six units, depending on which data you look at early on of total Sharp score per year.
We don't have a direct data of methotrexate effect early on.  We have it later on, but if you assume that it has an effect of at least .3 units, then you can draw from this comparison that Enbrel, which had a point estimate that was .5 better, and at worse, .3 worse, also has some effect, and so that's sort of what the question is getting at, is that.
Although not firmly data-driven, rather than looking at whether we believe it has an effect of four units or not, is it reasonable to presume, based on what we know about the disease and about methotrexate, that its effect is at least that large, in which case this provides some evidence of activity and efficacy?
DR. ABRAMSON:  Dr. Mills, would you like to address this question first?

DR. MILLS:  Well, from the standpoint of several things.  One, that you have to look at in terms of the historical data that has been provided for us from over the years of literature, we don't have a nice trial with methotrexate in this population to be able to address and say that indeed it's four to six, and we have a high confidence.
So from the standpoint here, you have to be somewhat reluctant to take a big step forward in this area.
From the standpoint Immunex has provided us an outstanding look at this group over one year, but this is a disease process that's going over many years, and so when looking at this, in looking at the historical data, and we're very reluctant to take Step 4 and say obviously this four to six window is going to be an idealized known given for us, and so that we can take this data and extend it, that's what we're looking for in terms of the input from the group here, is to give us some idea as to where we should take this data, and what we should look at long-term, because my concern is one year versus a long-term disease process.
DR. ABRAMSON:  But this gets a bit to the placebo discussion we were having.  It's real hard to put a one- or two-year placebo arm into a radiographic study these days.
So I guess you're kind of looking at equivalence or comparability to your comparator drugs arguably, but I don't know.
Janet, do you want to respond?

DR. ELASHOFF:  Well, strictly speaking, taking only the non-inferiority comparison by itself, I don't think you can conclude that Enbrel has an effect superior to placebo.
This is a different group than those historical controls have been based on, and to some extent, almost never in a trial without placebo can you be really sure that you're having an active effect.
I certainly understand why we don't want to use placebo, and it's a good idea to try not to, but you're always in the position, I think, of not being entirely sure that it works.
In this case, you have other measurements that do look better, so that supports the non-inferiority claim, but I think you always have a doubt in any trial like this.
DR. ABRAMSON:  So if they showed equivalency to methotrexate, how could you design a study except by comparison to another drug?
Janet, I'm wondering in terms of that dilemma.
DR. JAY SIEGEL:  Let me address that.
I'm actually quite involved in policy development internationally in this area and other areas, and I think her comments are right on target.

In some sense, you can never be certain about showing efficacy from non-inferiority trials because the margin that you set is based on a historical analysis of prior trials of the active control, and whenever you're comparing across trials, there's so many questions about the design and conduct, nature of patients, concomitant therapy, that all the concerns that arise with any historically-controlled trial arise in those underlying assumptions and the applicability of them.
So the bigger question is what can you do?  Well, we're at a setting, at least in the long-term probably, where placebo-controlled trials cannot be done.  This happens in a lot of diseases.  That leaves you with active control trials.
You cannot make an active control non-inferiority comparison valid simply because you have no other option.  If it's not scientifically valid, if there's no way to say, well, I know methotrexate has an effect at least this large, then there's no way to say for sure that you can show by non-inferiority an effect.

What we have here as the comments, I think, correctly describe, though, is something ‑‑ so first, in the theoretical where are you left, well, you're left is that this is an area in which you should design a superiority trial.  That's what was done, and that's what should have, I think, remained.
Now, here we have an ironic situation, where the superiority trial was done and had its data as a superiority trial.  It would have won on its preselected primary endpoint which was erosions.  It was changed to a non-inferiority trial because there were data on methotrexate effect on Sharp score and not on erosions alone.
It was changed, I should say, for a good reason, which was that there were inquiries that are appropriate about, well, would a non-inferiority finding be used as evidence of efficacy, and because if you think it should be, then it's best to consider how you would handle that prospectively, and the company put forward margins and percent retained numbers that they felt were appropriate ones to use prospectively, and if you're going to make that case, it's much better to do that prospectively.
But what we have is, you know, we're asking about this in B, then is that the effect on erosions, some of the effects at six months, a number of effects which would suggest superiority, which, unless you assume that methotrexate is harmful, which there's no data to suggest in this population on those outcomes, then that provides intrinsically evidence of activity.

But what we're asking about in A is the non-inferiority design and the extent to which that provides evidence, and the reason one might presume it provides evidence is that if you accept again the historical data that the natural progression is at four units a year or at six units a year, and then ‑‑ and methotrexate in this study ‑‑ the arm progressed at 1.3 units, and the Enbrel arm at .8 units, plus or minus .7 maybe, even if the natural progression of this population had been as low as two, there is, based on historical controls, the suggestion that it would be superior than placebo, but also, and I think importantly, based on comparison to methotrexate, there's a suggestion that it's within .3 of methotrexate, that at worse, the progression rate is .3 faster than methotrexate.
Again, as I stated in explaining Question A ‑‑ and my apologies for being overly wordy, but these are tough concepts, I think, and they're tough to face anew ‑‑ but if one can assume in this population, even though one doesn't have direct data, if one has a reasonably-strong presumption that methotrexate has an effect larger than .3, then these data, and I would agree entirely with the comment, they don't provide definitive evidence.

