Anticancer Drug Approvals in the Past Decade—Quality vs Quantity

The number of anticancer drug approvals by the US Food and Drug Administration (FDA) has increased exponentially in the past decade. This has led to a fundamental question of whether the FDA is approving therapies that are transformational or therapies that have only a marginal benefit over existing drugs. The study by Olivier et al¹ attempts to answer this question by estimating the proportion of drug approvals with a novel mechanism of action vs those that are next-in-class agents. The authors found that 37% of approvals between 2009 and 2020 were for drugs with new mechanism of action within a tumor type. Furthermore, while the proportion of such drug approvals (novel mechanism of action within a tumor type) has decreased from approximately 60% in 2009 to 40% in 2020, the absolute number has increased from 5 to 24 during the same period. When evaluating drug approvals across tumor types, the proportion of drugs with novel mechanism of action has decreased from approximately 40% to 10%, with the absolute number of such approvals marginally increasing from 3 to 7. These results provide an important benchmark for assessment of future FDA approvals in an era of rapid drug development. Furthermore, it shows that the sharp spike in number of anticancer drug approvals by the FDA in the last decade is primarily driven by approval of next-in-class agents and subsequent indications of a drug within the same tumor type.

Currently, the drug pricing structure in the US is such that next-in-class drugs or drugs with marginal benefit are priced the same as first-in-class potentially transformative drugs. Sarpatwari et al² empirically demonstrated that brand-brand competition after launch of next-in-class agents does not lead to a decrease in list price in the US. There are two philosophical arguments on why the biopharmaceutical industry may be incentivized to pursue next-in-class agents or look for additional indications within the same tumor type rather than focusing on transformational or novel drugs. First, pharmaceutical companies are able to set a similar price for both next-in-class agents that are less risky as well as novel first-in-class agents that require greater research investment and carry the risk of failure due to unexpected toxic effects or low efficacy. Second, as highlighted by Fojo et al,³ investing in a highly risky novel breakthrough therapy may cause investors to sell their shares due to lack of confidence, leading to decrease in company stock price. This may motivate companies to avoid pursuing risky avenues. Hence, structural policy reforms are urgently needed to incentivize pharmaceutical companies to pursue drugs and indications that are potentially transformative even if there is a high degree of risk associated with such programs.

In the interim, what can clinical investigators, regulatory authorities, companies, and policy makers do to ensure that the drug approvals are truly benefitting our patients? First, when a randomized clinical trial for a next-in-class drug is being launched, the study design and control arm should ensure that the trial will answer a clinically relevant question for patients and provide clinically meaningful benefit if approved. For example, if the next-in-class drug is potentially beneficial because of less toxicity or more convenient route of administration, a rational design would be a noninferiority trial against the first-in-class compound. An example of this is the phase 3 ELEVATE-RR trial,⁴ where acalabrutinib, a next-in-class bruton tyrosine kinase inhibitor, demonstrated a noninferior progression-free survival compared with ibrutinib (first-in-class agent) along with less cardiotoxicity. On the other hand, if the added value of the next-in-class drug is superior efficacy compared with the parent compound based on preclinical and/or early clinical data, a head-to-head superiority trial should be performed as a prerequisite for full approval. For example, the phase 3 ENDEAVOR trial⁵ in multiple myeloma compared carfilzomib-dexamethasone with bortezomib-dexamethasone and demonstrated superior progression-free and overall survival with the former. However, a next-in-class agent can still add value to clinical care in the absence of superior efficacy if it has a different toxicity profile such that treatment choice can be tailored based on individual patient characteristics. For example, although carfilzomib (a nonneurotoxic proteasome inhibitor) did not demonstrate superiority over bortezomib in the frontline setting,⁶ it is widely used for patients with baseline neuropathy. Second, if there is no significant advantage of a next-in-class compound over the parent compound in terms of efficacy, toxicity, or convenience, the next-in-class compound must have a lower price tag as a justification to stay on the market. Finally, when a drug with a new mechanism of action is launched, the registration trials should have a contemporary control arm to be able to delineate the incremental benefit over existing therapies. There are several examples of greater clinical benefit from a safe and effective next-in-class drug (eg, carfilzomib and pomalidomide in myeloma) compared with a first-in-class drug (eg, panobinostat in myeloma).

In summary, we have achieved great momentum in new drug development since the 1990s when the biopharmaceutical industry started getting involved in drug development. This has undoubtedly led to an increase in speed of drug development, which has translated to improved survival in several cancers.⁷ While there is certainly room for improvement to further incentivize companies to develop novel transformative therapies, parallel development of next-in-class agents is also needed, especially in drug classes that provide significant clinical benefit such that clinicians have the option of several agents with complementary toxicity profiles. We must maintain the momentum of drug development and FDA approvals that has been achieved in the past decades and additionally ensure that the new drugs or indications are providing clinically meaningful benefit to patients.

Published: December 14, 2021. doi:10.1001/jamanetworkopen.2021.39178

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Chakraborty R. JAMA Network Open.

Corresponding Author: Rajshekhar Chakraborty, MD, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, 161 Ft Washington Ave, New York, NY 10032 (rc3360@cumc.columbia.edu).

Conflict of Interest Disclosures: None reported.