Safety Issues: FDA Scientists Collide with FDA Managers

EXAMPLES demonstrating a collision between FDA safety officers and FDA leadership:  

·         In 1995, Dr. Leo Lutwak, FDA’s Chief medical reviewer of weight loss drugs , opposed approval of the diet drug, Redux (FenPhen) citing numerous reports about serious adverse effects—including, neuropsychiatric, pulmonary hypertension, and cardiac. The lethal drug was approved, killing tens of thousands of people by damaging their heart valves before it was withdrawn in 1997. Eventually the company (American Home Products) agreed to settle 11,000 lawsuits for close to $5 billion. [1]

 ·         In 1996, Dr. John Gueriguian was stripped of his safety review responsibilities after he raised concerns about potential liver damage and heart toxicity linked to the diabetes drug, Rezulin. His expert review of the Rezulin data was destroyed. In 1997, Glaxo-Welcome, European distributor of Rezulin, withdrew the drug from the European market citing deaths and liver damage in the US and Japan. FDA dragged its feet, issuing one after another label changes. [2]   

  • In 1998, a survey of FDA scientists by Public Citizen revealed that FDA approval standards had declined under pressure. The medical officers identified 27 new drugs that had been approved within the previous 3 years that they thought should not have been. [4]
  • In November 2004, Dr. David Graham, emerged as the most prominent FDA whistleblower whose riveting Congressional testimony was front-page news. He characterized FDA’s handling of Vioxx licensure as the worst preventable public health disaster in its history, resulting in 88,000 to 139,000 heart attacks of which 30,000-55,000 were fatal.  He identified five other drugs with lethal risks whose use is medically unjustifiable: the acne drug, Accutane, the anti-inflammatory cox-2  inhibitor Bextra, the statin, Crestor, the diet drug, Meridia (withdrawn 10/8/2010), and the asthma drug, Serevent.  He stated that “the FDA, as currently configured, is incapable of protecting America against another Vioxx. We are virtually defenseless."[6]

Unfortunately, the broad implications of Dr. Graham’s testimony have largely been ignored. Namely, the tragic health consequences that result from licensing unsafe drugs stem from the inherent conflict of interest that is a result of industry user fees. His analogy to FDA’s irrational 95% certainty standard before it recognizes the existence of a deadly drug hazard would be the equivalent to requiring that a pistol with 100 bullet chambers must contain at least 95 bullets before it could be said that the gun is loaded. [7]

He describes how FDA rigs the data reviewing process to cover-up serious adverse drug effects:

“human clinical pharmacology trials are typically done in Europe, yet clinical pharmacology reviewers at FDA have been barred from analyzing this information prior to studies being conducted in the US. Without being able to do this, we are unable to detect evidence of risks early and cannot provide guidance that would help with the development of the drug in terms not only of safety and proving efficacy, but also with the efficiency and cost effectiveness of the drug’s development. New labeling policies can also mask risks as they exclude the labeling of adverse events if they are under a certain percentage and/or not double the rate found with a placebo. By this rule, certain serious and potentially lethal adverse events that eventually resulted in a drug being withdrawn from the market would not have had any mention of the adverse events made in the labeling at all. On top of that, I frequently found companies submitting certain data to one place and other data to another place and safety information elsewhere so it could not all be pulled together and then coming in for a meeting to obtain an agreement and proposing that the safety issue is negligible and does not need further evaluation.”

“FDA’s response to most expected risks is to deny them and wait until there is irrefutable evidence postmarketing, and then simply add a watered down warning in the labeling. In fact, when patients exhibit drug toxicity, it is usually attributed to an underlying condition which we know is likely to make the drug toxicity worse. This also allows the toxicity to be dismissed as being unrelated to the drug in any way.” [8]

In 2006, the Union of Concerned Scientists surveyed 5,918 FDA scientists about the scientific integrity at the FDA.  Hundreds of scientists reported having been pressured by management to approve a drug despite scientific-based reservations about safety.

“Scientific discourse is strongly discouraged when it may jeopardize an approval. . . . Whenever safety or efficacy concerns are raised on scientific grounds . . . these concerns are not taken seriously."  [9] 

A follow up survey conducted in 2011 found that FDA scientists continue to complain about persistent interference by special interests; they fear retribution for sharing concerns about the FDA; they are uncertain about their right to publish controversial work in peer-reviewed journals or to talk with the press. Substantial numbers of respondents thought that FDA decisions were overly influenced by political interests (55%) or business interests (40%). And over a third of the respondents reported firsthand experience of interference in their work in the past year. 

The same year, the Institute of Medicine issued a devastating report documenting  significant interference with the FDA’s scientific work,  which compromises the agency’s ability to fulfill its mission of protecting public health and safety.  [10]

 

REFERENCES

1. FDA Doc Claims Fen-Phen Cover-Up, CBS News, Feb. 11, 2009.

2. Willman, D. "Physician Who Opposes Rezulin Is Threatened by FDA With Dismissal," The Los Angeles Times, March 17, 2000. The report won Pulitzer Prize.

3. Ibid

4. Wolfe, S. Congressional Testimony on FDA Deficiencies, Public Citizen, Feb. 27, 2008 http://www.citizen.org/Page.aspx?pid=710

5.  Waters, R. Lawmakers Open Probe of FDA: Agency Accused of Barring Safety Data on Antidepressants, The San Francisco Chronicle, March 31, 2004
http://www.sfgate.com/health/article/Lawmakers-open-probe-of-FDA-Agency-accused-of-2773090.php

6. Testimony of David J. Graham, MD, MPH, Nov. 18, 2004, Senate Finance Committee Hearing http://www.finance.senate.gov/imo/media/doc/111804dgtest.pdf

7. Ibid.

8. Rosenberg M. Former FDA Reviewer Speaks Out About Intimidation, Retaliation and Marginalizing of Safety,  TruthOut, July 2012 

9. Union of Concerned Scientists, Voices of Scientists at FDA: Protecting Public Health Depends on Independent Science,  2006
http://www.ucsusa.org/assets/documents/scientific_integrity/fda-survey-brochure.pdf   and follow-up

10. Institute of Medicine, “The Future of Drug Safety: Promoting and Protecting the Health of the Public” 2006.
http://www.iom.edu/Reports/2006/The-Future-of-Drug-Safety-Promoting-and-Protecting-the-Health-of-the-Public.aspx