Life Science Compliance Update

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March 27, 2012

FDA Advisory Committee Vacancies and Interests

FDA Conference Room
Advisory Committees at the Food and Drug Administration (FDA) are receiving a lot of attention lately.  Most of the concerns stem from the belief that members of these committees may have potential financial conflicts of interest.  

One side of the argument believes that panel members should have little to no connections to industry in order to sit on such panels.  Others, however, point to the fact that there are a number of vacancies on Advisory Committees (which can delay drug or device approval) and that working with industry is a prerequisite for the experience and expertise needed to provide the expert advice such committees offer to manufacturers. 

 In looking at the upcoming advisory committee meeting schedule for 2012, one could see that a good number of meetings were scheduled for some of the committees.   Oncologic Drugs Advisory Committee (ODAC) has seven meetings scheduled to cover 14 days during the year, but the committee has several vacancies now and more scheduled to come this year. 

Looking solely at the vacancies for drugs, biologics and devices, there are 116 vacancies.  According to FDA Track, the agency has made progress in filling vacant positions.  While the agency has a goal of reaching 10% vacancy, it is now at 20%, which is down from the 25% vacancy reported in October 2010.  

Below are listed the committees along with the current number of vacancies done by EyeonFDA.  These numbers were taken from each site of each advisory committee, but in addition, each of the committees will have some members who will also be rotating off this year, making the number of people needed to fill vacant slots even higher.

 Drugs

  • Anesthetic Analgesic – 8
  • Anti-Infective – 6
  • Anti-Viral – 5 (including the Chair)
  • Arthritis – 8 (including the Chair)
  • Cardiovascular – 1
  • Dermatological – 4
  • Drug Safety – 1
  • Endocrinology – 3
  • Gastroenterology – 4
  • Medical Imaging – 12
  • Non-Prescription – 5
  • Oncologic – 4
  • Peripheral/CNS – 5 (including the Chair)
  • Pharmaceutical Science – 14
  • PsychoPharmacologic – 1
  • Pulmonary Allergy – 1

 Devices

  • Anesthesiology – 4 (Including the Chair)
  • Circulatory – 0
  • Clinical Chemistry – 0
  • Dental – 0
  • Ear Nose Throat – 0
  • Gastro Urology – 0
  • General Plastic Surgery – 1
  • General Hospital – 0
  • Hematology – 0
  • Immunological – 2
  • Med Devices Dispute – 0
  • Microbiology – 0
  • Molecular & Cl Genetics – 1
  • Neurological – 0
  • Obstetrics – 0
  • Ophthalmic – 2
  • Orthopedic – 0
  • Reproductive – 6 (including the Chair)
  • Radiological – 0

Biologics

  • Allergenic – 0
  • Blood Products – 5
  • Cellular Tissues Gene – 1
  • Transmissible Spongiform – 2
  • Vaccines Related Biologics – 1 

In response to this incident, FDA posted a story on its new blog, explaining the nature of Advisory Committees in an attempt to bring some transparency and clarification to the issue.  The post was written by Jill Hartzler Warner, J.D., FDA’s Acting Associate Commissioner for Special Medical Programs. 

FDA Advisory Committees Background 

Advisory committees play an important role in FDA’s mandate to promote and protect the public health by allowing the agency to engage independent, technical experts from a variety of disciplines.  The committees are often comprised primarily of individuals working in academia; but also may have representation from private practices, professional and patient groups, regulated industry, and other government agencies. 

In circumstances where FDA staff seeks additional input because of such things as emerging research, the complexity of a new technology, or conflicting scientific data, FDA may turn to outside experts to provide important insights that would help inform our decision-making.  FDA often asks “these experts to advise them on a range of scientific questions – including whether the safety of a drug is properly characterized for patients or if a new device would provide meaningful benefit for patients.” 

While “FDA ultimately makes the final decision on all regulatory activities,” advisory committee experts, “which include patients, provide invaluable insights to the agency on how the broader public will approach a particular product or issue.” 