In fact, our question precludes drawing definitive conclusions, but that's part of the picture of what may or may not be a compelling picture taken in toto.
DR. ABRAMSON:  Dr. Simon?
DR. SIMON:  It seems like this is the classic conundrum, and perhaps you could help me understand it in the context of the regulatory guidance document, that clearly all of this brouhaha is created because it's not adhering to the guidance document, I presume, in that the world accepts methotrexate as a DMARD.
They throw that term around all the time.  It's never been adjudicated that way.  It's not been registered this way by the FDA.  It's not labeled as such, as altering structure by the FDA, that I'm aware of, and I also understand that the guidance document that was just out in 1999, I think, not so long ago, I presume the issue is to gain a label, such as altering structure, that you have to demonstrate that you're better than placebo in doing that, is that correct?
DR. SCHWIETERMAN:  I'd have to go back to the guidance document and check the exact language.  Certainly the spirit of it wasn't necessarily that all trials would need to be placebo-controlled trials for a 12-month study, but I don't have the guidance document in front of me to actually refer exactly to what you're ‑‑

DR. ABRAMSON:  Dr. Johnson might be more ready to answer that.
DR. JOHNSON:  I pretty much have it in my brain, I'm afraid.  Well, we fudged the issue is what it amounted to, and we said that it's preferable.
We probably made some allusion to the fact that if there are no established active controls, then you need to do a negatively-controlled trial, which doesn't necessarily mean placebo could be a lower dose.
But we also said something about in assembling the evidence, it is desirable that at least one trial be a difference trial or something to that effect.  Now, we didn't say specifically which claim that was directed toward, and the other thing that's been brought up, but I don't think been emphasized enough, is that we, too, are uncomfortable with an x-ray claim, period, which is why we wanted it hinged to a clinical claim.  It wasn't a freestanding claim like the others, unless it was a dramatic x-ray effect, which we also couldn't describe, though it attempted to in terms of the erosions.  That question was asked earlier.
DR. ABRAMSON:  Dr. Sharp?

DR. SHARP:  I'm a little uncomfortable with all the discussion about six points or four points or two points, because when you look at different people who are reading films and scoring them, nobody scores exactly the same.
I think the more critical issue here is how reliable is the methotrexate effect.  Now, that can be expressed as a percent, and you don't have to have absolute figures, although the model that FDA required Immunex to create, they had to plug in some figures.
I think you can do the whole thing without specific figures, and you could even take the figures that are already available from the study and say if methotrexate had 50 percent effect or 60 percent effect or 40 percent effect, you could look at it that way, and my guess is that that circumvent a lot of the discussion here about so many points, and I don't think it would come up with any different answer than they have gotten so far.
There was one other point, but I guess it slipped my mind.
DR. ABRAMSON:  You can come back.
DR. JAY SIEGEL:  Let me just say that there's nothing in this sort of design or model that would preclude doing it that way, absolutely, but we still don't have the data in this early population as to what percent effect methotrexate has.

DR. SHARP:  Oh, that was the point I was going to make.
In terms of the effectiveness early versus late, I must say I'm intrigued with the data in this particular trial that makes it look like methotrexate was much more effective in treating early RA than it was later on.
However, in the Arava trial, the leflunomide, 40 percent of those patients on methotrexate were less than two years' duration.  Now, there's still a discrepancy between the two populations, but I think that's reassuring, and in that particular trial, there was no difference in the effectiveness of methotrexate early or late.
DR. ABRAMSON:  Thank you.
I think I need a clarification as to what we're trying to address here, because there's statistical issues of definitions of non-inferiority and superiority in this.  But then there's the issue of whether a historical control is valid in this setting, and I think they're two distinct issues.

So I guess the question is if it were true that methotrexate and Enbrel were equivalent in their effect, if we assume that for the moment, what question do we need to address in terms of the ability to make a statement about concluding that therefore Enbrel protects against radiographic progression?
Let's assume for the moment that there's not a statistical question and take for granted or presume that these two drugs have equivalent effects from your perspective.
DR. JAY SIEGEL:  If you assume they have equivalent effects, all you need to know additionally is that methotrexate has an effect, but obviously we don't know that they have equivalent effects.  We know a confidence interval around the effects.
So really, what we need to get at to answer this question, to put it in a non-statistical but a scientific term, is we need to know how much effect it's reasonable to presume that methotrexate has in this population under these conditions.
To put it simply, if two drugs had exactly the same effect, but you studied them in a refractory population or in a population in which neither worked, then you might well get up with a lot of precision that they have the same effect, but it would not be evidence of efficacy because they could have the same lack of effect rather than the same effect.

So by showing that this is similar to methotrexate or at worse, .2 or .3 worse than methotrexate, one can only conclude that that means there's efficacy if we can conclude that methotrexate has an effect in this population, and obviously there's not direct data.  So it may not be a conclusive determination, but what we need to know, what we need to hear, and I think what you need to think about, is does being within .3 units in Sharp score progression of methotrexate provide evidence of efficacy on the basis of a presumption, if not proof, that methotrexate surely has at least that much benefit?
DR. ABRAMSON:  Right.  So let me still sort out these two issues for a moment, though.
We have two studies that I'm aware of that methotrexate is effective.  One is the Rich paper, which I've not read, and the other is the Arava data, in which Arava and methotrexate both did well.  So the question is, is there sufficient evidence that methotrexate is better than placebo is a first question?
Lee?
DR. SIMON:  Well, that's really the problem, because there is sufficient evidence that methotrexate's better than placebo based on the Arava data set.

