Jill Wechsler

FDA approved many new drugs and biologics last year based on limited clinical trials and utilizing accelerated review programs, notably to treat rare diseases and deadly cancers. In a report on Innovation in Drug Approvals of 2019, the Center for Drug Evaluation and Research (CDER) outlines these important gains, noting its use of expedited programs to advance access to 60% of 48 novel drugs approved last year.

While last year’s numbers of new molecular entities (NMEs) falls below FDA’s record 59 approvals in 2018, the latest list includes numerous first-in-class therapies and advances in care across a range of conditions, from heart disease, macular degeneration, tuberculosis, osteoporosis, urinary tract infections, and migraine, to sickle cell disease, Parkinson’s disease, multiple sclerosis, and cancers and blood disorders. The report also cites numerous decisions to approve indications for expanded uses and additional patient populations, as well as new dosage forms for already marketed medicines, including the use of innovative adult therapies for children.

These gains reflect CDER’s more efficient and predictable review process, as demonstrated by its success in meeting all user fee goals for timely assessments, reviewing 90% of applications in the first review cycle, and approving nearly 70% of new drugs in advance of other countries. The report points out that advances by sponsors in developing more targeted therapies for vulnerable patient populations, often based on genetic characteristics, benefit from the agency’s increased use of innovative and accelerated review procedures over the last four years.

But while emphasizing gains in expedited drug development and review, CDER Director Janet Woodcock emphasizes that the agency’s “high standards for safety and efficacy have remained unchanged.” This responds to some fears that speedy approvals based on limited studies raise risks related to long-term safety and efficacy. Woodcock states that the agency is maintaining its high approval standards in utilizing innovative methods and new regulatory tools to expedite application reviews and approvals to bring “a wide range of new drugs to patients in need.”

Advancing innovation

Support for innovative approaches to drug development also involves FDA public meetings and new guidances on a range of methods and policies for accelerating drug development and clinical studies. These include increased reliance on real-world data gleaned from electronic medical records, particularly for documenting additional indications of a medicine, for developing natural history studies, and to advance novel clinical trial designs for gene therapies.

A final guidance on Adaptive Design Clinical Trials for drugs and biologics issued in November sets out key principles for designing, conducting, and reporting results of such trials. In outlining recommendations for Bayesian adaptive studies, the advisory emphasizes the need to pre-specify rules governing such trials and appropriate ways to deal with deviations from the anticipated algorithm.

The agency also supports flexibility in considering when and how only one clinical trial may provide sufficient evidence on a new drug, as presented in a December draft guidance on “Demonstrating Substantial Evidence of Effectiveness for Human Drugs and Biologics.” Debate has raged for more than 20 years over the traditional FDA requirement that all new drugs must be studied in at least two randomized, blinded, placebo-controlled clinical trials. And although randomized trials often are preferred for demonstrating the benefits of a new drug, “there are circumstances where evidence generated using a variety of clinical trial designs, endpoints, and statistical methodology can support effectiveness,” commented FDA principal Deputy Commissioner Amy Abernathy, especially for rare diseases treatments. The guidance acknowledges that study designs with concurrent controls, active controls, and historical controls may be appropriate in certain situations-in addition to utilizing the “gold standard” randomized controlled trial (RCT).

Meanwhile, FDA is taking steps to better monitor the safety and performance of both investigational and approved therapies. The agency has established a more efficient system for sponsors to report electronically adverse events involving study participants to more effectively track safety signals that occur during clinical trials. And draft guidance issued in November clarifies FDA’s new authority to require postmarketing studies and clinical trials for new drugs that demonstrate reduced effectiveness, in addition to those experiencing safety problems.

Ideally, FDA flexibility in clinical trial design and more efficient application reviews will reduce the cost of clinical research and yield less expensive therapies for patients. So far, high launch prices for many critical new drugs benefitting from expedited FDA programs may cloud the larger benefits of these regulatory innovations and ultimately support legislation setting price controls for drugs.

Jill Wechsler is the Washington Correspondent for Applied Clinical Trials.