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Petition to Include an FDA Staff Presentation at Certain Advisory Committee Meetings

June 21, 2007

Andrew von Eschenbach, M.D., Commissioner
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

Dear Dr. von Eschenbach:

Public Citizen, representing 100,000 consumers nationwide, hereby petitions the Food and Drug Administration (FDA) for a policy statement requiring that all future advisory committee meetings discussing specific products include an oral scientific presentation by FDA staff on the products reviewed, including a thorough safety and efficacy assessment. In a study that we recently reported in the medical journal The Lancet,[1] we found that 49 public meetings of the FDA’s human drug advisory committees reviewing drug products since 1997 did not include an oral presentation on the product by the FDA (see Appendix). Because the sponsor can be relied upon to present—often in misleading terms—its own case, this leaves a seriously one-sided record upon which advisory committee members must make important public health recommendations. There is no excuse for such an omission, and it undermines the protective role that these committees play in helping ensure the effectiveness and safety of our nation’s medicines. 

The absence of an FDA presentation at an advisory committee meeting means the committee members are only presented, in person, with the data, analysis and opinions of the drug product’s sponsor.  The sponsor clearly has a strong incentive to cast a favorable light on its product. In advance of the meetings, committee members do receive briefing materials from both the drug sponsor and the agency, but there is no guarantee that members actually review the hundreds of pages of material in detail. 

It is quite possible that oral presentations at the committee meeting are significantly more effective at communicating the analysis and views of the FDA experts to committee members—and influencing their votes—than previously reviewed briefing materials. The disproportionate salience people generally attribute to recent experiences is a well-recognized cognitive bias, known as the “recency effect” in psychology.[2] And while some concerns of the FDA reviewer may arise in committee discussion even without an FDA presentation, these issues gain far greater force when they are part of an overall oral presentation by the agency.

In studying this issue, Public Citizen’s Health Research Group (HRG) used an existing database from a previous study on FDA advisory committees covering the period 2001-2004.[3] The database was expanded using similar methods to generate a database covering meetings between January 1, 1997, and June 30, 2006. Data were collected from meeting agendas and transcripts posted on the FDA’s Center for Drug Evaluation and Research (CDER) Web site.[4] We used the data to determine whether the FDA made an oral presentation at these meetings.   Oral FDA presentations were defined as scientific presentations of the FDA’s findings and views regarding a specific drug product (i.e., not reviews of applicable regulations or presentations of the questions to the committee). We did not include “general matters” meetings.

We found that the FDA did not make an oral presentation at 18% (49/275) of drug-specific advisory committee meetings between 1997 and mid-2006, but there was no trend over time. The proportion of meetings at which the FDA failed to give a presentation varied significantly over the nine-and-a-half-year period studied, but there was only one year (2004) in which the FDA presented at all relevant meetings. In 1997 and 2003, the FDA failed to give a presentation at one-third of the meetings. The drug sponsor presented at all but one of the meetings during this period.  This was a meeting of the Non-prescription Drugs Advisory Committee on June 12, 2003 regarding the generic over-the-counter medication syrup of ipecac.  The FDA did present at that meeting.

Advisory Committee Meetings on Drugs and the Occurrence of an FDA Presentation, 1997-2006*

 Year

Advisory Committee Meetings

Meetings Without FDA Presentation

Percentage of Meetings Without FDA Presentations

 1997

 35

 10

 29%

 1998

 33

 4

 12%

 1999

 40

 4

 10%

 2000

 26

 2

 8%

 2001

 31

 7

 23%

 2002

 23

 6

 26%

 2003

 39

 13

 33%

 2004

 15

 0

 0%

 2005

 24

 2

 8%

 2006*

 9

 1

 11%

 1997-2006*

 275

 49

 18%

 * Based on meeting data posted on CDER Web site by June 30, 2006.


It is unclear why the agency would fail to make a presentation at certain drug advisory committee meetings. One hypothesis is that the agency decided whether to present based on the anticipated outcome of the meeting.  We found a trend toward statistical significance between whether an FDA presentation was made and whether the committee voted favorably toward the drug product (RR: 0.76; 95% CI: 0.56-1.04). (This means that meetings with an FDA presentation were somewhat less likely to result in favorable votes for the drug.)  Conceivably, the FDA tended to present more often in meetings that had expected (and actual) outcomes unfavorable to the drug.  Alternatively, the presence of an FDA presentation might have made it less likely that the committee would vote in favor of the drug.  We found no relationship between FDA presentations and the “closeness”[5] of committee votes (RR: 1.05; 95% CI: 0.41-2.72).

