Mahnum Shahzad

Mahnum Shahzad

Thomas Pyle Postdoctoral Fellow, Department of Population Medicine
Harvard Medical School, Harvard Pilgrim Health Care Institute

Dissertation Title: “Essays on the regulation of the U.S. Pharmaceutical Industry”

Regulatory policy for pharmaceuticals seeks to balance high quality evidence generation with access. The papers in this dissertation interrogate this balance by focusing specifically on the U.S. Food and Drug Administration’s Accelerated Approval pathway and the Biosimilar designation.

Chapter 1 provides an overview of the quality and timeliness of confirmatory trials for indications approved using the accelerated approval pathway. The accelerated approval pathway allows drugs to be approved using surrogate endpoints thereby allowing products to reach patients faster with the stipulation that clinical benefit is verified after approval. An increasing number of drugs have been approved using this pathway. However, the recent approval of Aduhelm (aducanumab) for Alzheimer’s disease and reports of delays in confirmatory trial completion have led to immense public scrutiny of the FDA’s management of this pathway. Using data on accelerated approvals from 2002-2021, I study the quality and timeliness of confirmatory trials for accelerated approval indications. I find that overall, only ~25% of indications approved using this pathway have confirmatory trials that provide evidence of clinical benefit and complete the confirmatory trials within the timeline set between the firms and the FDA at the time of approval. Delays are a significant driver of this result. My results also suggest that quality and timeliness of trials improves as the FDA gains more experience regulating indications in a disease area.

Chapter 2 simulates the impact of several proposed policies aimed at reforming the accelerated approval pathway. These include policies that aim to make changes to processes leading up to accelerated approval such as ensuring that confirmatory trial protocols are submitted and confirmatory trials are started prior to approval, as well as policies focused on the post-approval period such as accelerated withdrawal within 5 years, accelerated withdrawal in case confirmatory trials are delayed, and other similar modifications to the FDA accelerated approval process. Using indications approved using this pathway between 2002 and 2021, I find that 23% to 30% of indications are in the scope of policies that aim at making changes to the pre-approval processes and 32% to 60% of indications would be withdrawn if the post-approval policies were enacted.

Chapter 3 (joint with Anita Wagner and Huseyin Naci) studies the relationship between pre-approval confirmatory trial initiation and timely completion of confirmatory trials. Our results show that pre-approval trial initiation is associated with higher 3-, 5- and in-time completion rates though the latter is not a statistically significant association. The relationship between pre-approval trial initiation and faster completion of confirmatory trials is also maintained within key subgroups: orphan indications, post-FDASIA approvals and non-cancer indications.

Chapter 4 (joint with Anita Wagner and Huseyin Naci) studies the impact of negative confirmatory trials on use of drugs for indications approved using the FDA’s accelerated approval pathway. The accelerated approval pathway allows drugs to be approved on the basis of a surrogate endpoint with the stipulation that clinical benefit is verified by confirmatory trials conducted post-approval. In some cases, these confirmatory trials have failed to confirm benefit. We use an event-study framework to study the impact of these confirmatory trials for 15 injectable oncology drug-indications on prescription volumes. Our results suggest that there is, on average, a 2.5-4.0% decline in usage per month after the results of the trial are made public and this result is maintained when focusing specifically on new initiations. We also document some limited heterogeneity in response across drugs. These results show that information about these negative confirmatory trials is taken up by prescribers even before a formal approval or withdrawal by the FDA providing evidence of the important role of other sources of information in this process.

Chapter 5 focuses on the Biologic Price and Innovation Act (BPCIA) of 2010 which aimed to increase competition in the biologics market by allowing an abbreviated pathway for the entry of biosimilar molecules. However, the promise of the pathway in delivering savings from biosimilar competition has been hampered by the low take-up of these molecules. One explanation for the low take-up is that physicians and patients are uncertain about the efficacy of these molecules as compared to the originators. This doubt is especially acute for cases where patients are already using the originator molecule with success. The FDA’s regulatory standards for patients being switched across molecule types explicitly discriminate between interchangeable molecules, which have shown similar efficacy, and biosimilars where this evidence has not been evaluated. This paper focuses specifically on the predictors and consequences of switching. For a set of 7 biologics that have biosimilars approved under the BPCIA, I use data from commercially insured and Medicare Advantage populations to provide a descriptive overview of the prevalence of switching behavior and the characteristics of patients that are being switched from originators to biosimilars and vice versa. I find that switching is relatively uncommon which is in line with limited incentives to switch patients. I also find that patients who are switching are different on many demographic characteristics from the full population of biologic users: a greater number of switching patients have fewer comorbidities, less likely to be on Medicare Advantage and more likely to be seen in outpatient settings than their non-switching counterparts. Finally, I study the trajectories of patients switching to biosimilars and find that a significant share continues to use the biosimilar over extended periods of time suggesting high levels of patient satisfaction after switching. This highlights a need for greater patient and provider education about biosimilars and their clinical effectiveness and a revaluation of FDA standards and communication regarding interchangeability and biosimilarity.

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