However, that patient population was different than this patient population.  However, if you'll just bear with me in a Talmudic way, if you believe that the patients had more disease, meaning longer-term disease, in the Arava data set, even with 40 percent with less than two years of disease, where this population was all less than three years of disease, you had a similar kind of biologic measurable signs and symptoms response which was reasonably correlatable to the predictable x-ray response in the Arava data set.  That also has happened here.
So why should someone expect that a drug that worked in an older population would not work in a younger population ‑‑ meaning, you know, not as long disease ‑‑ that gave you a similar signs and symptoms response?  Meaning why should that be disparate?  Why should that be separated?  We're already making so many assumptions, that it's not unreasonable to make that great leap in this circumstance with this lack of information.
The dilemma that I have is that inherent to this data set, which is I think is fascinating, is a biologic discrepancy.  There is a big difference between joint-space narrowing effects and erosion effects, and it seems to be even bigger when you've had more disease for longer periods of time.

What we know biologically of how erosions take place, meaning osteo class-driven, cytokine-driven events, that may be a very different phenomenon from joint-space narrowing.  The dissolution of cartilage may progress at a very different rate and respond to different things.
Nonetheless, I do think that we can argue this forever, but if we're going to accept the Arava data set, we have to accept the reality that there is similar responses between Enbrel and methotrexate in inherent decrease in progression, and it seems real.
DR. ABRAMSON:  So you think there is evidence that methotrexate retards x-ray progression, based on the available data?
DR. SIMON:  I would say that, based on the available data, it appears that methotrexate does slow progression of disease.
DR. JAY SIEGEL:  And if I understand your logic, let me get this clarification, you're saying, in addition to that, that while there isn't evidence in early disease, it's not an unreasonable presumption that it would be as effective or more effective in early disease than in later disease?
DR. SIMON:  Given the fact that 40 percent of the population in the Arava data set did have early disease, that there weren't discrepant behaviors in that patient population, I think that's a reasonable assumption.

DR. ABRAMSON:  Immunex, please.
DR. VAN DER HEIJDE:  I would like to add to that, that it's all circumstantial evidence that we have, that if you look to the data that is available at this moment, it looks that there seems to be a linear rate in progression.  So that's the progression that can be seen later on in disease is also seen in early disease, and studies that are against that, they show that there is more progression in early disease, not less progression in early disease.
So then I think the minimum, if you want to have a number, would be four, and in early disease, it would even be higher and not lower.
If you take the study that was mentioned by David Felson, is that if you have methotrexate as an early drug, it's more effective than using it later on.  This would make it seem unlogical that it would not work in early disease, and in all the trials I've seen that x-rays were involved, it's very rare that in an early disease population, it's such a low rate of progression as around one.
DR. ABRAMSON:  Dr. Felson?

DR. FELSON:  Yes, there is actually another ‑‑ it's a meta-analysis of comparative trials with methotrexate in second-line drugs, and actually the first author is Graciela Alarcon, who's here, who was in the Journal of Rheumatology, and it shows I thought very nicely that methotrexate, compared to other second-line drugs which have approval for structural modification, is as or more effective than those drugs in preventing.  So that's indirect evidence of methotrexate's effect on inhibiting structural progression.
I don't know if Graciela wants to comment on her own study.
DR. SHARP:  She probably does.
(Laughter.)
DR. SHARP:  We're talking about, was it, two studies you came up with?  There are additional studies, besides that.  Jurisin compared methotrexate to Imuran, and there's no reason to believe that Imuran is worse than placebo, and methotrexate was significantly better, and Weinblatt and Barbara Wiseman at Boston compared methotrexate to auranofin, and it was better.  Again, I don't think auranofin is worse than placebo.

DR. ALARCON:  Actually, I didn't want to bring the meta-analysis because that actually is a collection of data from the 1980s with patients with longstanding disease, and I didn't think it was fair to compare it to the patients.
The Rich study, though, I believe, is our study as well, and this is a study which is small and dirty, done by a fellow in ‑‑ that doesn't mean all the fellows are dirty workers, but the point is that it was no money, just he wanted to look at what happened when you administer methotrexate as the first DMARD.
So given all those limitations, what we show is the patients that didn't have erosions to begin with, the probability that you don't develop erosions is much greater than if you already have erosions to begin with using methotrexate as the first DMARD.
DR. ABRAMSON:  Thank you.
So I guess for the piece of this, the consensus that we have is that methotrexate, given studies that are imperfect, the literature that exists supports methotrexate as effective in retarding progression, I think, the way the literature is there.
So now the question is the second half of this question.  Is the study valid from a statistical point of view?
Janet, I don't know if you were going to comment on that or you want to make another comment.
DR. ELASHOFF:  It was another comment.

The extent to which we start relying on historical control to flesh out the conclusion means that it's more important to be collecting a lot of potential predictor information and analyzing that in as much detail as possible because that is relevant to these issues of how much early versus late and this kind of patient versus that kind of patient, and is this population really applicable to that, and presumably one could in fact do something in this other study that people are quoting to compare the early versus the late in that data.
DR. ABRAMSON:  So now, the other piece of this question, I think, is only selected people can really debate effectively, and that's this issue of superiority and non-inferiority.
I'd ask the people who understand that issue, I don't know, Janet or David, to make some comments on it.
DR. ELASHOFF:  Okay.  I don't think much of the definition of non-inferiority that was used here.
However, the actual confidence interval is suggestive that they're pretty close, and as other people said, the other evidence, which is presumably relatively correlated with this, erosion specifically did come out superior.

