In June 2017, Yale CRIT hosted an international conference titled "Ensuring Safety, Efficacy, and Access to Medical Products in the Age of Global Deregulation." The following blogpost is the eleventh installment of a blog series with commentaries from the conference participants. The views and opinions expressed in this blogpost are those of the authors and do not necessarily reflect the position of Yale CRIT. For more blogposts related to this series, see here or click the tag "YaleCRIT17" below.

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In June 2017, thanks to the support of the Arnold Foundation, faculty at Yale University invited a group of concerned academics, patient advocates, legal and medical experts, and leaders from international organizations from different corners of the world to talk about serious problems and dysfunctions of how medicines are developed, tested, reviewed, marketed, and used. In preparation for this gathering, members of the Yale Collaboration for Research Integrity and Transparency (CRIT) prepared a white paper. It makes an important case to reaffirm the FDA's "historic mandate to ensure the medical products used by all Americans are safe and effective…"¹ We gained many insights from reading this paper and participating in the workshops that prompted us to generate seven points about pharmaceutical policy that may be worthwhile considering.

First, from before 1906, when the Pure Food and Drugs Act was passed, through the Vioxx crisis in 2004 to today, organized pharmaceutical lobbying has consistently tried to undermine Congressional efforts to protect patients from unsafe and ineffective drugs, often with considerable success. Before 1906, this powerful lobby centered on the manufacturers of patent medicines, while the manufacturers of 'ethical' drugs supported the Act.^2,3 In the ensuing decades, however, and especially after the major reforms in 1938 and the 1960s, the manufacturers of prescription drugs ascended as a major lobbying force to minimize the requirements that new drugs be clinically "safe and effective." Historical research details the ways in which regulations have been diluted and FDA enforcement minimized throughout the decades. Perhaps most relevant is Darrow's well-documented history of minimum standards for the FDA approving new products as safe and effective.⁴

Second, the term "safe and effective" needs to be put in quotes because formal criteria for what constitutes safety have never been established. Even the way that we talk about the positive and negative outcomes of using drugs is distorted. The term "risk-benefit ratio" hides what the "risk" is—of adverse side effects. This example of pharma-English also implies that the benefit is a sure thing, when in fact it is a probability like the risk. Honest English would call it the harm-benefit ratio, i.e., the chance of adverse effects compared to the chance of clinical benefits, not the "risk-benefit ratio."

"Safety," the term preferred by the industry that avoids mentioning the risks of harm from adverse reactions, has long been recognized as being tied to effectiveness. The ratio of benefits to harms is supposed to be positive; but this ratio is generated through end-points selected by the sponsoring company in clinical trials designed by the company or its agents, where the goal is to minimize evidence of harmful side effects and maximize evidence of benefits. The end-points may be clinical improvements or surrogate measures which may or may not correlate with outcomes that are meaningful to patients. If effectiveness is in doubt, then so is the benefit to harm ratio. As Caleb Alexander told KaiserHealthNews, "All too often, patients and clinicians mistakenly view FDA approval as [an] indication that a product is fully safe and effective. Nothing could be further from the truth."^5,6

The FDA has never required that companies prove that new drugs are clinically better for patients than existing drugs. Sometimes such evidence is presented. Without this evidence, getting drugs approved faster often means patients and their physicians get drugs whose relative clinical benefits are not known. Nor are their risks of serious harm. Policy leaders and the public need to know this history of compromise, rather than accept an account that portrays the FDA as once having been effective in protecting the public from unsafe and ineffective drugs but now in jeopardy.^3,7 This knowledge is important so that reforms are not just designed to return to an idealized past, but rather to address the longstanding practices of approving drugs with weak evidence about their clinical effectiveness and risks of harm.

Strengthening  pre-market testing should have two objectives: first, evidence showing that new drugs are clinically effective when compared to existing drugs is the key to ensuring that drugs are effective, and second, that their safety profiles are better understood. Post-market assessments are uneven and weak.^6,8 In addition, pre-market testing needs to be more inclusive of the people who will be using the medication once it is on the market.  Currently, clinical trials after the short, phase-1 safety trials often use exclusion criteria that result in people with co-morbidities, the elderly, women, people of color, and people from marginalized populations being under-represented.^9,10 In effect, the FDA sanctions discrimination by age, gender, severity of illness and other attributes.