The lack of an FDA presentation has the potential to influence the committees’ proceedings.  On May 17, 2006, for example, the Peripheral and Central Nervous System Drug Advisory Committee held a meeting to review an application by Novartis to add an indication to the cholinesterase inhibitor Exelon (rivastigmine) to treat the dementia associated with Parkinson’s disease. In its briefing materials for rivastigmine, the FDA had identified serious failures in the Novartis application: The company failed to demonstrate that dementia associated with Parkinson’s disease was clearly defined or could be clinically evaluated as a distinct form of dementia, and Novartis could not show that rivastigmine had any clinically meaningful benefit in well-designed and well-conducted studies, let alone that such findings could be replicated. 

Had the agency made a presentation on rivastigmine and countered the sponsor presentation, advisory committee members might have given more than the limited attention they gave to the problems identified in the FDA briefing materials. Proceeding without an FDA presentation, the meeting concluded with a committee vote favorable to the new indication for Parkinson’s. The agency, apparently overruling the reservations articulated by its reviewer, soon acted to approve the ill-supported indication.

In passing the Federal Advisory Committee Act in 1972, Congress ordered agencies to ensure “the advice and recommendations of the advisory committee will not be inappropriately influenced by…any special interest, but will instead be the result of the advisory committee’s independent judgment.”[6] An advisory committee cannot make an “independent judgment” if committee members are more familiar with the drug sponsor’s point of view than that of the FDA. That committee members hear from the FDA experts is critical, for it is the FDA, not self-interested drug companies, that is entrusted with protecting the public.

In the interest of improving drug safety and ensuring that advisory committee advice is informed not only by the perspectives of drug sponsors but also by the analysis and views of FDA experts, we strongly urge you to issue a policy statement requiring that all advisory committee meetings addressing specific products include an in-depth presentation to the committee by FDA experts on the products.