So in this particular trial, I'm not especially worried about that issue, but in other trials, one could be extremely worried about the non-inferiority serving as a basis for a claim.
DR. JAY SIEGEL:  Thank you.  I think that's useful.
I would point out that if this trial had not been changed to non-inferiority but used the same endpoints that it's using as a non-inferiority trial, we'd be having much the same discussion because what we would be looking at would be a very near-miss on this primary endpoint of total Sharp score and some important data on the erosions and other endpoints which suggest activity and a near-miss, but not against placebo, a near-miss against a drug that we all believe to have some activity, and so in a sense, for those who haven't quite caught on to all the non-inferiority concepts, you could look at it that way.
Does a near-miss to being superior to an active control on one endpoint with support of secondary endpoints in which there was suggestion of superiority add up to evidence of efficacy?
DR. ABRAMSON:  I think we've been discussing B.  Let me read it.

"To what extent do other radiographic endpoints, including data on the number of erosions at six and 12 months original primary endpoint, and data on the six-month Sharp score support the efficacy of Enbrel in delaying radiographic progression?"
So I guess, Dr. Siegel, has this been addressed in these ‑‑ Ken?
DR. BRANDT:  Yes.  I'd like to ask a question for clarification or for edification, and I guess to Dr. Sharp, and it relates to the issue of the total Sharp score and the contribution thereto of narrowing as opposed to erosions.
Certainly if we look at knees and standard radiography, there are all sorts of terrible issues that relate to joint-space narrowing that pertain to positioning and reproducibility of positioning, especially in a multicenter study, where radiographs were obtained in multiple cities.
Can we be confident that narrowing as you see it on the film is true narrowing and not related to position?  Have there ever been correlations made between, say, cartilage thickness by MRI and joint-space measurements on a radiograph in rheumatoid hands?
Do we know that we're really looking at cartilage thinning?  Lee brought this issue up a few minutes ago.

DR. SHARP:  Well, I don't know that we can establish it's always cartilage thinning.
I think the book of the evidence is that it usually is.  In a very lax joint, you can have distraction, of course, and a lax joint again with an excess amount of fluid, you might have spurious widening, if you will.
I did some simple geometric calculations of how much impact a change in focal distance, for example, x-ray tube to hand, would make in joint space, and it's obviously quite significant in hips and knees, but it's a few hundredths of a millimeter in finger and wrist for reasonable assumptions.  So I don't think that's very likely to be an issue in terms of joint-space narrowing.
The whole question ‑‑ if you want me to address it now ‑‑ the whole question of joint-space narrowing and erosion, I think, is a very interesting one.  Is it appropriate?
DR. ABRAMSON:  Yes, please.

DR. SHARP:  Together with my colleagues back in Houston back in the 1960s, we started developing a method for scoring the radiographs.  We were convinced that erosion and narrowing were separate phenomena, and everything that's happened since then has tended to convince me that we were correct in doing so, particularly what Lee referred to a minute ago.
The pathogenetic mechanisms now are, I think, reasonably well worked out.  I think it's fairly conclusive that osteo class driven by TNF-alpha and IL1-beta and perhaps activated T cells produce a factor that helps to generate osteo class.  There's a recent paper from Lee's institution in the ANR about that.  That is related to the development of erosions.
I don't know that there's very much proof, but I think most of us believe that metalaproteases are responsible for loss of cartilage.  Maybe Ken Brandt wants to comment on that.
With these two different mechanisms, I think it's not at all surprising that we come up with a different result for erosion and joint-space narrowing.
Put it up, yes.
Historically, in many studies, joint-space narrowing has been as important or more important in discriminating between two different kinds of treatment, and as a matter of fact, in the Arava study that's been referred to so often, the P value for joint-space narrowing comparing methotrexate to placebo was a good deal lower than for erosions.

Now, here, the joint-space narrowing score comparing Enbrel to methotrexate are about the same.  One would therefore conclude that you're having an effect on narrowing by Enbrel, and erosion scores are different in that Enbrel appears to be having more effect than methotrexate, and I think that merely tells us that Enbrel works better in terms of some of the things that drive erosions.
But it also works against the joint-space narrowing.  It just doesn't show a difference with methotrexate.
DR. ABRAMSON:  Perhaps, Dr. Sharp, you can help us with one of the next questions, which says, "Please comment on the use of erosion scores versus the Sharp score as a preferred outcome measure."
So do you lose information by combining these two endpoints?
DR. SHARP:  I don't think you lose information.

Well, the Sharp total score is a composite score, narrowing and erosion, and the two are associated.  There's a highly-significant, statistically-significant association, but they're not tightly linked.  The two are driven separately, and I think in a large database, I've forgotten the exact figures, but I believe it's about .6 for Pearson correlation coefficient between the narrowing scores and the erosion scores.
Now, a composite score, if they're both working, you get a little bit extra lift out of it using your composite score.
I think many rheumatologists focus on erosions because although they're not specific for rheumatoid, they're pretty close to that.  They're fairly unique in rheumatoid.  You don't see erosions in very many other situations, and certainly the pattern of erosions is quite specific.
DR. ABRAMSON:  This losing information means the failure to pick up differences in the action of a drug, for example, as you showed between erosions and joint-space narrowing.
Dr. Brandt?
DR. BRANDT:  There's another issue, and that relates to looking at this as means, as we saw in that last slide, and again, I guess it's a reflection of disease with narrowing, how often does narrowing improve in individual patients?
DR. SHARP:  We've always assumed that was reader error.
(Laughter.)
DR. BRANDT:  Maybe not.