Before each meeting, FDA screens all advisory committee members who are special government employees or regular government employees for potential financial conflicts of interest.  FDA asks the members to report to the agency any past and all current involvement or relationships with the products, companies, and issues related to the meeting.  Members are required to report all current financial interests that could be affected by the outcome of the advisory committee proceedings and any FDA decision based on the committee’s recommendations.  For example, this might include stocks and investments and consulting arrangements.   In addition, they report involvements that might present an appearance of a conflict, to the best of their knowledge. 

FDA carefully reviews each financial interest reported by each potential committee member and determines whether any would disqualify them from participating.  If a member has a potential financial conflict of interest, they may not participate unless a waiver is granted, allowing them to participate.  The agency also reviews other interests that may raise an “appearance” of a conflict and has the discretion to have the member not participate if the circumstances would cause a reasonable person with knowledge of the relevant facts to question his or her impartiality in the matter. 

When the FDA decides to grant a waiver to a committee member, FDA posts the waiver on its website before the meeting, along with the type, nature and magnitude of the waived financial interest.  If no financial conflict was determined by the agency, the information submitted by the committee members is considered confidential and by law, FDA does not release that information to the public. 

Warner said that FDA makes clear to “committee members that failure to report relevant known financial interests to FDA prior to participation in an FDA advisory committee meeting is illegal and subject to possible criminal penalties.” 

Recent FDA Advisory Panel Dispute 

According to Warner, “a lack of understanding about FDA’s selection and evaluation process, as well as federally mandated limitations on the type of information FDA can share publicly, have sometimes resulted in confusion and misunderstanding among the public” regarding Advisory Committees.  Consequently, these issues came to light on December 8, 2011, involving an advisory committee meeting that discussed drospirenone-containing oral contraceptives.  

The incident involved Paula Hillard, a professor at the Stanford School of Medicine.  Hillard voted on the safety of two drugs that were created by a company she had done some work for in the past.  The FDA committee was convened to evaluate the significance of recent studies showing that Yaz and Yasmin, popular oral contraceptives manufactured by Bayer HealthCare Pharmaceuticals.  Some of the data may have suggested that Yaz statistically increased the risk of potentially dangerous blood clots.  The elevated risk has been linked to the presence of drospirenone in the contraceptives. 

Three studies, all sponsored by Bayer, suggested that the risks posed by Yaz or Yasmin, and other contraceptives not containing drospirenone, were comparable.  Seven other studies, however, asserted that Yaz and Yasmin posed an elevated risk of harmful blood clots. 

The committee voted 15 votes to 11 that the benefits of Yaz and Yasmin continued to outweigh the risks documented in the studies.  The committee did however, support a change in labeling to advise physicians of the higher risk.  A blog post noted that four committee members, including Hillard and the committee’s chair, had prior affiliations with Bayer or the manufacturers of similar generic contraceptives.  All four voted in support of the contraceptives but denied any link to their prior ties to Bayer or the existence of any conflict of interest.  

Warner noted however, that based on FDA’s review of the members’ reported financial interests, the agency “did not identify any financial interests that would have precluded their participation.” 

Hillard acknowledged that she had periodically served as a consultant to Bayer and other pharmaceutical firms, but said that she had done no such work during the 12 months preceding the committee’s decision.  Hillard emphasized that she had satisfied all requirements for the disclosure of potential conflicts of interest to the FDA, as well as making prior consulting affiliations available to the public through the medical school website. 

“It was the FDA’s decision that I satisfied the process for reporting conflicts of interest,” Hillard said. “The FDA allowed me to sit on the committee… I’m in favor of disclosure of potential conflicts, and I feel that I can be objective.”  Hillard said that she had sat on several advisory committees in preceding years and had each time completed a confidential form regarding conflicts of interest for the FDA. 

According to Hillard, her decision to support Yaz and Yasmin’s continued sale stemmed from flaws in some of the studies linking the contraceptives to a higher risk of clots. She said that the disproportionate inclusion in the survey of women diagnosed with polycystic ovary syndrome, which elevates the base risk of blood clots, likely distorted results.  This led Hillard to conclude that, while all contraceptives containing estrogen carried some risk, Yaz and Yasmin posed no more risk than other contraceptives and less than the risks posed by pregnancy. 

