FDA Meetings aren’t what many people think they are, especially when it comes to CMC-focused discussions. Beliefs surrounding one’s CMC compliance strategy run the gamut from the pessimistic “What if the FDA wants much more to be done than is currently scheduled?” to the euphoric “Our manufacturing process for preparing and controlling clinical product for earlier phases is also considered good enough to go forward into later-stage clinical trials and even commercial manufacturing.”
Let’s look at seven common opinions about formal meetings between the FDA and Sponsors or Applicants of PDUFA Products regarding CMC compliance.
Unlike gambling, the house here is on the Sponsor’s side. Sponsors must understand that it is not about believing that it knows more about its process and product than the FDA; it involves the FDA as a partner.
Gambling operates differently. When the individual wins, the house loses. So, the house makes sure the odds are stacked in its favor. Whether the feedback is positive or negative, attending these meetings takes away the unknown. If the feedback is positive, that’s a good thing. If the feedback is negative, that’s also a good thing. The sponsor can now deal with the issue(s) that received negative feedback before the next submission or meeting.
Since the FDA ultimately controls the drug product’s fate, it can only be advantageous for a Sponsor to ensure that the reviewer openly understands the science behind the manufacturing process and product. For example, when the correct data is generated and presented, not only does the Sponsor and the FDA win, but ultimately so does the patient.
The first problem with this view is that there are no guarantees for most things in life. According to sound phase-appropriate rules, many people who develop their product will generate data they otherwise would not have had.
Meetings between the Sponsor and the FDA can help provide further assurance that no major CMC strategic surprises could significantly delay the marketing application’s review and approval.
The problem with this view is that it doesn’t address the CMC compliance strategy. Sponsors devote considerable expertise, expense, and time to understanding the science of how the drug product works in humans and how to administer the drug product. However, for approval, every product ultimately requires CMC compliance data to demonstrate the science of how the drug product can be manufactured consistently. A development strategy that only addresses clinical is only half a strategy. Half strategies seldom work for long.
This recalls musician Miles Davis’s famous comeback. Someone once complained to him that, “You can’t dance to your music.” To which, Davis replied, “No, you can’t dance to my music.”
Sponsors should be selective in how limited time, resources, and money are invested. Investments should be made wisely as understanding the science does not come cheap with the reality that only a small percentage of drugs make it into the marketplace.
The goal, however, is to increase the level of manufacturing process knowledge and understanding, not just to generate volumes of scientific data.
Some brilliant regulatory consultants make the argument for pure unpredictability (the “it depends” response, though they never apply it to their situations). If meetings were all about luck, no amount of experience, strategy management techniques, and guidance interpretation would improve an interaction. Yet virtually every experienced consultant can look back at mistakes made 15 years ago that they would not make today.
There is nothing to learn in a luck-based venture, such as a lottery; however, there is a learning curve with FDA Meetings. Any critical issue, e.g., starting material designation, qualification of impurities, approach to specifications, identification of any other CMC issues, including manufacturing site and process changes, will require time and resources to correct if the FDA believes the Sponsors’ CMC regulatory compliance strategy is not sufficient or practical for that matter.
The FDA does not expect a company to agree with them in every instance, but they expect thoughtful consideration and a scientifically justified engagement.
The Sponsor has one very important advantage these days. It has information that is much more widely available today than it was before the internet.
To quickly fix everything late in the game, though (make the process more robust and commercial) is frequently the result of discovering holes in the scientific understanding of the manufacturing and control of the process.
Some say, “If you have to ask, ‘Can we submit updates to the application after we submit the application?’, you are not ready!” Sponsors should let manufacturing and product knowledge, not business dates or marketing desires, drive the submission date.
This has its roots in the time-honored advice not to fight the trend. Generally, that’s good advice. The FDA can be temporarily blind (without data). A CMC perspective aims to provide enough information to permit the respective reviewer to determine whether the methods used in manufacturing the drug and the controls used to maintain its quality are appropriate and adequate. Education starts early.
Manufacturing process changes are inevitable in development and even desired in certain instances. To identify the impact of any manufacturing process change, a careful evaluation of all foreseeable consequences for the product should be performed.
In consideration of this evaluation, appropriate criteria can be established. They should be discussed up front, e.g., routine batch analyses, in-process control, process validation and/or evaluation data, characterization, and stability.
Dialogue with the FDA is helpful during the development of a drug product. After all, you will ultimately need the FDA to approve your product before commercialization. One of the mechanisms for applicants to request feedback from the FDA is the formal FDA Meeting process. In this process, a person or organization anticipating the need to make a future submission to the FDA (e.g., IND, NDA/BLA) can make a written request to obtain feedback before, or during, preparation of the submission.
Meetings help ensure no major CMC strategic surprises that could significantly delay the marketing application’s review and approval.
This Standard Operating Policy and Procedure (SOPP) serves as a guide for the Center for Biologics Evaluation and Research (CBER) staff for scheduling and conducting regulatory meetings between individuals in CBER and representatives of the regulated industry (including sponsors/applicants of user fee-related products) and/or individual sponsor-investigators to address issues relating to product development.