DR. SHARP:  Maybe not.
I think in terms of some of the swelling that may occur in cartilage in the early stages of osteoarthritis, there may well be some improvement, if you will, but I don't know that we can rely on detecting it by current methods.
Now, I think some of the computer-based methods that actually measure joint space and some of the things that I've been interested in, perhaps we could, because it's ‑‑ you can really measure very fine differences.
That's an interesting point.  Since I brought that up, in looking at an old database I have, doing actual measurements of joint space didn't behave any better in discriminating between gold therapy and placebo in scoring.
Scoring is basically pretty reliable.
DR. BRANDT:  Years and years ago, Dave Hammerman showed in histochemical studies of rheumatoid articular cartilage in areas very remote from pannus, depletion of proteoglycans, particularly in the middle zone, and I'm not sure that that's not reversible.
DR. ABRAMSON:  We're going to have ‑‑ thank you ‑‑ one comment from Lee, and then we need to sort of move along and get through the questions.

DR. SIMON:  Well, actually, I'm just a little uncomfortable with what Ken just said.  You may believe that that may be reversible, but remember that a lot of the evidence that we're talking about are people with long-term disease, not short-term disease, and I'm not aware of a lot of good data after 20 years of rheumatoid arthritis where we have evidence that Highland cartilage is repaired to the extent that you have normalized joint space under those circumstances.
You theoretically may be correct in the early on disease.  I'm still a little uncomfortable making that assumption in the longer-term disease.
DR. ABRAMSON:  Thank you.
Let's go back to Question B, because, ultimately, Question F, we need to take a vote on, and in many ways, B becomes a critical discussion point that we need to come back to.
So "To what extent do other radiographic endpoints, including data on the number of erosions at six and 12 months and data on the sixth-month Sharp score, support the efficacy of Enbrel in delaying radiographic progression?"
Again, I'd like to hear first from Dr. Mills as a radiologist on the panel here.

DR. MILLS:  From the standpoint here, looking over all of these films, you do have evidence that the radiographic changes are being delayed through one year.
Now, from that standpoint, what is the relevance, and what's the credibility of that result for you as a panel to look at?
My concern is for you to again realize that you've got a patient population that's early RA.  You have a grouping you're evaluating, and you're saying we are seeing some radiographic delay.  You don't have a long-term follow-up, and you don't have a good historical comparative data set to work with.
But, yes, the radiographic findings are there.  They're very reproducible in terms of the analysis.  We're able to determine them, and again we have an excellent data set from Immunex to say those findings are real.  Now, the significance is what we're asking for.
DR. ABRAMSON:  What do you think about the separation of Enbrel from methotrexate and the erosion score?
DR. MILLS:  Do I feel that there's a width there that's adequate?
DR. ABRAMSON:  Yes.

DR. MILLS:  It's my impression in looking at the data that it's adequate, but that's for you to come back.  You know, that is my opinion in looking over the information.
Whether or not that that means clinically ‑‑ remember, you're taking care of the patient, not the x-ray, in terms of what does that mean for you.
DR. ABRAMSON:  Any other comments on Question B?
(No response.)
DR. ABRAMSON:  Okay.  Let's skip to Question E.  "Please comment on the apparent" ‑‑
DR. JAY SIEGEL:  Can I ask something about D?  Because it follows on all these discussions and on the comments by Dr. Sharp and Dr. Simon.
So the pathophysiology is different, and based on that pathophysiology, you might expect an anti-TNF to have more effect on erosions, and in fact, in this trial, it appears that that may have been the case, and that is in fact what was prospectively looked at, and so my question is, if, on the next trial of Enbrel or some other anti-TNF, somebody wants to use erosions as a primary outcome for radiographic assessment as opposed to Sharp score, is there likely to be objection from this committee to doing that, if that's what they feel is the most sensitive measure for the effect of that drug?

DR. ABRAMSON:  Well, I mean, I think we are ‑‑
DR. JAY SIEGEL:  You're going to reserve the right to object to anything, right?
DR. ABRAMSON:  I think we don't understand the pathophysiology of those two processes very well.  We're just learning about it.
I think it's important to collect information so that you can make these discriminations because then you may learn from this kind of study to go back into the biology of the differences.
So I would answer yes, that I think that these may be two separate things.  They're both very important, and they should not necessarily have to have both in my own view.
DR. FELSON:  Just to play devil's advocate, I guess I would say no.
I mean, I think that it sort of gets at the central question of what we're interested in when we talk about preventing structural deterioration anyway.
Are we interested in using a biomarker of a synovial pannus eroding into bone at the lateral margin of a joint or are we interested more in the sort of global impression of what's happening to the structure of the joint as it progresses in rheumatoid arthritis?

I think I would argue that the latter is what we're interested in, and the best way we know how to define that latter entity, that latter construct, is by using some kind of summary score, either a summary joint-space narrowing/erosion score or the Larsen score, which summarizes it as a global score, and which I don't think any of us are recommending using, but I think to focus on erosions alone doesn't necessarily give us what I think in the clinical trial methodology groups we would call content validity, meaning it doesn't give us the range of outcomes we're interested in.
It doesn't get the whole picture of what goes on in the joint, which is structural deterioration.
DR. ABRAMSON:  Okay.  Lee?
DR. SIMON:  But my problem with that, David, is that the structural deterioration may take place at a certain point, regardless of how much active inflammatory disease is taking place.
So therefore, although it's convenient and nice and may achieve a certain validity in the kinds of studies that you're talking about, it may actually reject the provision or the reality that a certain amount of damage will ensue, and that we consider the osteoarthritis of the burnt-out rheumatoid arthritis.

