FDA Reorganization Meets Demands for Expedited Approvals

An overview of the regulatory activities of the Office of Oncology Drug Products (OODP) and the Office of Hematology and Oncology Drug Products (OHODP) from 2008 to 2016 suggests that the FDA has made consistent use of regulatory mechanisms to expedite approvals during that period.¹Investigators from the Office of Biostatistics, Center for Drug Evaluation and Research completed an analysis to determine if changes in the laws, regulations, and the agency that occurred after 2007 had an effect on regulatory approvals.

Between January 1, 2008, and December 31, 2016, the FDA approved 239 oncology and hematology marketing applications, resulting in the approval of 260 indications. Fifty-three (22.2%) of these applications were granted accelerated approval, 29 (12.1%) were converted from accelerated to regular approval, and 157 (65.7%) received regular approval. Furthermore, 141 (58.9%) were designated for priority review. Since 2013, the FDA has granted the breakthrough designation on 25.7% of applications approved by OODP/OHOP. All these therapies received priority review, further expediting their development and approval. Between 13.3% and 46.7% of applications approved each year were for new molecular entities (NMEs). From 2011 to 2016, the researchers found that an average of 10.5 (63 overall) NMEs were approved each year.

The number of drug applications for approval in oncology has risen dramatically since 2007. To address this increase, the FDA created the OODP, which oversees new drug applications and biologic licensing applications. In 2011, the OODP was reorganized and renamed the Office of Hematology and Oncology Products (OHOP) based on disease-specific therapeutic areas and was reorganized into 4 divisions: Products 1, Products 2, Hematology Products, and Hematology Oncology Toxicology. This reorganization was intended to standardize and expedite the process of reviewing applications in oncology and hematology drug products.

New regulations have also changed the way products are regulated and approved. In 2007, Congress enacted the Food and Drug Administration Amendments Act (FDAAA), broadening the agency’s authority to assess various safety issues. FDAAA reauthorized the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act and granted the FDA the ability to require postmarketing requirements (eg, safety studies) to assess safety issues related to an approved product, which had previously been voluntary. The act also gave the FDA the authority to require Risk Evaluation and Mitigation Strategies for approved products.

Additionally, the enactment of the Food and Drug Administration Safety and Innovation Act (FDASIA) in 2012 added flexibility to the agency’s ability to expedite development and approval of promising drugs, with the goal of increasing early access to these therapies for patients with serious conditions. FDASIA bolstered the FDA’s ability to review promising applications expeditiously through the creation of the breakthrough therapy designation and by providing the FDA the ability to consider breakthrough-designated products for expedited priority review.

A previous report reviewed the approval actions that the OODP took from July 1, 2005, through December 31, 2007.²The investigators at that time reported that regulatory action was taken on 58 of the 60 marketing applications, and 53 were approved. A variety of clinical trial endpoints were used in the approval trials.

The longer time frame reviewed in the current study allowed for the exploration of trends and consistencies in drug approvals during this time. For instance, the use of interim analysis seems to be increasing. There is also a continued robust use of accelerated approval and other expedited programs, including the more recent breakthrough therapy designation.

Upon submission to OHOP, drugs can receive either standard review (10-month review cycle from time of filing) or priority review (6-month review cycle from time of filing). Priority review is most commonly granted for products that treat a serious condition and, if approved, would provide a marked improvement in safety or effectiveness.

Two types of FDA approvals exist for drugs or biological products: regular and accelerated. Regular approval requires that a drug or biological product demonstrate substantial evidence of clinical benefit or improvement in an established surrogate endpoint for clinical benefit. Accelerated approval was promulgated in 1992, primarily in response to the AIDS/HIV crisis, to provide an expedited method to approve drugs for patients who have serious or life-threatening diseases when these drugs show activity based on surrogate markers that are reasonably likely to predict clinical benefit above that of available therapies.

The results suggest that the FDA has made consistent use of regulatory mechanisms to expedite approvals over time. According to the report, there seems to be no discernable trend in percentage of applications granted priority review or accelerated approval over time. The decision to grant either of these expedited pathways depends on the totality of evidence, severity of disease, available treatments, current understanding of surrogate endpoints, and a balancing of benefit versus risk. The availability of NMEs also does not seem to have a discernable trend, as evidenced by the number of approved applications supporting NMEs over time. However, novel therapies are not limited to NMEs and include novel combinations, which have risen in the past few years.

The investigators noted limitations to the study, including a focus on oncology and hematology products that may not represent the FDA’s actions in other disease areas. In addition, there is significant heterogeneity among the diseases reported, resulting in different endpoints that may not be appropriate for other diseases and different sample sizes necessary to show benefit. Lastly, the report considers only the primary endpoints of the trial used to support approval of an application. Approvals are also dependent on many other factors that may affect the risk-benefit assessment of the product, such as safety, tolerability, and secondary endpoints.

References:

1. Zhou J, Vallejo J, Kluetz P, et al. Overview of oncology and hematology drug approvals at US Food and Drug Administration between 2008 and 2016 [published online August 4, 2018].J Natl Cancer Inst.doi: 10.1093/ jnci/djy130.
2. Sridhara R, Johnson JR, Justice R, Keegan P, Chakravarty A, Pazdur R. Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007.J Natl Cancer Inst.2010;102(4):230-243. doi: 10.1093/jnci/djp515.