Lessons with James Mencel, Senior Drug Substance Consultant, DS InPharmatics
DS InPharmatics' Senior Drug Substance Consultant, James Mencel, provides us with insight on his background with CMC management and the impact that expedited drug development programs have had on the pharma industry. Learn how to break down regulations, breakthrough designations, and the best practices suitable when it comes to these programs.
Typically, it takes at least eight years for a new drug to complete the journey from initial discovery to the marketplace. Phase 3 trials alone can take five to seven years on average. The longer the process, the more the costs of drug development.
Lately, there has been a lot of expedited activity, especially in the smaller biopharma space. Despite the potential for helping life-threatening conditions, it presents some unique challenges for CMC on the verge between phase two and phase three programs. Fast-tracked CMC development programs are, by nature, different from standard programs.
The primary goal for FDA is, of course, bringing lifesaving products to patients. Where there is a good case for it, they throw their full weight behind expedited drug development. Industry's interest in this is both scientific and business. Apart from the breakthrough itself, accelerated strategies speed getting to proof-of-concept and first-in-human studies to inform decisions on developability and later development strategies that achieve faster approval and commercialization.
The benefits of accelerated CMC development must be weighed against the risks of incomplete product and process understanding. Any CMC development program's goal should be to ensure the consistent production of a safe and effective commercial product.
The pace of development does not compress or change the content of the new Drug Application (NDA/BLA) CMC Quality Modules. There may be flexibility on the type and extent of the CMC data expected at the time of NDA/BLA submission compared to what can be provided during NDA/BLA review or after approval. However, much of this depends on product knowledge, process knowledge, and robustness of control strategy, plus the risk of skimpy CMC data vs. patient benefits.
From the beginning, align CMC development with clinical development. Design the current process to be still viable and dependable if the program gets expedited and goes commercial. Build a process capable of supplying all the needed data for CMC submission.
Throughout the development, regular meetings can streamline paths for qualifying expression systems, establishing comparability among sites, and planning inspections. Improved communication at the BLA review cycle can accelerate resolving issues and gaining consensus on what should be submitted after approval.
There are many ways to speed up drug development, but almost all of them lead to squeezed timeframes for CMC. The FDA becomes aware that there is stress on CMC, but they won't budge on quality.
Instead, what they do is meet with sponsors much more frequently than usual to help them navigate expedited development for the suitability, quality, and efficiency of the drug substance and product.
So, the expedition gets regulatory support for development. The stress for CMC remains, though, and at the end of the day, the filing must occur, and the FDA must approve.
Expect a lot of negotiation. ICH establishes procedures for expedited development, testing, and marketing of new therapies intended to treat persons with life-threatening illnesses where no good alternative treatment exists. However, there is no bending on sound scientific approaches.
For instance, the FDA may allow a shortened amount of stability, but they'll require reliable data from previous development stages and the same chemical process on the same site.
Suppose you approach the FDA with a request to switch sites. In that case, the agency will hear your argument for the request to change from where you made your pivotal clinical trial or registration batches to where you will do your process validation.
You must have a strategy that shows consistency in material made on both sites. That is something that the FDA will greenlight mostly only in expedited development because they understand that you don't have a three or four-year window. In Phase Three, you have a one-year window to do as much as you would do in three years.
There is both business and scientific interest as explored. Let's say you have an anti-cancer agent program based upon a model that's been shown to be essentially validated. When you've got a receptor site and a validated model and a molecule that hits it, many sponsors approach the FDA for expedition before they even get to phase one. This mostly happens for discoveries around hard-to-treat ailments.
One other acceleration pathway can emerge in the course of clinical development. You start getting impressive data that shows the therapeutic potential of substances for illnesses that have no cure. The FDA would be open to hearing your case.
Even so, corporate entities involved in this should ascertain whether everything they have is ready because, at this stage, the information goes public. There will be an expectation for traction and success. If there isn't the necessary infrastructure for this progress, this won't be good for optics.
Pay attention to the chemistry at every point along the way. If there is talk of the expedition, get development people involved and perfect everything from chemical process to testing and data—your current process could be the commercial route.
Anticipate flaws in advance because things such as polymorph and the particle size cannot be changed after a certain point. Plan for everything to work as expected when you get to phase three trials.
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