So thus, one might actually get a good response to the drug to stop the disease, and yet because so much damage had already taken place, there's still further progression that you would not alter with the particular intervention that you're using.
So I think that the problem is, is that we're short of understanding all the biology.  We have a lousy imaging technology, although it's the best that we have.   There's more stuff coming on the horizon maybe that will help us a lot more, and no one has really done a good job of correlating the x-ray change to function.
So we don't even know what the small x-ray change means in the context of what you asked for, is what's important for the clinical outcome.
DR. ABRAMSON:  Yes?
DR. MILLS:  I'd like to make a comment, also, in terms of getting all of the information.  You certainly want it all.
My concern right now in seeing the data from this trial is that we appear to have two different response rates that are working.  Your joint-space narrowing seems to be working at a different time interval, certainly not in this interval for this patient group; whereas, the erosions are being affected.

So you want to get all of the information and certainly bring it back to the clinical evaluation.  The concern is, is that we are seeing these different response rates.  So they may propose a trial to us with erosions only, but we want to see all of the data to come in, so this committee can assess it, because, frankly, you have a very limited historical data set right now, which time we reach back for it, we find it is to certain extents flawed, and so when extending back into our evaluation, we say, we've got to have this data and evolve it from here.
DR. ABRAMSON:  You know, it's a very important discussion because we've taken x-rays to become a gold standard, when in fact they're the surrogate endpoint for clinical outcome.
So now we begin to get this data, and we have to then validate what's predictive of disability and problems.  So it's another piece of information that's not available.
DR. FINCK:  Can I just add as the sponsor that I don't think there'd be a time when we would only read for erosions.
DR. ABRAMSON:  Right.

DR. FINCK:  Obviously, we want as much complete data on the pathophysiology of this as the members of the committee.
But I do think there are differences in the way drugs work and how they affect the mechanisms, and that you might actually see a differential effect as we saw in this trial.
DR. ABRAMSON:  Right.
DR. JAY SIEGEL:  And the question was not suggesting that one should only read for one element, but one likes prospectively to determine a primary measure for various reasons.
DR. ABRAMSON:  David?
DR. FELSON:  I guess I want to make a measurement comment, which is, I'm not sure you saw different effects in this trial.
I mean, you saw parallel curves for methotrexate and Enbrel for joint-space narrowing, and if one assumes that methotrexate has substantial effects on joint-space narrowing, then Enbrel does, also.
Okay.  You saw slightly greater effects in erosions, and I'm not sure that the differential effects are really clinically important or meaningful.  I mean, it's just not at all clear that the distinctions that are being made among all these different trials in terms of what changes with what are all that meaningful.

DR. ABRAMSON:  One last comment from Dr. Sharp, and then we'll go to F.
DR. SHARP:  I have a comment that x-ray changes don't correlate well with other things.
There are many studies that show that the x-ray score correlates not at a very tight level but correlates with function, correlates with deformities, correlates with limitation of motion.
We know that there are measurement problems with some of these, and we also know that the curve against time of disability is a different shape than x-ray.  Disability early in the disease is pain and swelling.  Later on, it's anatomical damage.
But these things do correlate, and if you project the change that we see over one year of observation over, say, a 25-year life span of many patients with rheumatoid, the difference between really active treatment and placebo in bygone years when placebo treatment was legitimate is really very striking, and you would predict there'd be a big difference in the functional ability and the deformities at the end of 25 years of effective treatment, and that assumes that treatment continues to be effective throughout, which we don't necessarily know at this point.

DR. ABRAMSON:  Okay.  Thank you.
All right.  Let's move on to the last question on this page.
"This trial was conducted in patients with early RA, less than three years' duration.  Do the data support a claim that Enbrel delays radiographic progression in patients with early RA?  And to what extent can the radiographic data be generalized to patients with longstanding disease to support a general claim for delaying radiographic progression?"
So anyone like to comment first on this?  Yes, Dr. Simon?
DR. SIMON:  Well, I actually have a question as it relates to this question, because the slide that was presented by the sponsor didn't use this terminology.
What are we asking in that context?  Are we talking about just slowing progression or are we talking about prevention of damage?
DR. JAY SIEGEL:  Well, on the slide I guess the sponsor used the word "preventing," and maybe the guidance document uses the word "preventing."

As you see from the data in this trial, progression occurred on both arms.  Neither arm was better or even as well off at the end of the trial as they were at the beginning of the trial, and I don't think, if you read the document, it wasn't presumed that the standard for getting a claim regarding progression was that there be no progression whatsoever, that the disease stabilized, and that's why the question is in terms of whether there could be a claim of delaying.  Maybe there's other wording that would be better than delaying, but diminishing or whatever.
DR. SIMON:  Well, that reason that becomes even more important is they did show other slides that showed evidence there were no new erosions, and I became confused because that could be construed as not having new erosions as a more biologically-evident event that you've prevented that disease process, because the progression of erosions may not be due to ongoing inflammatory disease.  It may be due to the previous damage that took place that couldn't be healed, and so I think this is a much more complex issue, and I think it does turn on what data we have, which is, what emphasis would we place on the data showing no new erosions in this year-long period, and were there any differences between the two products in that context?