Sincerely, 

Asa Tapley
Research Associate

Peter Lurie, M.D., M.P.H.
Deputy Director 

Sidney M. Wolfe, M.D.
Director
Public Citizen's Health Research Group


Appendix

Advisory Committee Meetings on Drugs without an FDA Presentation, 1997-2006† *

Meeting Date

Proprietary Name

Established Name

Committee Name

10-Feb-97

Silver Acetate Lozenge

silver acetate

Drug Safety and Risk Management

27-Feb-97

Bidil

hydralazine hydrochloride-isosorbide dinitrate

Cardiovascular and Renal Drugs

27-Feb-97

Coreg

carvedilol

Cardiovascular and Renal Drugs

28-Feb-97

Posicor

mibefradil dihydrochloride

Cardiovascular and Renal Drugs

28-Feb-97

Integrilin

intrifiban

Cardiovascular and Renal Drugs

26-Jun-97

Corlopam

fenoldopam

Cardiovascular and Renal Drugs

26-Jun-97

Lovenox

enoxaparin

Cardiovascular and Renal Drugs

17-Sep-97

Actiq

fentanyl citrate

Anesthetic and Life Support Drugs

24-Oct-97

Plavix

clopidogrel

Cardiovascular and Renal Drugs

19-Nov-97

Prandin

repaglinide

Endocrinologic and Metabolic Drugs

28-Jan-98

Integrilin

eptifibatide

Cardiovascular and Renal Drugs

10-Apr-98

Aggrastat

tirofiban hydrochloride

Cardiovascular and Renal Drugs

9-Jul-98

Pletal

cilostazol

Cardiovascular and Renal Drugs

23-Oct-98

Hirulog

bivalirudin

Cardiovascular and Renal Drugs

28-Jan-99

Tikosyn

dofetilide

Cardiovascular and Renal Drugs

29-Jan-99

Natrecor

nesiritide

Cardiovascular and Renal Drugs

29-Apr-99

Betapace

sotalol hydrochloride

Cardiovascular and Renal Drugs

3-Nov-99

Prozac

fluoxetine hydrochloride

Psychopharmacologic Drugs

28-Jan-00

Novantrone

mitoxantrone hydrochloride

Peripheral & Central Nervous System Drugs

1-May-00

Altace

ramipril

Cardiovascular and Renal Drugs

14-Feb-01

Zyprexa

olanzapine

Psychopharmacologic Drugs

15-Feb-01

Zeldox

ziprasidone mesylate

Psychopharmacologic Drugs

25-May-01

Natrecor

nesiritide

Cardiovascular and Renal Drugs

9-Aug-01

Remodulin

treprostinil

Cardiovascular and Renal Drugs

9-Aug-01

Extraneal

icodextrin

Cardiovascular and Renal Drugs

10-Aug-01

Tracleer

bosentan

Cardiovascular and Renal Drugs

11-Oct-01

Diovan

valsartan

Cardiovascular and Renal Drugs

17-Jan-02

Avapro

irbesartan

Cardiovascular and Renal Drugs

18-Jan-02

Pravigard Pac

pravastatin-aspirin

Cardiovascular and Renal Drugs

12-Apr-02

Cozaar

losartan potassium

Cardiovascular and Renal Drugs

18-Jul-02

Atacand

candesartan cilexetil

Cardiovascular and Renal Drugs

18-Jul-02

Pravigard Pac

pravastatin-aspirin

Cardiovascular and Renal Drugs

19-Jul-02

Vanlev

omapatrilat

Cardiovascular and Renal Drugs

7-Jan-03

Coreg

carvedilol

Cardiovascular and Renal Drugs

12-Mar-03

Doxil (for Kaposi's sarcoma)

doxorubicin hydrochloride lipo

Oncologic Drugs

12-Mar-03

Doxil (for ovarian cancer)

doxorubicin hydrochloride lipo

Oncologic Drugs

12-Mar-03

Ontak

denileukin diftitox

Oncologic Drugs

12-Mar-03

Ethyol

amifostine

Oncologic Drugs

13-Mar-03

Mylotarg

gemtuzumab ozogamicin

Oncologic Drugs

13-Mar-03

Depocyt

cytarabine lipo

Oncologic Drugs

13-Mar-03

Celebrex

celecoxib

Oncologic Drugs

13-Mar-03

Temodar

temozolomide

Oncologic Drugs

10-Jun-03

Humatrope

somatropin

Endocrinologic and Metabolic Drugs

24-Sep-03

Namenda

memantine hydrochloride

Peripheral & Central Nervous System Drugs

25-Sep-03

Provigil

modafinil

Peripheral & Central Nervous System Drugs

09-Dec-03

Ranexa

ranolazine

Cardiovascular and Renal Drugs

24-Feb-05

Atacand

candesartan cilexetil

Cardiovascular and Renal Drugs

16-Jun-05

BiDil  

isosorbide dinitrate, hydralazine hydrochloride

Cardiovascular and Renal Drugs

17-May-06

Exelon

rivastigmine tartrate

Peripheral and Central Nervous System Drugs

  * Based on meeting data posted on CDER Web site by June 30, 2006.
    Meetings discussing specific products were considered "product meetings," while those discussing more general scientific issues were considered "nonproduct meetings." We treated meetings that covered a single topic over more than 1 day as 1 meeting. Conversely, we considered a meeting that discussed multiple products sequentially over 1 day to be multiple meetings (1 for each product).



[1] Tapley AL, Lurie P, Wolfe SM. Suboptimum use of FDA drug advisory committees. Lancet. 2007 Dec 23;368(9554):2210.

[2] Costabile K, Klein S. Finishing Strong: Recency Effects in Juror Judgments. Basic & Applied Social Psychology 2005;27:47-58

[3] Lurie P, Almeida C, Stine N, Stine AR, Wolfe SM. Financial Conflict of Interest Disclosure and Voting Patterns at Food and Drug Administration Drug Advisory Committee Meetings. JAMA 2006;295:1921-8.

[4] Advisory Committee transcripts, briefing materials, agendas, rosters and charters. CDER. (Accessed June 6, 2006, at http://www.fda.gov/oc/advisory/acdrugs.html.) Note: The August 7, 1998, and December 1, 1998, meetings of the Arthritis Drugs Advisory Committee and the November 16, 1998, meeting of the Oncologic Drugs Advisory Committee were omitted due to lack of available transcript on the CDER Web site. In addition, the May 11, 2001, meeting of the Nonprescription Drugs Advisory Committee discussing the switch to over-the-counter status of a number of anti-allergy prescription medications was omitted from the third study due to the complexity of the legal and regulatory issues involved.

[5] A “close” vote was defined as a vote in which less than 80% of the votes were favorable/unfavorable to the drug product.

[6] Pub. L. 92-463, § 5 (b) (3), Oct. 6, 1972, 86 Stat. 770. Also: C.F.R. 21 § 14.40 (f) (3).

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