In the era of Breakthrough Therapy and Fast Track drug designations, chemistry, manufacturing and controls (CMC) submissions can cause delays to bring a drug to market, said Drew Barlow, vice president, regulatory affairs at Syner-G Pharma Consulting.
Companies need to provide enough information to satisfy the regulatory requirements while recognizing that providing too much information early will result in the need to make changes later, Barlow said, speaking on a panel focused on different approaches to preparing required CMC data to the FDA during the early clinical phase of drug development at the Drug, Chemical & Associated Technologies Association’s DCAT Week ’19, in New York.
The initial Investigational New Drug submission must be focused on safety and contain information such as drug dose form, investigation population parameters and dosage quantities, Barlow noted. Phase 1 reports are still mainly safety-focused, with inclusions of methods of manufacture, toxicology studies and impurity profiles.
As drug trials progress beyond Phase 1, the agency expects reports to contain preliminary efficacy data, and as manufacture is scaled up companies need to report if new stability or impurity issues occur, Barlow said.
Abizer Harianawala, senior director, product development and technical operations at TARIS Biomedical, shared insights during the session from his experience in developing compounds with designated Breakthrough Therapy status. Harianawala reminded listeners that a shorter clinical timeline means less CMC time, creating the need to prioritize tasks and focus on important trial aspects such as risk assessment.
By locking down active pharmaceutical ingredient (API) production, formulation and packaging methods early, companies can address these methods in early CMC versions without needing to revise later, he said.
“By locking down API production, formulation and packaging methods early, companies can address these methods in early CMC versions without needing to revise later”
Using cGMP qualified ingredients from the earliest clinical trial phases and qualifying secondary contract manufacturing organizations (CMOs) before clinical trials begin are additional ways to prevent unwanted delays, Harianawala said. To avoid delays, stability studies need to be locked down early, he added while other sections such as specifications can be tightened later on.
Ken Shultis, managing partner at Rondaxe, addressed the different styles of CMC submissions used within the pharmaceutical industry, and discussed which styles were most appropriate for which situations. Researchers using a “minimal style” of CMC preparation include very little information when summarizing early trial phases, he said. The advantage of this methodology is that early-phase write-ups move quickly, and there is less need to resubmit information that has changed as the trial has progressed. One of the big disadvantages to this method is that there is still a lot of work left to do close to the submission deadline, he added.
Shultis described the “NDA-ready” style where a company assembles everything as each trial phase is performed as though the FDA will be receiving those summaries as a finished product. This method allows the team to use the CMC as a project management tool, and spreads regulatory work out evenly across all trial phases. The disadvantage is that any major changes in the project will result in wasted effort as early CMC work needs to be redone.
Finally, Shultis described a “transition-style” CMC submission, where the document begins as a “bare-bones” outline which is fleshed out as the trials progress. This method provides reviewers with a good baseline, he noted, but still requires a great effort immediately preceding the submission deadline.
This article is an excerpt from the full DCAT Week ’19 conference report developed by the team from Newport Premium, a Cortellis solution, from Clarivate Analytics. Additional topics, reported on by analysts Shannon Bennett, Molly Bowman and Emily Kimball, include:
- Pharma industry outlook – A look at the forces of disruption driving change.
- The future of pharma/biopharma manufacturing and supply – “The future is now,” the panelists observed, citing patient centricity, niche technologies, product mix and partnerships that spur innovation.
- Sourcing and procurement: The next generation – Complex products create complex supply chains, speakers emphasized.
- How investors and other parties impact drug-development decisions – This session looked in investor influence on clinical trials, CMC issues and manufacturing capacity.
The full DCAT ’19 report is available here.
For more information on generics and APIs from all angles, see Newport Premium.
See Cortellis CMC Intelligence, also, a resource for granular data on CMC requirements in countries around the world.