We've not had good evidence before about no new erosions in the historical data sets that we've already referred to.  So I think that there is something that we have to grapple with there, and then the other issue is, is that it probably did slow progression, but how important that is, I don't understand.
DR. ABRAMSON:  All right.  To add to that, we based a lot of our prior discussion on using the historical controls in the literature, and we referred to the leflunomide database, and leflunomide does have approval, have some language in the label about preventing progression.
At some level, we have to discuss how comparable this language needs to be, since we base some of our conclusions on the comparator methotrexate in that study.
So to the extent that this says more than that label says, I think we have to be careful, and I think we need to discuss that.
Kent?
DR. JOHNSON:  I think, actually, if that was the language we used, it may have been a mistake, because it speaks to a higher achievement than actually usually occurs, and we've actually remedied that in the OA document that's rolling along.

It should be pointed out, and maybe everybody's aware of this, that we have not recognized ‑‑ in the document, anyway ‑‑ a stand-alone claim, as I mentioned before, and leflunomide was approved on the basis of a couple trials, both of which had a placebo anchor, and from an evidentiary point of view, the methotrexate was irrelevant and the sulfasalazine which were the active controls.
DR. ABRAMSON:  Okay.  All right.  So any other comments on this?
(No response.)
DR. ABRAMSON:  Can you give us a clarification then in terms of Lee's comment and the Arava, as to, if we are going to take a vote here ‑‑
DR. SIMON:  What are we voting on?
DR. ABRAMSON:  Yes.  What are we voting on?  Are we in essence endorsing the request for the label change or are we ‑‑ you know, what is it then?
DR. JAY SIEGEL:  Well, we need advice as to what to label, if anything, regarding the x-rays.
I guess I would say that I think that's potentially an important point.  Jeff may be able to address it or the company better than I can, the difference between progression that occurs from expansion of preexisting lesions versus the development of new lesions.

I would let it suffice from my remarks to say that that's an exploratory analysis, that the measurement of erosion as primary analysis was the measurement as done in the Sharp score, which takes into account both of those, and it is with regard to that measurement that I was commenting that both groups progressed, although arguably greater progression on methotrexate.
Although I wouldn't want to restrict your thinking to the wording that we put here, I think that Kent's comments would be consistent with mine, that given this sort of finding, if we believe it merits a claim that the right wording isn't to prevent progression, if in fact there's less progression on one arm than the other arm, and whether the right wording is "delays progression" or some other is something we'd be open to, but I think the bigger question is, is there enough meaningful data about the effects of progression to indicate that this does affect x-ray progression, and then we can figure from there what sort of wording.
The second part of the question, of course, relates to our concern if we know it happens in a one-year database, in fact, and the biggest difference was at six months, and obviously simply because the trial only lasted a year, we don't know beyond that, does that support a general claim or a claim for the first year of treatment or what?

DR. ABRAMSON:  Bill?
DR. SCHWIETERMAN:  Yes.  I'd just like to second what Jay had to say.
The issues about radiographic progression, unfortunately, make the guidance document obsolete because there's no discussion about many of these issues.  Healing of erosions, patients who are non-progressing, delaying radiographic progression and so forth.  There's no hierarchy of claims in that particular subset, all of which matter.
We're not sure what those answers mean, but we deliberately did not phrase questions in this particular meeting here because there was enough on the agenda already, and, B, it would be, I think, a little bit premature to go into this at this particular point but not really premature.
Suffice it to say that this committee will be seeing from the agency questions and potential changes to the guidance document and all these things because we're having to face these questions right now, the sponsors that are coming to us.
DR. ABRAMSON:  Okay.  So why doesn't the committee look at the first question under F?

"Do the data support a claim that Enbrel delays radiographic progression in patients with early RA?"
Before we take a vote on this, are there any other comments that people want to make?  Janet?
DR. ELASHOFF:  It seems to me that the claim, the more specific one is about what the data show, the more defensible the claim.  So what we specifically, for example, see is a lower erosion score rather than more general words, like radiographic, more general words, like progression, and more general words, like delay.
DR. ABRAMSON:  Well, you see some comparability to methotrexate, which, as we said before, might be preventing joint-space narrowing by previous studies.
DR. SIMON:  In the comment you made before, are we not trying to set a new bar here?
I mean, the problem is, is that we do have precedent, and I would like to know what was written in the Arava label, because that really does make a difference, because whatever that said, we have to be careful to construct this in a similar fashion, if we believe this evidence is real.
So could somebody help me with this?
DR. ABRAMSON:  Where's the PDR?
DR. GARRISON:  We have the Arava label, if you would like it.

DR. ABRAMSON:  Okay.  Perfect.  Thank you.
DR. SIMON:  That's exactly what I was going to suggest, that in fact as per Janet's observation, this is addressing the observations.  We can choose to maximize and minimize based on the issue, but it addresses all the questions we've really asked just now.
DR. ABRAMSON:  All right.  So the caveat in the first question here, though, is the phrase "early disease," because I guess that ‑‑ so, let's take a vote just on that.
Assuming that the "delays radiographic progression" for the moment includes language on retardation, let's have a show of hands for those who believe that Enbrel delays radiographic progression in patients with early RA.
(Show of hands.)
DR. ABRAMSON:  Okay.  So it's ‑‑
MS. REEDY:  Unanimous.
DR. ABRAMSON:  So the harder question, "To what extent can the radiographic data be generalized to patients with longstanding disease to support a general claim for delaying radiographic progression?"
Again, given that the Arava thing is non-qualifying, comments?

