ODAC Confidential: The seven deadly sins sponsors commit again and again at FDA presentations

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Over and over again, I’ve seen the same missteps, clumsy excuses, and faulty logic during sponsor presentations to the FDA Oncologic Drugs Advisory Committee, repeated as if part of a tragic, regulatory update to the movie Groundhog Day. 

For five years, I served as a member of ODAC, and was even privileged enough to chair the committee for two of those years. To my knowledge, there is no exit interview of ODAC members in which we are asked to recount what “mistakes were made” during those pharma presentations to the agency. 

Yet, the transgressions that occur as sponsors present trial data to FDA and ODAC are common–and recurring. 

These transgressions can lead the agency and the advisory committee to question the candor of the sponsor or their motivations for drug development. I suspect that avoiding these transgressions, which have more to do with basic communication skills than they do with science, could even result in a more favorable review.

So, throwing caution to the wind and acknowledging the inherent folly of trying to briefly summarize an appearance before the FDA, I went ahead and did so, calling these lapses the “seven deadly sins at FDA presentations:”

  1. Spinning trial data. The data are the data, and the people in the room at FDA are smart enough to interpret it correctly. Attempts to inflate data to make it seem better than it is, or engaging in what the British economist Ronald H. Coase coined “torturing the data,” as in, “If you torture the data long enough, it will confess to anything,” will result in members of FDA and ODAC concluding that the sponsor also has an inflated sense of the likelihood of the drug getting approved.
  1. Sloth. This is commonly manifested as “We didn’t do that analysis,” or “We don’t have that data.” When referring to an obvious question, this can come across as sheer laziness. But it is often interpreted by many in the room at FDA headquarters hearing this response as “We did the analysis, but it didn’t favor our drug, so we’re not showing the data.”
  1. Placing business objectives ahead of improving people’s lives. During a hearing on the Avastin metastatic breast cancer indication in 2011, one representative from the drug’s sponsor made this comment: “Yes, we do feel that the study was a big success, because it led to labeling for the medication.” Insert emoji of hand slapping forehead here. Product labeling may be how success is defined to stockholders, but not to cancer patients. They want to live longer and feel better!
  1. Wrath. When I sit on an ODAC panel, I take the job seriously. Very seriously. I look at it is a service to my government and that my primary responsibility is to protect—or improve—the health of the public. Consequently, I’m going to ask difficult questions about clinical trial results. When a sponsor or presenter responds with anger or gets defensive, it’s natural to assume that that person is overcompensating for flawed data, or a flawed study.
  1. Misreporting negative trial results. In simple terms, FDA summarizes drug efficacy as “Lives longer or lives better”—improved survival or improved quality of life. It is often difficult to demonstrate improved patient-reported outcomes in randomized trials, though, either because instruments measuring quality of life may not be sensitive to change, or because side effects from the drug mitigate improvement in quality of life, or because a drug simply doesn’t improve quality of life. Rather than simply reporting that a drug did not improve quality of life, sponsors will frequently state, “Quality of life was no worse with our drug.” I can take a placebo to feel no worse. Heck, I can eat a piece of chocolate to even feel better. But I wouldn’t recommend a chemotherapy that doesn’t allow my patients to live longer, just so they feel no worse.
  1. Gluttony. The overindulgence of a substance to the point of waste.Patients should be exposed to a drug just long enough to treat their cancers, and not a second more. Continuing a drug as a “maintenance” strategy needs to demonstrate benefit to that strategy discretely from the up-front, often more intensive part of a treatment regimen, and not just because that happens to be how the trial was designed (and will lead to more units of drug sold).
  1. Blaming trial design for a failed study. To be blunt, this sounds like a “You” problem. Sponsors are responsible for designing and conducting studies. If those studies yield a negative result showing no benefit for a drug, or excess toxicity for a drug, it is disingenuous to then claim that if only the study had been designed better, the drug would have been shown to be safer or more effective.  Okay—so design a better study, conduct it, and then submit a New Drug Application.

The idea to summarize these strategic errors came to me as I was writing a book on the fascinating history of the FDA, the medical tragedies that led to its birth and evolution. The book—Drugs and the FDA: Safety, Efficacy, and the Public’s Trust—was inspired by the above-mentioned tumultuous hearing on the breast cancer indication for the drug Avastin. 

I focused on the Avastin hearing because it was the first time the FDA had recommended removal of a drug for a specific cancer indication and a company refused, prompting the agency to develop administrative procedures for resolution of such disputes and to conduct a special meeting of a panel. 

The O.K. Corral showdown occurred on June 29, 2011. I sat with the five other voting members of ODAC at a small table in the Great Room in Building 31, at FDA headquarters.

What was my mental state?

I felt as if the dispute we were being asked to adjudicate put to the test the entire accelerated approval mechanism and the authority the agency had to both approve drugs quickly and withdraw them should they prove less safe or effective than initially thought. 

The public seemed to realize the importance of the hearing as well. The so-called Great Room was bursting with people, seeming not quite Great, but rather Barely Adequate for the proceedings. 

The meeting concluded with us unanimously voting “Yes” on three questions, in effect recommending that the agency pull the drug’s accelerated approval for the metastatic breast cancer indication.

Just as Karen Midthun, MD, the FDA presiding officer, thanked all who attended the proceedings and recognized the difficult decision-making in which the FDA (and special government employees like us) engages, frustrated members of the audience rose from their chairs on the other side of the rope cordons that normally separated spectators from representatives of FDA, the pharmaceutical company, and ODAC, to charge our table. 

Armed security guards rushed in to try to hold them back.

What were the three unanimous votes that led to this reaction from members of the raucous crowd? 

First, that follow-up AVADO and RIBBON1 trials failed to verify the clinical benefit of Avastin (of an improvement in progression-free survival of approximately 6 months) for the breast cancer indication that was initially shown in the ECOG 2100 trial that supported the drug’s accelerated approval; 

Second, that the available evidence on Avastin demonstrated that the drug had not been shown to be effective for the breast cancer indication;

And finally, that the drug had not been shown to be safe for the breast cancer indication and did not present a clinical benefit justifying the risk.

A few months later, Margaret Hamburg, MD, then the FDA commissioner, followed our advice and withdrew the breast cancer indication from Avastin’s label.

In the end, I believe the case of Avastin—repeated recently with the pre-term delivery drug Makena—actually demonstrated that the accelerated approval mechanism works well. 

This issue has been playing out in the agency’s stance on “dangling indications,” defined as indications that got on the market under the accelerated approval mechanism but failed to demonstrate patient benefit in confirmatory trials.

Data are data, and our job as clinical experts is to carefully weigh the balance of safety and efficacy of a drug in voting to improve the lives of cancer patients, or to protect the health of the public—even if that leads to unfortunate situations when angry people storm the podium.

Mikkael A. Sekeres, MD, MS
Professor of medicine, Chief, Division of Hematology, Sylvester Cancer Center, University of Miami
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Energy and Commerce Committee Health Subcommittee Ranking Member Rep. Anna G. Eshoo (D-CA), Ranking Member Rep. Frank Pallone, Jr. (D-NJ), and Oversight and Investigations Subcommittee Ranking Member Rep. Kathy Castor (D-FL) wrote to FDA Commissioner Robert M. Califf to urge the agency to move forward with guidance to improve the diversity of populations represented in clinical trials.
Mikkael A. Sekeres, MD, MS
Professor of medicine, Chief, Division of Hematology, Sylvester Cancer Center, University of Miami