Expedited regulatory product approval in the time of COVID-19.

The COVID-19 pandemic has given us a new appreciation for the need for scientifically-driven research and development. The availability of vaccines within a relatively short period after the onset of the pandemic is a wonder from my perspective. Hand-in-hand with the science was a flexible regulatory environment, making vaccines available initially through an Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration, and then full approval. This leads to another question – are there other life-saving and sight-saving treatments which should enjoy a similarly faster regulatory pathway to treating patients?

The short answer is that the U.S. there IS a pathway – actually several pathways. I wrote about this issue, and how it might apply to ophthalmic drugs about ten years ago [1]. Briefly, the key U.S. law governing drug approval is the 1962 Kefauver-Harris amendment which requires “substantive evidence of safety and efficacy” of a new pharmaceutical in well controlled studies. A subsequent law was the Orphan Drug Act of 1983 which provided financial incentives and consulting support for development of drugs to treat rare diseases (defined as less than 200,000 affected Americans) [2]. In 1992, the FDA issued regulations for Accelerated Approval, allowing earlier approval of drugs to treat serious diseases. In 2012, Congress passed the Food and Drug Administration Safety Innovation Act, which amended the Federal Food, Drug, and Cosmetic Act, to allow FDA to base accelerated approval on whether the drug has an effect on a surrogate or an intermediate clinical endpoint. This regulation, called “Subpart H″, allows for an accelerated conditional approval of a drug based upon a surrogate basis (21 CFR 314.510). The Sponsor is obligated to conduct post-approval studies with the drug using the “real” endpoint. There have been nearly 300 drugs approved using this pathway. For the most part, they are drugs for treatment of cancer and of pain [2]. If subsequent studies with the “real” measure do NOT show a favorable benefit-risk, then the approval will be withdrawn. This has occurred, perhaps most notably with the removal of bevacizumab's conditional approval for the treatment of breast cancer [3]. As I review the list of approvals via this route, I do not see any drugs for the treatment of ocular disease, much less treatment of ocular surface disease. Decades before this law was enacted, the U.S. FDA and many other regulatory authorities approved treatments for glaucoma based on the lowering of intraocular pressure (IOP). Technically, these approvals are NOT Subpart H, and there is no obligation for follow-on studies on prevention of visual field progression. They are based upon the worldwide agreement that elevated IOP is a major risk factor for glaucoma.

The U.S. FDA Center for Drug Evaluation and Research has four key expedited programs for serious conditions for drugs and biologics - Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review. The qualifications and the benefits of each program are presented in an FDA guidance [4]. In my experience, “Breakthrough Therapy” designation is the most valuable. However, it requires clinical evidence of efficacy, typically from pilot trials with concurrent controls. Other centers at FDA also have similar programs. The Center for Biologics Evaluation and Research has “Regenerative Medicine Advanced Therapy Designation”, which was part of the 21st Century Cures Act of 2016 [5]. The Center for Devices and Radiological Health has the “Breakthrough Devices Program” [6].

In June 2021, Biogen received approval for a Biologic License Application for its aducanumab-avwa (Aduhelm™) for the treatment of Alzheimer's disease. The basis for this approval was the reduction of amyloid beta plaque (as evaluated using positron emission tomography in three controlled trials). This FDA approval was in contrast to the negative vote of an external, non-binding, advisory panel in November 2020. In this “accelerated approval”, FDA cited 21 CFR 601.41, requiring a post-approval study by the Sponsor “… in order to verify the clinical benefit of aducanumab, conduct a randomized, controlled trial to evaluate the efficacy of aducanumab-avwa compared to an appropriate control for the treatment of Alzheimer's disease. The trial should be of sufficient duration to observe changes on an acceptable endpoint in the patient population enrolled in the trial” with a due date for a protocol of October 2021, and completion and reporting of that long-term trial by 2030.

