What Happens if Post-Approval Studies Are Delayed or Do Not Show Benefit?
The FDA’s accelerated approval pathway provides faster access to medications for patients with serious or life-threatening conditions. However, critics allege there are undue delays in withdrawing approvals for drugs for which studies have not confirmed clinical benefit. “In recent years, there has been considerable controversy about accelerated approval,” says Kerstin Vokinger, MD, JD, PhD, professor at Switzerland’s University of Zurich-affiliated faculty at Harvard Medical School’s Program on Regulation, Therapeutics, and Law.
One example is the FDA’s accelerated approval of aducanumab, for which clinical trials showed unclear therapeutic value for patients.1 The accelerated approval process has become more common, particularly for cancer drugs.2 “However, the added therapeutic value of drugs approved through accelerated approval was unclear,” Vokinger says.
Vokinger and colleagues assessed the therapeutic value of 146 drug indications that received accelerated approval in the United States and the European Union from 2007 to 2021. They found 38.9% of these carried high added therapeutic value.3 Approximately two-thirds of the drugs granted accelerated approval did not appear to offer high added therapeutic value at the time of approval.
“This underscores the importance of timely completion of required post-approval studies for drugs, and of ensuring that these confirmatory studies test clinically meaningful endpoints,” Vokinger says.
Another group of researchers examined the status of 278 drugs that were approved under the program from 1992 to 2021, along with the status of confirmatory studies for those drugs.4 Clinical benefit was confirmed in most cases. Half of accelerated approvals were converted to traditional approval in a median time of 3.2 years, which shortened to a median of 2.3 years in the past decade.
“The FDA has increasingly used available tools to reduce the timeline for completion of studies confirming clinical benefit,” says Ginny Beakes-Read, JD, BSN, the study’s lead author and an executive director of global regulatory and research and development policy at Amgen.
Beakes-Read and colleagues offered recommendations to address concerns about the approval pathway. For example, they suggested boosting public confidence with more transparency on the status of post-marketing studies.
“History shows that the accelerated approval program is generally working well, and significant legislative changes are not necessary,” Beakes-Read asserts. “Any changes to the program should be informed by cumulative experience, not outliers."
A third group of researchers studied accelerated approval of 48 non-oncology drugs over a 26-year period. They found that although approval was expedited by a median of 53.1 months, post-approval, safety-related label modifications often were added in boxed warnings, and clinical efficacy sometimes was not confirmed.5
“The biggest problem with post-approval studies is that they delay the availability of clearer evidence until after the market for the drug is already established,” asserts Jonathan Darrow, SJD, LLM, JD, MBA, BS, assistant professor of medicine at Harvard Medical School and faculty member at the Harvard Center for Bioethics.
Once patients are established on a treatment, and physicians become used to prescribing it, what the actual evidence later turns out to be matters less. “You never have a second chance to make a first impression,” Darrow says.
The average period of market exclusivity for drugs, before generic entry, is less than 14 years.6 “If a post-approval study produces evidence eight or nine years after the fact, this can be the majority of the patent period,” Darrow notes.
Dissemination of information in a way that changes clinical practice can take many years, sometimes longer than a decade.7 This means during the profit-maximizing period, the benefit of drugs may be less clear. Thus, patients taking the drugs may be overestimating benefits and underestimating harm.8
“As patents expire and clearer evidence is produced, the market can then be shifted to the next new product, and the cycle can continue,” Darrow says.
To address this, Darrow says more efforts are needed to understand the end of the drug life cycle, rather than the beginning. One important question is: How often are drugs still used after post-approval studies are released?
“The major ethical concern is lack of disclosure of uncertainty,” Darrow says.9
Better disclosure of expected benefit and harm is needed. “If patients are informed of how poor the evidence and benefit is, they may be less willing to take the drugs,” Darrow explains.
Physicians and insurers also will be less willing to prescribe and pay for them.
“Affecting the income of the business conducting the study is the best way to ensure it is finished on time,” Darrow suggests.
