Twenty-five years of novel drug approvals in rheumatology

Abstract

The field of rheumatology has experienced dozens of novel drug approvals in the past two and a half decades, but the regulatory mechanisms underpinning these decisions are not well understood. In the USA, the Food and Drug Administration (FDA) evaluates the safety and efficacy of novel drugs through the New Drug Application (NDA) process. When additional content expertise is required to evaluate scientific or technical matters, the FDA may convene Human Drug Advisory Committees. To better understand the landscape of rheumatology NDAs and the FDA use of advisory committees, we performed a review of all rheumatic disease drug applications from 1996 to 2021 that were granted approval by the FDA. Our review identified 31 NDAs, seven of which utilized an advisory committee. The indications for using advisory committees and their influence on ultimate approvals was not clear. Recommendations to improve transparency and increase public trust in FDA decisions are provided.

The field of rheumatology has experienced dozens of novel drug approvals over the past two and a half decades, but few practicing rheumatologists understand the regulatory mechanisms underpinning these decisions. In the USA, the Food and Drug Administration (FDA) is responsible for evaluating the safety and efficacy of novel drugs through the New Drug Application (NDA) process, which has come under greater scrutiny in the wake of recent controversial approvals, such as aducanumab [1]. In particular, the role of Advisory Committees, which provide content expertise to ensure that FDA regulators are able to adequately interpret the available data and weigh potential risks and benefits, has been unclear. The objective of this review is to describe the FDA process for NDAs and to evaluate the past 25 years of approval decisions.

The NDA is the formal process for acquiring FDA approval, whose purpose is to provide enough information to allow reviewers to make decisions regarding safety, efficacy and manufacturing. In general, a novel agent first undergoes testing in laboratory and animal models to ensure bio-plausibility as well as in vivo safety. If results appear promising, investigators submit an Investigational New Drug Application to the FDA, which is required prior to initiating human trials. Once approved, the development process generally progresses through three steps. First, in a Phase 1 trial, the safety of the novel agent will be evaluated in a small cohort of healthy people. Second, Phase 2 trials investigate multiple doses of the agent and provide additional safety data as well as preliminary data for efficacy. Finally, Phase 3 trials are conducted to demonstrate the efficacy of the drug in the target population. All available data from preclinical and clinical studies are then included in an NDA, which is filed at the FDA and starts the process of formal review [2].

In cases where additional content expertise is required to evaluate scientific or technical matters, the FDA may convene Human Drug Advisory Committees [3]. These committees provide ‘independent opinions and recommendations from outside experts’ [4], who evaluate the available data, weigh potential risks and benefits, and provide recommendations for approval or denial. Advisory committee meetings are open to the public, allowing patients, industry representatives and other invested parties an opportunity to offer testimony. Though the process itself is well described and minutes from meetings are publicly available, the decision to involve an advisory committee is ‘usually at the discretion of the division director in one of the FDA's five product centers’ [4]. Recent FDA approvals [5, 6] and assessments of FDA standards in oncology [7] have brought into question the degree to which the FDA approval process accomplishes its stated goals.

Similar to oncology, the field of rheumatology has witnessed an expansion of novel biologic and targeted ‘blockbuster’ drugs. In rheumatology, the Arthritis Advisory Committee handles the majority of rheumatic disease drug applications. It consists of 11 members, 10 of whom are currently rheumatologists, and any member of the public is welcome to attend meetings to offer testimony to this committee. The committee has met four times in the past three years to discuss the approvals of avacopan, tanezumab, nintedanib and febuxostat. Of these four most recently reviewed drugs, two (avacopan and nintedanib) were approved, and one (tanezumab) was denied after an advisory committee vote that was 19:1 against its approval. The fourth, a review of the urate lowering agent febuxostat, evaluated safety signals and resulted in an update to the prescribing label.

In Europe, new drugs are approved by the European Medicines Agency (EMA) through a marketing authorization application (MAA). Like the FDA’s process, the MAA ensures safety, efficacy and quality of a drug in a thorough review of all pharmacological, kinetic and clinical trials. Unlike the FDA, the MAA relies on a Committee for Medicinal Products for Human Use (CHMP), which includes members from each European Union (EU) Member State, up to five EU experts in relevant fields and a team of assessors in national agencies. The CHMP forms two teams that independently review the medicine, and each creates an assessment, which are then evaluated by appointed peer reviewers and subsequently discussed during a CHMP plenary meeting. The final CHMP recommendation for approval or refusal of a new medicine is determined by a formal vote [8].