Third, since 1992, public funding for the FDA to act as an independent regulator that protects patients from unsafe or ineffective drugs has been increasingly replaced by user fee legislation that allows companies to extensively fund FDA reviewers. It furthers this historically minimal protection of the public and patients through a bold, explicit conflict of interest: the agency that is expected to protect public health also has a second paymaster to serve—the pharmaceutical industry.⁷ Equally, the criteria for new drugs to be approved as clinically effective and relatively safe have become steadily thinner and more indirect (yet at immense cost), by expanding the use of surrogate outcomes and approving new drugs more rapidly and with lower levels of evidence.

Evidence from the last 30 years indicates that most new drug products have few or no clinical advantages over existing ones, though the FDA concludes they are effective with respect to the end-points selected by the sponsoring company in their sponsored trials.^11,12 With each five-year renewal of the user fee legislation, companies and their trade association are explicitly allowed to negotiate the conditions for how their fees can be used by the FDA. These now make up about half of the Congressional budget for the FDA, with most going to pay for the reviews of the companies' drugs.^13,14 The combination of weaker regulatory standards and the dual loyalty of the FDA means that the benefit to harm ratio may well be worse than for the thousands of established, post-patent drugs already on the market.^12,15,16 Physicians and patients just don't know for several years what the real, clinical benefit to harm ratio is for new drugs.^6,17-20

Fourth, adverse side effects from prescription drugs are very high. Aggregating studies published between 1964 and 1995 shows that 6.7 percent of people admited to acute care hospitals in the US have serious adverse drug reactions (ADRs) and 0.32 percent of hospitalized patients die due to an ADR, yielding a total of 106,000 deaths per year in those in hospital.²¹ More recent figures put the total number of deaths in the US due to ADRs at 128,000 annually,²² which, to put into context, places it between 140,000 deaths attributable to stroke and 110,500 attributable to Alzheimer's disease.^11,23 Americans experience 81 million milder adverse reactions, though they can still disrupt people's ability to work, care for others, or drive. Deaths from overdosing, prescribing errors, and self-prescribing which fill the headlines are quite different from the risks of properly prescribed drugs but add to this large toll.²⁴

Fifth, the FDA oversight of the probability of harm is weak and minimal. After contributing to the risks of adverse reactions by approving drugs more rapidly and thereby minimizing the probability of identifying major safety problems, the FDA devotes significantly fewer resources and personnel to addressing the massive level of harms, because it gives safety much lower priority than accelerating approval of new drugs. The call for more funds to reduce the risks of harms misses the point about priorities. In addition to better funding, we need to call for Congress and FDA leaders to give higher priority to the widespread risks of harm to patients.

The FDA's limited ways of gathering evidence that drugs are harming patients has significantly contributed to the situation today whereby only a small percent of actual adverse drug reactions are captured. Asessing the consequences of ADRs ultimately depends on whether physicians who prescribed the drug report them, how they are interpreted by the companies who profit from a drug's sale since most ADR reports are initially sent to the company, and finally the decision by the same unit in the FDA which approved the drug as "safe." As Jerry Avorn pointed out, "We already know that there is horrendous underreporting of side effects. Ninety to 99 percent of serious side effects are not reported by doctors."²⁵  Companies are obligated to pass on what reports they get to the FDA, but there is documentation that they skew the meaning of the reports.²⁶

Within the FDA, the division charged with approving new drugs (CEDR) is responsible for handling evidence that drugs they initially approved as safe enough to be marketed are causing serious harms to patients. Calls for an independent safety board, like the one that exists for airline safety, have been advocated for years.²⁷

Sixth, like the pharma-English term "risk-benefit ratio," the pharma-English term, "off label" should be avoided. The use of the term "off-label" is too benign and should be replaced by "unapproved," a term that conveys the message that these are uses that have not been subjected to rigorous clinical trials and approved by the FDA. Behind many unapproved uses are troubling and even illegal marketing strategies, leading to patient harms.^28,29

