Breakthrough Drugs Raise Development and Production Challenges

The FDA program to expedite the development and approval of innovative drugs for serious and life-threatening conditions is a great success, but the abbreviated development timeframe involved raises numerous difficulties for manufacturers seeking to ensure product quality and timely supply. Expert review teams in the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are meeting deadlines and goals for assessing breakthrough designation requests and for expediting reviews of these drugs, but the process is resource intensive and has raised questions about how FDA can keep up with a growing number of candidates.

When the breakthrough program was established as part of the FDA Safety and Innovation Act of 2012, stakeholders envisioned about two to three designations a year. By the end of May 2015, FDA had received 308 requests for breakthrough status and had granted the designation for 90, approximately 30%. Nearly 15 important new therapies have come to market more quickly as a result, contributing to the recent rise in new drug approvals. FDA acting commissioner Stephen Ostroff pointed out at the annual meeting of the Food & Drug Law Institute (FDLI) in April 2015 that two-thirds of 2014’s near-record 51 new molecular entities (NMEs) took advantage of at least one expedited review program, and many were first-in-class therapies.

Achieving fast approval of a breakthrough therapy creates challenges for manufacturers looking to develop CMC data in roughly half the time, noted Brian Kelley, vice-president for bioprocess development at Genentech. The process, he explained at the April 2015 CMC workshop sponsored by the Drug Information Association (DIA), is resource intensive, and accelerated timelines necessitate new approaches to product and process development to ensure a reliable supply of a quality product at launch. The breakthrough designation “does not mean that sponsors can do less,” he said; they just “need to start sooner.” This may involve front-loading of crucial product and process characterization activities, and reaching agreement with FDA on which actions for optimizing process and methods can wait until after launch.

High priority for FDA
Expedited quality assessments raise difficulties for FDA, as well. New drug applications (NDAs) for breakthrough therapies often contain less manufacturing information than usual, requiring innovative risk-mitigation strategies to ensure product safety. Agency reviewers are agreeing to less stability data at submission, accepting amendments during the review cycle, and increasing postmarketing commitments to cover residual risk, explained Dorota Matecka, acting branch chief in the Office of New Drug Products in CDER’s Office of Pharmaceutical Quality (OPQ), at the DIA workshop and again at the ISPE/FDA/PQRI Quality Manufacturing Conference in June 2015. Matecka noted that CDER will schedule CMC-specific meetings during development to advise on these issues, often including CDER upper management and subject matter experts.

Robert Wittoft, pharmacist in OPQ’s Office of Process and Facilities (OPF), similarly urged early discussion of residual product quality risks. Manufacturers need to decide dosage form and methods validation strategies much sooner, he said at the CMC workshop, and should “plan for the unexpected,” such as facility qualification failures and changes in manufacturing schedules. Effective communication with contract manufacturers is crucial, as is a transparent presentation in the application of design evolution and a rationale for commercial manufacturing process and controls.

John Groskoph, senior director at Pfizer, observed that for most breakthrough therapies, market applications are being filed with FDA after Phase II studies, approximately two years ahead of a traditional NDA that is based on Phase III data. The time reduction presents “significant challenges to the development team,” he commented, and may be further complicated if the firm seeks to file simultaneous applications in Europe, Japan, and emerging markets, as well as in the United States.

Japan, for example, has established the SAKIGAKE designation program for innovative medicines and medical devices that are developed first in Japan and offer “radical improvement” over existing therapies to treat critical diseases, explained Yoshihiro Matsuda of Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), at the CMC workshop. He described a greatly accelerated development and approval process for such therapies, combined with stronger postmarketing oversight. The initiative, he noted, requires risk-based assessment strategies and a product quality lifecycle management plan, combined with clear analysis of what can be evaluated during review, and what can be analyzed later after approval.

Groskoph noted that successful launch of a breakthrough drug involves addressing numerous issues: data availability, meaningful and practical specifications, robust manufacturing processes, clinical or commercial site production, site readiness for pre-approval inspection, deferral of Phase III studies to post approval, and the need for comparability protocols to facilitate postapproval changes. Communication with FDA is important throughout the breakthrough development process, he added, to facilitate agreement on strategies for dealing with unexpected production problems.

For biologics, breakthrough designation may prompt greater focus on the reliability of the Phase I cell line, process and formulation, as shorter pivotal trials may truncate optimization of the Phase III process, added Kelley of Genentech. A key decision for manufacturers is whether to devote more resources to the project early to front-load process characterization and validation activities, even before gaining the breakthrough designation. Such an approach may involve testing lots before assay validation is completed; filing with broader specifications with the aim of tightening them post-launch; launching from the clinical site and transferring to commercial post-launch; and including a postapproval lifecycle management plan in the application to support deferral of certain activities. But, Kelley commented, “you can’t place bets” on potential breakthroughs too frequently without overly straining company resources.

Sustainable program?
The growth in breakthrough designation requests is prompting FDA and stakeholders to examine options for refining breakthrough criteria so that FDA will be able to manage the program. The agency is examining past designation decisions and why it turned down certain requests to see if the bar is too low; a goal is to better educate manufacturers on which promising experimental products really qualify for breakthrough status.

FDA “can’t sustain a program where everything is a breakthrough,” commented John Jenkins, director of CDER’s Office of New Drugs, at an April 2015 workshop on breakthrough therapy designation criteria organized by the Brookings Institution. FDA officials explained that extensive resources are involved in determining designations and in supporting development and accelerated review of breakthrough candidates. Manufacturers acknowledged that designation denials could decrease if sponsors sought breakthrough status only for therapies that offer truly substantial improvements in patient care. And they indicated that additional resources from industry are warranted to support the unexpectedly large breakthrough program.

While FDA can quickly approve products with clear outstanding value, Jenkins noted that such efforts may be stymied by manufacturing problems and inspection delays. There are situations where the clinical data are good, but where sponsors “have to get manufacturing and facilities in line,” he said. Sites for inspections need to be identified early, Jenkins advised, especially for overseas facilities that may raise travel difficulties. Kay Holcombe, senior vice-president of the Biotechnology Industry Organization, urged close examination of ways to prevent approval delays due to difficulties in making a drug according to specifications. “If this is a hurdle at the end,” she said, “we need to deal with it more effectively.

Article DetailsPharmaceutical Technology
Vol. 39, No. 7
Pages: 14-15

Citation:
When referring to this article, please cite it as J. Wechsler, "Breakthrough Drugs Raise Development and Production Challenges," Pharmaceutical Technology 39 (7) 2015.