DR. SIMON:  Well, unfortunately, in that they designed an early RA trial, and the Arava data set was not designed that way, in fact, it limits the observation.
If we're going to be evidence-driven, the evidence we have is that it's early on.  In a broader data set, as was the Arava data set, the evidence was clear in both early on and later.
We can argue back and forth to adjudicate this, but, nonetheless, that's what the evidence is.
DR. ABRAMSON:  Other comments?
(No response.)
DR. ABRAMSON:  So let's take a vote.  "To what extent can the radiographic data be generalized to longstanding disease to support a general claim?"
So everyone who thinks it can be generalized, if you could raise your hand.
(No response.)
DR. ABRAMSON:  Everyone who thinks it cannot be generalized, raise their hand.
(Show of hands.)
DR. JOHNSON:  Maybe I'm misunderstanding what's going on.  Let me just ask something.

You're comfortable with generalizing backwards from bad disease to mild disease to validate a methotrexate effect, yet you're not comfortable with generalizing forward from early disease to late disease?  Maybe it's logical or maybe it's scientific.
DR. SIMON:  No, not at all.  That's why I used the term "Talmudic" in this discussion.  I mean, it was an entire construct of assumption.
We don't have assumptions here.  We have evidence that in early disease, there seems to be slowing in progression of damage.  That's all we know.
DR. ABRAMSON:  The language says, "Do the data support a claim for early RA"?  Clearly, yes.
Any other comments?
DR. VAN DER HEIJDE:  Yes.  May I add a comment?
DR. ABRAMSON:  Oh, yes.  I'm sorry.  I didn't see you.
DR. VAN DER HEIJDE:  What you can see in the literature, that it's mainly disease activity that's driving if there's radiographic progression or not, and so it's mainly if you have disease, active disease, and if there's early disease or late disease, that's driving, if there's progression or not, and it's not really a difference in disease duration.
DR. ABRAMSON:  Lee?
DR. SIMON:  Actually, I would take great issue with that.

There is historic evidence looking at pathologic specimens from patients with rheumatoid arthritis before we had such excellent therapy, where you could actually determine that in non-inflammatory conditions, in patients with pannus that was not driven by inflammatory cells, there was still destruction going on.
One could argue that in the heterogeneous biologic process, that we don't understand entirely what happens, and, furthermore, there's excellent evidence that people will have progression of disease when the disease burns out, meaning that their x-ray evidence of progression gets worse, and yet they have very little evidence of clinical active inflammation.
DR. ABRAMSON:  Jeff, yes?
DR. JEFFREY SIEGEL:  This issue of generalizability of x-ray findings from early stage disease to later stage disease is an issue we didn't really face when we were drafting the RA guidance document.  It's something that has arisen relatively recently.

Given that you feel that the data really don't support a generalization, would you recommend or could the committee comment on whether it would be desirable to have a separate study, separate data, in early versus late or whether we should recommend the sponsors include later stage patients as well as early stage patients in x-ray trial?
DR. ABRAMSON:  It really does create a Catch-22 for the corporation, because we've always wanted early studies, and now someone does an early study, and you say, well, you limit your indication to early disease.
I don't know how to answer.  It's always easy to say do another study, but I don't know what the answer is.
DR. SIMON:  Well, actually, this is really inherent to the problem that we're confronted with.
The company, as I understand it, was driven by two different questions.  The first was they wanted to get approval for early use.  They were limited in that, at least from a managed care point of view, and, unfortunately, I think they came with both that question, and they designed in the same trial this other question about structure, and, unfortunately, I would not have designed these two questions together to be answered by the same study.  That's not what I would have done.
DR. ABRAMSON:  Dr. Garrison?
DR. GARRISON:  Just a couple of points.

I think that if you look at the patients enrolled in our trials, initially, they were all less than three years of duration of RA.
We have two-year data, a data set that will be complete in a month.  So you can look at those patients at the outer limits here of being of five years' duration of RA, and this is within our one large, very complete data set.
I think I'm not as familiar with the Arava data set as many of you are.  There were differences in disease duration in those trials.  They ranged from 3.7 years to about 7 years' disease duration, and the label there does not exclude very early use, and I guess the underlying ‑‑ well, I guess I'm having a difficult time with this, showing the consistency of the clinical response in all of the studies that we've done, peds, you name it, longstanding disease, very short disease.
We've shown that we have the same clinical effects here, and it is a leap to think that you'll have the same kinds of radiographic effects, but I do believe that the disease is linked, clinical and radiographic activity is linked.

DR. ABRAMSON:  Right.  I think that's an important point, and I think what Dr. Simon was getting at is that we don't know what disease at 15 or 20 years is like in terms of its responses.  So we presume it would be likely to respond similarly.
I think the agency should just understand that this vote reflected the way this language, this question ‑‑ we were asked a very simple question ‑‑ "Can this data be generalized?" ‑‑ and we answered no.
I think how this label comes out is a different question that ought to be in the discussion between the sponsor and the agency, and the Arava database and labeling, I think, is a model.  I'm speaking for myself right now.
I think we were responding to a very directed question, and I think this other discussion is much more complicated, and it should go on separately.
DR. SCHWIETERMAN:  Yes.  I apologize if this is somewhat confusing.
Clearly, we have to have collaboration with the Center for Drugs, and we do that anyway with many, many things, and I think we'll take this advice to collaborate and work out a meaningful and fair comparison between the product.
DR. ABRAMSON:  Okay.  I want to thank the sponsor and the committee and everyone here.
We will reconvene for a closed session at 2:30.

(Whereupon, at 1:50 p.m., the open session was adjourned.)