Further, FDA rules, heavily influenced by industry advocates, have long allowed extensive and widening use of unapproved uses by limiting FDA oversight of direct sales pitches by companies. Some unapproved uses reflect genuine patient benefits, and some reflect physicians' lack of alternatives for a given patient. However, de facto, FDA oversight of company marketing that leads to much of the off label prescribing, is minimal.³⁰ Experts have found that three quarters of unapproved uses have no evidence of benefit,³¹ and risks of harm increase as use proliferates.³² Yet the company friendly rules and practices of the FDA do little to keep companies from coopting physicians and patient groups to advocate for unapproved uses.^30,33 Current First Amendment challenges to allow direct marketing for unapproved uses are an extension of these practices, not a break with the past. The stakes are high, because prescribing for unapproved indications undermines what limited protection is available from the FDA. 

Finally, physicians are no bulwark to patient safety, and their ignorance about this subject is made even worse through their interactions with industry sales representatives who consistently fail to convey adquete safety information.³⁴ Further, physicians who prescribe a drug because they think it will benefit the patient are inclined to dismiss, deflect, or ignore patient complaints of adverse reactions.³⁵ Companies hire popular or prominent physicians as "key opinion leaders" and spend nearly all of their large promotional funds to increase prescriptions for their new drugs with little or no therapeutic gain,³⁶ while new drugs sometimes have uncertain risks of serious harm that have proven in the past to be substantial.¹⁷ This makes all the more urgent that any new drug-candidate must demonstrate that it is equally or more clinically effective than existing drugs, based on trials that reflect the practice population likely to take that drug. This would save health care systems billions.  

Donald W. Light is a medical and economic sociologist who received in 2016 the Edmund Pellegrino Medal in Bioethics for his work on institutional barriers to more effective, safer, and affordable drugs. Light is currently an affiliate of the Medical Ethics Division at NYU Langone Health and a professor of comparative health policy at the Rowan University School of Osteopathic Medicine. Light has authored The Risks of Prescription Drugs (Columbia 2010), and Good Pharma (Palgrave 2015).

Joel Lexchin taught health policy at York University in Toronto from 2001 to 2016 and since 1982 has worked as an emergency physician at the University Health Network. His two most recent books are: Private Profits vs Public Policy: the Pharmaceutical Industry and the Canadian State (University of Toronto Press, 2016) and Doctors in Denial: Why Big Pharma and the Canadian Medical Profession Are Too Close For Comfort (Lorimer, 2017).   

 