Sid Wolfe – Yanked from FDA Advisory Committee 

In a rare incidence, FDA recently removed Sid Wolfe from the Drug Safety and Risk Management Advisory Committee, due to an ‘intellectual conflict of interest.’  Wolfe, who heads the Public Citizen Health Research Group, said he was removed because he publishes a newsletter called ‘Worst Pills, Best Pills News’ and the Worst Pills web site, in which the group has labeled Yaz and Yasmin as ‘do not use.’ Why?  The listings say these can cause dangerous elevations in blood potassium levels and, more recently, because they also significantly increase the risk of blood clots and an increased risk of blood clots in the lungs. 

The decision was made by Janet Woodcock, Director of FDA’s Center for Drug Evaluation and Research (CDER).  Wolfe has served on the panel for more than three years and said he has recused himself on four previous occasions in which Public Citizen had pending citizen petitions to ban the various drugs that were being discussed.  Wolfe eventually sat on the advisory panel but was unable to vote.  

Wolfe noted that, “If intellectual conflict of interest means being informed and subsequently having opinions on a drug, many more members of advisory committees, even without a financial conflict of interest, would have to be excluded because they know too much. The resulting committees would be noticeably less well-informed than now is the case, and the FDA and the public would be the losers.” 

“For members of a scientific and technical advisory committee, possessing information and expert views on matters within the purview of the committee is not a conflict of interest.  To the contrary, qualified experts are likely to have developed views on a variety of subjects based on their professional experience, including their own independent research and their review of data compiled by other researchers.  The fact that experts have acquired information and reached conclusions in the course of their work should not be a disqualifying factor and, as a legal matter, does not render the advisory committee not ‘fairly balanced,’ under the Federal Advisory Committee Act,” he says. 

“Disqualifying advisory committee members because they have views on scientific matters threatens the utility of advisory committees in several ways.  First, it deprives agencies of advice from the very experts most qualified to give it – those who have actual knowledge and research experience concerning the subjects to be addressed by the committee.  Second, it deters qualified scientists from accepting appointment to advisory committees out of concern that their very expertise may become a matter of distracting controversy. And finally, it encourages politicization of scientific matters as interested parties seek to exclude scientists whose views are inconvenient to them.” 

This is not the first time however, that Wolfe has raised issues on an FDA advisory committee. During an August 2010 FDA panel meeting, Wolfe attempted to discuss publicly available documents that reflected poorly on Jazz Pharmaceutical to responsibly market a drug that was being reviewed that day.  The episode led to an unusual exchange between Wolfe and an FDA official.  The panel was reviewing Jazz Pharmaceuticals’ drug Rekinla for fibromyalgia.

FDA’s Arthritis Drugs Advisory Committee and Drug Safety & Risk Management Advisory Committee voted 20-2 against recommending Rekinla (sodium oxybate) for a supplemental indication for treatment of fibromyalgia on August 20, 2010; sodium oxybate is currently approved for the reduction of daytime sleepiness and cataplexy in patients with narcolepsy under the trade name Xyrem.

Following the agency’s formal presentations, Wolfe, during the question and answer session, explained that he had obtained publicly available documents that cast negative light on the trustworthiness of the sponsor to responsibly market Rekinla if the panel delivered a positive recommendation and FDA approved the drug.


To resolve parallel criminal and civil allegations of off-label marketing for Xyrem by their Orphan Medical division, Jazz entered a guilty plea and paid $20 million in monetary penalties as part of a settlement with the US Attorney’s Office for the Eastern District of New York.   Committee Chair Kathleen O’Neill (University of Oklahoma College of Medicine) tried to cut Wolfe off, saying the session was only for questions to FDA and could only address the material in front of the panel on that day.


Wolfe continued to read a summary of the off-label marketing settlement and said he eventually would have a question.  With Wolfe unwilling to stop reading, FDA took the seemingly unprecedented action of cutting off Wolfe’s microphone.  That step has become routine during the open public hearing where there is a time limit but this was one of their own advisory committee members.

Wolfe turned the microphone back on and finally got to his question: Why, he asked, did FDA not mention the Xyrem off-label settlement in its presentations to the committee?  After all, he argued, it was relevant to the decision at hand: could the sponsor be trusted to market Xyrem—also known as gamma-hydroxybutyrate (GHB)—to a much broader indication than it was already approved for?