The approval of the Janus kinase (JAK) inhibitor tofacitinib highlights differences between the FDA and EMA. The FDA approved tofacitinib in November of 2012 for rheumatoid arthritis after a 13-month review. An advisory committee had been convened and voted favourably on the efficacy and safety of tofacitinib, ultimately recommending approval. As part of the approval, additional safety studies were required. The EMA, on the other hand, rejected the initial approval in 2013 on grounds of uncertainty regarding its safety profile, referencing concerns about opportunistic infections, cardiovascular risk and malignancy. Additional studies led to a resubmission in 2016 and ultimately approval in March of 2017, four years after its initial rejection. The recently published ORAL-SURVEILLANCE [9] study confirmed these initial safety concerns, reflecting favourably upon the greater caution of the EMA process.

To better understand the landscape of rheumatology NDAs and their use of advisory committees, we performed a review of all rheumatic disease novel drug applications for the past 25 years (see Supplementary Data S1, available at Rheumatology online, for methodology). Our review identified 31 novel drugs that were ultimately approved (Supplementary Table S1, available at Rheumatology online). Over three in four approvals were for biologic DMARDS and the most common indications were for rheumatoid arthritis, plaque psoriasis/arthritis and systemic lupus erythematosus (Table 1). We also investigated the frequency by which NDAs included an advisory committee in their deliberations. An advisory committee convened in seven out of the 31 NDAs, which included approvals for nintedanib, baricitinib, tofacitinib, secukinumab, ustekinumab, avacopan and pirfenidone. This low utilization of advisory committees is consistent with other fields of medicine; since 2010, advisory committee use has decreased from 55% of new drug approvals to 6% [10].

In our evaluation of rheumatology advisory committees for approved rheumatic disease drugs, we observed substantial variation between drugs with respect to advisory committee safety assessments. The mean safety vote was 76% in favour (s.d. 20%), but the range was 52–100%. While this may delay the time to access novel therapeutic agents, it may also have ancillary benefits, such as ensuring an adequate review of benefits and safety from experts in the field of rheumatology.

In light of these data and recent commentary encouraging reform of the advisory committee process [10], we agree with recent calls to improve the use of FDA advisory committees and would suggest the following considerations from the perspective of the rheumatologist. First, guidelines and criteria for when to use an advisory committee should be developed. Prior use of FDA advisory committees in rheumatology appears to be arbitrary, both with respect to drugs within classes and when comparing between classes. Advisory committees were convened for two JAK inhibitors (baricitinib and tofacitinib), for instance, but not for the more recently introduced upadacitinib. A committee was convened to evaluate the novel c5a inhibitor avacopan and the antifibrotic agent nintedanib, but none were involved in the novel calcineurin inhibitor voclosoporin. Clearer guidance for when to expect advisory committee involvement would improve transparency and clarify expectations for drug developers. At a minimum, an advisory committee should be convened for novel molecular drugs and for those in classes with known severe adverse effects (e.g. JAK inhibitors). Ideally, advisory committees would become an integrated aspect of all NDAs, an approach that would more closely resemble the one used by the EMA.

Second, the role of advisory committee advice in the ultimate decisions made by the FDA should be clarified. After the public hearings for the avacopan advisory committee, for instance, rheumatologists and patients with rheumatic diseases were understandably confused. Some advisory members felt that avacopan had a steroid sparing effect, while others thought observed differences in glucocorticoids were ‘a result of the nature of the design’, and questioned ‘the clinical relevance’, of the observed differences. Instead of approving avacopan as a steroid sparing therapy or requiring additional data, the FDA approved it as an adjunctive therapy, a role for which it has never been studied. How the FDA integrated advice from the advisory committee and the reasons for ignoring, modifying or accepting advisory committee advice should be made clear. We would suggest that the FDA be required to share this information at the time of drug approval or denial.

Decisions made by the FDA have profound implications for rheumatologists, patients with rheumatic diseases and society writ large. Advisory committees play an important role in this process, but over the past 25 years, fewer than one in four new drug approvals in rheumatology utilized an advisory committee. Greater transparency in when advisory committees will be used and how their recommendations will affect FDA decision making could improve the process and increase public trust in FDA decisions.

Supplementary material

Supplementary material is available at Rheumatology online.

Data availability

Data will be made available upon reasonable request.

Contribution statement

K.H., N.A. and M.P. all made substantial contributions to the conception or design of this manuscript. All authors made substantial contributions to the acquisition, analysis and interpretation of data for the work, drafted the work or revised it critically, gave final approval of this version to be published, and agree to be accountable for all aspects of the work.

Funding

M.P. is supported by a Rheumatology Research Foundation Scientist Development Grant.

Disclosure statement: M.P. receives research funding from clinical trials by Abbvie (SELECT-GCA) and Astra Zeneca (MANDARA) and receives consulting fees from Novartis. The remaining authors have declared no conflicts of interest.

Ethical approval information: This study did not use patient data and institutional review board approval was not required.

References