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In the wake of last month’s controversial Food and Drug Administration approval of Biogen’s Aduhelm, Alzheimer’s Association CEO Harry Johns condemned the “negative voices” concentrating on the flaws in the FDA’s approval as “not pro-patient.”

The Alzheimer’s Association wasn’t the only patient advocacy organization applauding the FDA’s questionable decision, which was based on changes in a surrogate endpoint for Alzheimer’s disease — reduction of amyloid in the brain, an outcome the FDA had previously rejected and that dozens of previous studies had failed to associate with better dementia outcomes.

“We are heartened by the FDA’s decision to speed new treatments to people with Alzheimer’s and we need them to do the same for people with ALS [amyotrophic lateral sclerosis] immediately,” Neil Thakur, chief mission officer of the ALS Association, told NPR. The ALS Association has long been pushing for approval of new treatments and for more lax FDA approval standards. Apparently, more lax approval standards count as being “pro-patient”: The organization’s president and CEO, Calaneet Balas, recently remarked that ALS patients should “determine the risks they’re willing to take and the value they see in the benefits, not anyone else.”

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Before its Aduhelm decision, we believe the FDA’s worst approval in recent memory belonged to Exondys 51, a drug to treat Duchenne muscular dystrophy. Patient advocacy organizations (PAOs) vociferously supported its approval at a heated FDA advisory committee meeting. Following a controversial approval, in which Janet Woodcock, who was then director of the FDA’s Center for Drug Evaluation and Research, called for “the greatest flexibility possible” in determining Exondys 51’s effectiveness, patient advocates lamented the $300,000 per year price tag Sarepta put on the drug.

It is understandable that patients and families hope for — and will push for — new therapies, and that patient advocacy organizations will represent those priorities. But no-holds-barred advocacy for approval of therapies, based on insufficient data and without regard to price, has its own history of failing to be “pro-patient.”

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Revamped role for patient advocacy organizations

PAOs are crucial to the process of drug development. The FDA has cemented their role in creating the CDER Patient-Focused Drug Development Program. Drug products developed without meaningful input from patients or caregivers may be effective by standard metrics yet may ignore the way those products will be used, tolerated, or paid for. In some areas, including Alzheimer’s disease and Parkinson’s disease, patient advocacy organizations are paying for an ever-growing share of research as pharmaceutical companies pull back.

Given these realities, we believe that patient advocacy is at a crossroads. To that end, we propose three best practices for PAO involvement in drug discovery.

Advocate for drugs that identify meaningful clinical endpoints. The last few decades have ushered in an era of biomarker-centered drug development. There are potential advantages to this approach, especially for diseases with outcomes that may take years to measure. Biomarkers allow for earlier entry to the market based on indicators that are reasonably likely to correlate with meaningful clinical outcomes. The issue is that few biomarkers are truly validated for this purpose and some — including progression-free survival in oncology and the reduction in amyloid plaques in Alzheimer’s disease — may not correlate with more meaningful clinical outcomes.

Drugs approved based on surrogate endpoints via the accelerated approval pathway are given long periods of time in which to validate their effectiveness, with companies rarely meeting extended deadlines to complete post-market studies. For Exondys 51, the deadline was May 2021, but the company is reportedly years behind on such studies. For Aduhelm, Biogen has been given nine years to complete follow-up studies.

Patient advocacy groups should focus on getting drugs approved for their effects on meaningful clinical endpoints, even though demonstrating improvement in a surrogate endpoint is far easier than demonstrating benefit to patients. When biomarkers must be used, they should be validated (such as HbA1c for diabetes), and follow-up studies should be both mandatory and completed on a shorter timeline. PAOs should prioritize funding for such follow-ups, both to ensure that their constituents are receiving cost-effective treatment and to minimize improvidently-targeted follow-on research.

Insist on clear inclusion/exclusion criteria. PAOs should demand that clinical trial populations are representative of the patients with the disease. Exondys 51, for instance, was only studied in patients with Duchenne muscular dystrophy due to a specific mutation in exon 51 (hence the drug’s brand name), but the drug was approved for use in all patients with the disease. Similarly, Aduhelm was tested only in people with mild-to-moderate symptoms of Alzheimer’s disease but the FDA awarded a broad indication for use in Alzheimer’s disease until public protest — not PAO protest — caused it to modify its recommendation.

Patient advocacy groups should also be aware of the diversity of clinical trials. Alzheimer’s disease is estimated to be more prevalent in Black and Hispanic people than in white individuals, yet there were only 11 Black and 67 Hispanic participants enrolled in the “successful” trial for Aduhelm, compared with 1,285 white participants. In fact, Biogen listed only white and Asian categories in its investor presentations despite a 2020 Centers for Disease Control and Prevention report projecting that by 2060 2.2 million Black Americans and 3.2 million Hispanic Americans will be affected by Alzheimer’s or other forms of dementia.

Press for cost-effectiveness. PAOs should be the leading players in arguing for more reasonable drug prices. Hardly anyone else is suited for the role. Individual patients are powerless. The FDA historically has not considered cost as part of the approval process, though interim FDA Commissioner Woodcock and others at the agency have taken the financial stability of companies like Sarepta into consideration when making approval determinations. With the FDA seemingly concerned about corporate revenue streams, patient advocacy organizations must use their power as funders of research and patient representatives to insist upon the affordability of medications.

Practically speaking, cost is often less important to patient groups when they’ll be borne mostly by federal programs or by private insurance. In the case of Aduhelm, however, there are likely to be substantial out-of-pocket costs, even to those covered by Medicare. Even though the FDA walked back its inappropriately broad approval for the drug, off-label prescribing will likely generate excess spending for patients with more advanced dementia.

Cost will also be a consideration for diseases that hit more people who are younger than 65, the age at which Medicare coverage kicks in. It’s also important to consider the fact that drug companies are allowed to discuss health care economic information on off-label uses with insurers, pursuant to the 21st Century Cures Act. In fact, the FDA has organized a meeting later this month to discuss coverage of Aduhelm and similar Alzheimer’s disease therapies with insurance companies and other stakeholders.

If patients were paying out of pocket for a drug with proven outcomes, they would at least be paying for value. For now, patients are paying an increasing share of costs for expensive drugs that lack effectiveness data. Paying a high cost for unknown effectiveness is, by definition, not cost-effective. Yet the Alzheimer’s Association’s gentle pushback against Biogen’s pricing of Aduhelm has been derided as a “box-checking exercise” rather than a critique backed by sustained public pressure. Such pressure can be politically difficult for patient advocacy groups which, like the Alzheimer’s Association, receive significant funding from drug manufacturers, but it ought to be a vital part of their mission.

As researchers who study clinical trials and drug approvals, we want nothing more than to see the development and approval of transformative drugs that are made accessible to patients at reasonable cost. We believe that patient advocacy organizations are best situated to make the case for higher approval standards that produce better-quality therapies, ones that stand the best chance of delaying or reversing disease progression.

As the FDA expands its consideration of the patient perspective in drug development, refocused objectives are needed. The paradigm must be shifted from “any drug at any cost” to “the best drug at the right cost.” Patient advocacy organizations must demand more, both from the pharmaceutical industry and from the FDA.

Michael S. Sinha is a physician, lawyer, adjunct faculty member at Northeastern University School of Law in Boston, and visiting scholar at the school’s Center for Health Policy and Law. Stephen R. Latham is the director of the Interdisciplinary Center for Bioethics at Yale University.

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