References

1. Yale CRIT authors. What's in Your Medicine Cabinet? Ensuring the Safety and Efficacy of Prescription Drugs, Biologics and Medical Devices in the United States. New Haven, CT: Yale Collaboration for Research Integrity and Transparency; 2017 (June).
2. Young JH. The Toadstool Millionaires: a social history of patent medicines in America before federal regulation. Princeton, NJ: Princeton University Press; 1961.
3. Hilts PJ. Protecting America's Health: The FDA, Business and One Hundred Years of Regulation. New York: Alfred A. Knopf; 2003.
4. Darrow J. Pharmaceutical efficacy: the illusory legal standard. Washington and Lee Law Review. 2013;70(4):2073-2136.
5. Lupkin S. Nearly 1 in 3 recent FDA drug approvals followed by major safety actions. Kaiser Health News. 2017 (May 9). https://khn.org/news/1-in-3-recent-fda-drug-approvals-followed-by-major-safety-actions/.
6. Pease A, Krumholz H, Downing N, Aminawung J, Shah N, Ross JS. Postapproval studies of drugs initially approved by the FDA on the basis of limited evidence: systematic review. BMJ. 2017;357:j1680.
7. Davis C, Abraham J. Unhealthy Pharmaceutical Regulation: Innovation, Politics and Promisory Science. New York: Palgrave Macmillan; 2013.
8. Lexchin J. Those who have the gold make the evidence: how the pharmaceutical industry biases the outcomes of clinical trials of medications. Science and Engineering Ethics. 2011;18(2):247-261.
9. Downing N, Shah N, Neiman J, Aminawung J, Krumholz H, Ross J. Particcipation of the elderly, women, and minorities in pivotal trials supporting 2011-2013 U.S. Food and Drug Administration approvals. Trials. 2016;17:199.
10. Goldacre B. Bad Pharma: How Drug Companies Mislead Doctors and Harm. London: Faber & Faber; 2012.
11. Light D, Lexchin J, Darrow J. Institutional corruption of pharmaceuticals and the myth of safe and effective drugs. Journal of Law, Medicine & Ethics. 2013;41(3):590-600.
12. Light D, Lexchin J. Pharmaceutical R&D—what do we get for all that money? BMJ. 2012;344:e4348
13. FDA. HHS FY 2017 Budget in Brief—FDA. Washington DC: U.S. Food and Drug Administration;2017.
14. Avorn J. Paying for drug approvals - who's using whom? New England Journal of Medicine. 2007;356:1697-1700.
15. Kantarjian HM, Steensma D, Sanjuan JR, Elshaug A, Light D. High cancer drug prices in the United States: reasons and proposed solutions. Journal of Oncology Practice. 2014 (May).
16. Gøtzsche P. Deadly Medicines and Organized Crime: How Big Pharma has Corrupted Healthcare. Oxford: Radcliffe Medical Press; 2013.
17. Lexchin J. New drugs and safety: what happened to new active substances approved in Canada between 1995 and 2010? Archives of Internal Medicine. 2012;172(21):1680-1681.
18. Giezen TJ, Mantel-Teeuwisse AK, Straus SMJM, Schellekens H, Leufkens HGM, Egberts ACG. Safety-related regulatory actions for biologicals approved in the United States and the European Union. Journal of American Medical Association. 2008;300:1887-1896.
19. Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, et al. Timing of new black box warnings and withdrawals for prescription medications. Journal of American Medical Association. 2002;287:2215-2220.
20. Carpenter D, Zucker EJ, Avorn J. Drug-review deadlines and safety problems. New England Journal of Medicine. 2008;358:1354-1361.
21. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients. Journal of American Medical Association. 1998;279(15):1200-1205.
22. ISMP Quarter Watch. A critique of a key drug safety reporting system. Institute for Safe Medication Practices;2015 (Jan).
23. Light DW, ed The Risks of Prescription Drugs. New York: Columbia University Press; 2010.
24. National Vital Statistics System. Provisional Drug Overdose Death Counts. Washington, DC: U.S. Centers for Disease Control and Prevention;2017 (Aug).
25. Ganguli I. Is your doctor in denial? The Washington Post 2007 (Aug 28).
26. Mundy A. Dispensing With the Truth: the Victims, the Drug Companies, and the Dramatic Story behind the Battle over Fen-Phen. New York: St. Martin's Press; 2001.
27. Rodwin M. Indepedent drug testing to ensure drug safety and efficacy. Journal of Health Care Law & Policy. 2015;18:43-80.
28. Eguale T, Buckeridge D, Verma A, et al. Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA Internal Medicine. 2016;176(1):55-63.
29. Kesselheim AS, Mello MM, Studdert DM. Strategies and practices in off-label drug use and adverse drug events in an adult population PLOS Medicine 2011;8(4):e1000431.
30. GAO. Drug safety: FDA needs to further address shortcomings in its postmarket decision-making process. Washington DC: Government Accounting Office;2007.
31. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166(9):1021-1026.
32. Brody H, Light DW. The inverse benefit law: how drug marketing undermines patient safety and public health. American Journal of Public Health. 2011;101(3):399-404.
33. GAO. FDA's oversight of the promotion of drugs for off-label uses. Washington DC: Government Accountability Office;2008 (July).
34. Mintzes B, Lexchin J, Sutherland J, et al. Pharmaceutical sales representatives and patient safety: a comparative prospective study of information quality in Canada, France and the United States. Journal of General Internal Medicine. 2013;28(10):1368-1375.
35. Golomb Bea. Physician response to patient reports of adverse drug effects. Drug Safety. 2007;30:669-675.
36. Lexchin J. The relation between promotional spending on drugs and their therapeutic gain: a cohort analysis. CMAJ Open. 2017;5(3):E724-E728.