The accelerated approval mechanism is based on using a surrogate biomarker that is expected to be a valid proxy for clinically important benefits that were not evident in the clinical trials in question.
“Either the clinical trials were too short or too small to detect clinical benefits,” explains David Knopman, MD, associate director of the Mayo Clinic Alzheimer’s Disease Research Center.
The value of accelerated approval has been shown for some cancer and HIV drugs. For those drugs, shorter duration trials showed changes in surrogate biomarkers that, with longer term follow-up, predicted genuine, clinically important benefits in survival. “That is the ethical benefit,” Knopman says.
On the other hand, if the surrogate biomarker ultimately has no relationship to meaningful clinical benefits, “an accelerated approval would lead to exposing many patients to a drug that is useless,” Knopman cautions.
Accelerated approval tries to strike the right balance between pushing drugs to market early based on promising evidence and requiring companies to produce confirmatory evidence while the product is on the market. Holly Fernandez Lynch, JD, MBe, co-authored a paper describing why that tradeoff has not always worked.10
“The ethical issues are essentially how to consider the interests of patients today, who are willing to accept uncertainty in the hopes that a drug works because they don’t have time to wait, and the interests of patients tomorrow, who would prefer to have stronger evidence about what works and what doesn’t,” explains Fernandez Lynch, an assistant professor of medical ethics at the University of Pennsylvania.
Importantly, the FDA does not have to approve a drug for patients to have access to it.
“Rather than accepting weaker evidence for approval, it may be preferable to focus on widening access to clinical trials and making better use of the expanded access pathway for pre-approval access,” Fernandez Lynch says.
It is critical for patients to understand the uncertainty that surrounds accelerated approval drugs. That must be part of the informed consent process.
However, says Fernandez Lynch, “just saying, ‘We’ll leave it up to patients to decide’ shirks an important obligation for FDA, to make sure that the drugs available to patients have been demonstrated safe and effective, and to hold companies responsible for producing that evidence.”
1. Alexander GC, Knopman DS, Emerson SS, et al. Revisiting FDA approval of aducanumab. N Engl J Med 2021;385:769-771.
2. Darrow JJ, Avorn J, Kesselheim AS. FDA approval and regulation of pharmaceuticals, 1983-2018. JAMA 2020;323:164-176.
3. Vokinger KN, Kesselheim AS, Glaus CEG, Hwang TJ. Therapeutic value of drugs granted accelerated approval or conditional marketing authorization in the US and Europe from 2007 to 2021. JAMA Health Forum 2022;3:e222685.
4. Beakes-Read G, Neisser M, Frey P, Guarducci M. Analysis of FDA’s accelerated approval program performance December 1992-December 2021. Ther Innov Regul Sci 2022;56:698-703.
5. Omae K, Onishi A, Sahker E, Furukawa TA. US Food and Drug Administration accelerated approval program for nononcology drug indications between 1992 and 2018. JAMA Netw Open 2022;5:e2230973.
6. Grabowski H, Long G, Mortimer R, Boyo A. Updated trends in US brand-name and generic drug competition. J Med Econ 2016;19:836-844.
7. Morris ZS, Wooding S, Grant J. The answer is 17 years, what is the question: Understanding time lags in translational research. J R Soc Med 2011;104:510-520.
8. Schwartz LM, Woloshin S, Welch HG. Using a drug facts box to communicate drug benefits and harms: Two randomized trials. Ann Intern Med 2009;150:516-527.
9. Darrow JJ, Dhruva SS, Redberg RF. Changing FDA approval standards: Ethical implications for patient consent. J Gen Intern Med 2021;36:3212-3214.
10. Lynch HF, Robertson CT. Challenges in confirming drug effectiveness after early approval. Science 2021;374:1205-1207.
Essentially, the ethical issues are how to consider the interests of patients today, who are willing to accept uncertainty in the hopes a drug works because they do not have time to wait, and the interests of patients tomorrow, who would prefer to have stronger evidence about what works and what does not.
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