Subsequently, the editors of JAMA Internal Medicine published three perspectives on this approval [7]. Senior management at FDA presented the basis of their approval in peer-reviewed journals, frankly stating that there were some discrepant results in the studies. They also noted the safety risks. In the end, in considering the benefits and risk of this treatment, FDA considered the degenerative nature of Alzheimer's disease, and testimonials from patients and their families. FDA conditionally approved the treatment using the accelerated pathway, with the previous statement post-approval requirement for additional studies [8]. The second perspective was from Crosson (affiliated with a Health Management Organization) who noted the possibilities for harm from the medication and that “the cost of this drug alone might threaten the financial viability of the program,” they argue that the Centers for Medicare & Medicaid Services “should use independent clinical and pharmacologic experts to evaluate the strength of the evidence for the efficacy and safety of aducanumab and arrive at its own findings.” [9] The third perspective from academicians Gyawali et al. drew on the experience with accelerated approvals with oncology drugs, call for reforming the FDA's accelerated approval pathway. Among Gyawali et al.‘s recommendations were timely completion of postapproval trials, the verification of clinical benefit with clinical end points, and the “prompt and automatic” withdrawal of an indication for a drug granted under accelerated approval if the confirmatory trial is negative [9].

Neurology also published perspectives on this topic [10]. Salloway and Cummings present the clinical trial reports showing consistent reduction of β-amyloid (Aβ) on amyloid PET [11]. In a counterviewpoint, Knopman and Perlmutter argue that the clinical benefit of aducanumab seen was small, amounting to 3 months’ worth of delay in clinical decline [12]. New England Journal of Medicine also had articles on this topic [13,14]. Commentaries in the medical literature continue, including cost-effectiveness calculations and public policy discussions [[15], [16], [17]].

With hundreds of accelerated approvals over the years, why has the approval of aducanumab been so controversial? Is it because of the indication (Alzheimer's disease), the validity of the biomarker, Aβ, to predict disease progression, the weight of the efficacy evidence, or the safety concerns? I think it is all of those – but primarily it is the cost. The initial “wholesale average cost” was initially estimated at approximately $56,000 per patient per year [18], and more recently as $28,200 (March 2022) [19]. The ocular gene therapy Luxturna® (voretigene neparvovec-rzyl) is at least ten times this cost – but as a gene therapy, it is thought to be longer acting. As well, the U.S. patient population with the label “confirmed biallelic RPE65 mutation-associated retinal dystrophy” is 3000 or less [20] – many orders of magnitude less than the U.S. population with, or at risk for Alzheimer's disease. Thus the estimates for the impact of this cost per patient times the number of patients has many concerned about the impact on federal and state budgets [[21], [22]]. In late 2021, Medicare announced increased insurance premiums for beneficiaries for 2022, with some claiming it is due to the anticipated costs of including aducanumab on the formulary. However, subsequently, the magnitude of this increase was announced – it is approximately $1 per month – which I consider negligible. In February 2022, the U.S. Centers for Medicare and Medicaid Services proposed last month to limit coverage of Biogen's drug Aduhelm® (aducanumab-avwa) to patients enrolled in clinical trials sanctioned by the agency. These announcements are now moot, given that in early May 2022, the company announced they would not be selling the product in the U.S. at this time. However, Medicare's “coverage with evidence of development” [23] may have impact on future accelerated approvals.

In my opinion, the carrot-and-stick accelerated approval – wherein there is the potential for making novel therapies available earlier for patients with blinding or sight-threatening disease, but with the condition that the approval may be removed if this is not borne out in longer-term “real” studies – is a good balance of benefit/risk. Stated differently, if this pathway (and the other expedited programs) did not exist, many patients and health care providers would advocate for its creation. I believe that the accelerated programs used by FDA to meet the COVID-19 pandemic have proven to be worth the risk. A critical review of the early approval pathways in the U.S. and Europe has been recently published [24].

In a potentially similar situation, Amylyx has a New Drug Application pending with the U.S. FDA for its AMX0035 (sodium phenylbutyrate and taurusodiol) for the treatment of amyotrophic lateral sclerosis. In an meeting in March, a non-binding advisory panel voted in favor of efficacy, based upon a single Phase 2 study. It will be interesting to see FDA's decision (due in June 2022), and the healthcare system response.

In ophthalmology, and ocular surface disease specifically, unfortunately, other than IOP for glaucoma, there is no validated biomarker [25]. Thus to date, the accelerated approval has not been used in our field. The optimist in me feels that our continued research will find better biomarkers, as well as finding novel treatments, some of which might one day be suitable for an accelerated approval.

Declaration of Competing Interest

Gary D. Novack PhD consults with numerous pharmaceutical and medical device firms.