FDA Division of Anesthesia & Analgesia Products Bob Rappaport stepped in and first instructed Wolfe to stop talking when the panel chair requests that he stop talking, explaining that it was her prerogative.  Rappaport continued that Wolfe’s reading of the documents were the first time he had ever heard of the off-label case and that it was not relevant to the Rekinla review despite the fact that both Xyrem and Rekinla are the same drug (sodium oxybate).   

Rappaport then admonished Wolfe for not providing the documents to FDA earlier, noting that he had called FDA's advisory committee management staff earlier in the week to raise an issue, but had not provided the information he was reading at the meeting.  An FDA official returned after the lunch break and the open public hearing with a prepared statement: 

“The issue that Dr. Wolfe raised this morning is a matter related to compliance and is not related to the topic under discussion today, unless there has been an accusation of data integrity problems with this application – and I’m not aware of any data integrity concerns.  The only other way that the case referred to by Dr. Wolfe could be pertinent to this application would be if it was brought up to impugn the sponsor in the hopes that the committee would be punitive towards them in your deliberations and recommendations regarding this application.  However it is important for you to recognize that that would not really be punitive to the sponsor but would really be punitive to the patients.” 

The agency later said “the issue raised this morning by Dr. Sidney Wolfe related to Jazz Pharmaceuticals marketing practices and compliance activities for sodium oxybate is not related to the topic (that was) under discussion. The FDA weighs all of the comments made by committee members equally but will only be considering the safety and efficacy information discussed today as it evaluates sodium oxybate to treat patients with fibromyalgia.” 

Discussion 

In April 2010, Commissioner Hamburg highlighted a draft guidance for FDA staff and advisory committee members that outlined her desire to create a more consistent and transparent process for disclosing conflict of interest waivers granted by the agency.  It is worth noting that since FY2007, the rate of conflict of interest waivers granted by the FDA has been declining sharply.  In FY2007, the agency granted waivers for 15 percent of meeting participants; in FY2011, we granted only 1%.   

Given FDA’s interest in this area, the agency has been working closely with outside stakeholders and the Institute of Medicine to explore whether a common financial disclosure form or website could be created making it easier for individuals to report their financial interests.  

Warner noted that, “In its design, this approach could allow individuals to report information in a standard and consistent way, serving as a resource for agencies like FDA looking to receive reliable information while at the same time reducing burden on our experts.”  She also noted that FDA is exploring the administrative steps in review of conflict of interest screening and evaluating whether the process can be streamlined.   

Conclusion 

The vacancy rate on standing committees does not reflect the actual vacancies at hearings.  Because the FDA is not giving interest wavers any longer, many standing committee members are conflicted out of their participation at public hearings.    So many committees may have only two or three standing committee members allowed to participate in a panel and less involved physicians brought in to fill in the roster for that meeting.  One recent hearing we attended only had three permanent members.  This is not helpful as one hopes for consistency and some foreknowledge of the system by the panel prior to going to an advisory panel. 

With PDUFA V talks getting more attention with the upcoming approval for the fifth reauthorization needed by the end of the summer, several Senators and Representatives have introduced legislation that would relax the conflict of interest rules. 


FDA Commissioner Hamburg, testifying during the PDUFA reauthorization hearings several weeks ago, however, indicated in her testimony that such rules may not be relaxed.  As these hearings get more heated, particularly in light of the significant attention that FDA has been getting and in an election year, we may see Congress attempt to get the proposed legislation into the PDUFA negotiations.  

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Pharmaceutical companies are having a hard time sorting out this conflict of interest issue. So if I buy Norco as a pain killer, would I have to think twice about it because pharmaceutical companies are hiding different things from the consumers? How do I keep the trust I have for my medicines to work if they have this issue? Just a thought from an average consumer.

As Congress begins debating the PDUFA/MDUFA re-authorization, pharmaceutical companies have been lobbying to remove these conflict of interest policies at the FDA. Recently, we've seen a number of bills proposed that would strip this from the agency. A new analysis came out this morning showing that over the last three years, the pharmaceutical drug and medical device industry has spent $700 million in lobbying expenses - dwarfing all other industries. A blog post on the analysis can be found here: http://blog.ucsusa.org/money-talks-and-what-its-saying-may-harm-the-fda.

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