Examining Manufacturing Readiness for Breakthrough Drug Development

AAPS PharmSciTech, Vol. 17, No. 3, June 2016 ( # 2016) DOI: 10.1208/s12249-015-0455-1 White Paper Examining Manufacturing Readiness for Breakthrough Drug Development Earl Dye,1,13 Annie Sturgess,2 Gargi Maheshwari,3 Kimberly May,4 Colleen Ruegger,5 Usha Ramesh,6 Heow Tan,7 Keith Cockerill,8 John Groskoph,9 Emanuela Lacana,10 Sau Lee,11 and Sarah Pope Miksinski12 Received 15 October 2015; accepted 13 November 2015; published online 25 November 2015 KEY WORDS: breakthrough therapy; CMC; FDA. INTRODUCTION In July 2012, Congress passed the Adva ncing Breakthrough Therapies for Patients Act as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). Section 902 of FDASIA provides for designation of a drug as a breakthrough therapy Bif the drug is intended alone or in combination with one or more other drugs, to treat The opinions expressed in this manuscript are those of Earl Dye, Annie Sturgess, Gargi Maheshwari, Kimberly May, Colleen Ruegger, Usha Ramesh, Heow Tan, Keith Cockerill, John Groskoph, Emanuela Lacana, Sau Lee, and Sarah Pope Miksinski and do not necessarily reflect the views or policies of the FDA. 1 Technical Regulatory Policy, Genentech, a Member of the Roche Group, 1399 New York Ave, NW, Suite 450, Washington, DC, Washington 20005, USA. 2 Regulatory-CMC, Bristol-Myers Squibb Company, New York, New York, USA. 3 Biologics Process Development & Commercialization, Merck & Co., Inc., Kenilworth, New Jersey, USA. 4 Biologics CMC Regulatory Affairs, Merck & Co., Inc., Kenilworth, New Jersey, USA. 5 Technical Research and Development, Novartis Pharmaceuticals Corporation, Hannover, New Jersey, USA. 6 Regulatory Affairs, CMC, Pharmacyclics Inc., Sunnyvale, California, USA. 7 Quality and Technical Operations, Pharmacyclics Inc., Sunnyvale, California, USA. 8 Regulatory Affairs, Amgen, Thousand Oaks, California, USA. 9 Global Chemistry Manufacturing & Controls, Pfizer Inc., New York, New York, USA. 10 Biosimilars and Biologics Policy, Office of Biotechnology Products, CDER, U.S. FDA, 10903 New Hampshire Ave, Silver Spring, 20993, Maryland, USA. 11 Office of Pharmaceutical Quality, CDER, U.S. FDA, 10903 New Hampshire Ave, Silver Spring, 20993, Maryland, USA. 12 CDER, U.S. FDA, 10903 New Hampshire Ave, Silver Spring, 20993, Maryland, USA. 13 To whom correspondence should be addressed. (e-mail: ) serious or life-threatening diseases or conditions and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies (1).^ Breakthrough designation is a mechanism that the U.S. Food and Drug Administration (FDA) can grant to sponsors to expedite the development of these promising therapies. As part of the program, the FDA and sponsor collaborate in a dynamic, multi-disciplinary, resource-intensive process to determine the most efficient path using an Ball hands on deck approach^ involving senior managers and experienced review staff and more frequent and interactive communications (2,3). The objective is to expedite design and review of the clinical development program so that trials are as efficient as possible, and the number of patients exposed to potentially less efficacious treatment is minimized. As a consequence, clinical development timelines involving the traditional three distinct phases could be reduced from 7–10 to 3–5 years. The shorter clinical development programs will have significant impact on product and process development timelines requiring the manufacturing organization to reconsider traditional approaches to product and process development and undertake their own resource-intensive, cross-functional team approach to ensure a sustained supply of safe and efficacious product at the time of approval. To ensure success, the manufacturing organization should have good communications with the clinical organization to facilitate identification of potential candidates for breakthrough designation early and help gate or accelerate the appropriate Chemistry, Manufacturing, and Controls (CMC) and current Good Manufacturing Practice (cGMP) development activities. It is important to understand that breakthrough drug development programs are resource intensive; sponsors need to be selective about which programs to take forward and ensure management support. Moreover, a collaborative, cross-functional approach between development, commercial, and regulatory operations, with early and robust discussions, is essential to ensure successful development and launch of a breakthrough drug product. In March of 2015, Friends of Cancer Research (Friends) convened a group of industry and FDA stakeholders familiar with developing breakthrough drugs to explore options, 529 1530-9932/16/0300-0529/0 # 2016 American Association of Pharmaceutical Scientists Dye et al. 530 manufacturers of small molecule and biologic products have for front-loading certain critical manufacturing activities to speed development of breakthrough therapy drugs. This expert group also explored options for science- and risk-based approaches to mitigating the potential risk of having less CMC information at the time of launch versus the benefit of having these innovative new products available to patients sooner. The considerations captured in this white paper outline approaches that sponsors have taken to successfully manufacture breakthrough products as well as new approaches that aim to further explore potential efficiencies in bringing breakthrough products to market. These ideas were presented at a public forum, convened by Friends, on June 10 in Washington, DC, in an effort to seek broad feedback on the recommendations put forth to expedite rate-limiting steps in CMC and cGMP for products demonstrating high clinical benefits while ensuring an adequate supply of safe and efficacious product at the time of approval (4). BREAKTHROUGH DEVELOPMENT PROGRAMS MAY PUT CMC/GMP ACTIVITIES ON CRITICAL PATH Timelines for completing CMC/GMP activities for a breakthrough product will be driven by the design of the clinical development program for the breakthrough product. Each development program will vary depending on the complexity of the product, how soon accelerated CMC development activities begin, availability of platform technology, relevant prior knowledge, and timing of designation. If the breakthrough designation is granted at an early development stage following promising preliminary clinical data, some of the phase III CMC-enabling activities may need to be accelerated. On the other hand, if a breakthrough designation is granted to a product in late stage development, the challenges for manufacturing readiness may be less burdensome but may also need to be addressed in a more compressed time frame. While drugs approved under the breakthrough pathway still need to meet statutory requirement for product quality, safety, and efficacy, balancing risk to product quality and availability for patients is critical. Therefore, deve (...truncated)