Approach for A Successful FDA End of Phase II (EOP2) CMC Meeting
The following three rules of engagement are recommended to take place at an End of Phase II meeting, either face to face or by telephone. Each rule helps to ensure a successful negotiating strategy based on the actual discussions with the Agency. Note the fundamental position of the approach in every case:
1. Bring the discussion to the data presented on e.g., the process capability and robustness, acceptance criteria, effectiveness of the analytical capabilities etc.
By the end of Phase 2 clinical studies, a company has devoted considerable time, expertise and expense to understanding the science of how the drug product works in humans and how to clinically administer the drug product to maximize its medical benefit and minimize its medical risks. But have similar resources been expended to understand the science of how the drug product can be manufactured consistently to yield the desired quality?
Today, basing manufacturing decisions scientifically on enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters is fast becoming the norm. The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the process design, specifications, and manufacturing controls.
Good Drug Development is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based upon sound science and quality risk management. Sponsors are well advised to invest in process science and process characterization and really get to know the manufacturing process and its outcome.
2) Seek clear understanding of the FDA position
Want to avoid CMC regulatory compliance delays? Seek out regulatory authority advice. This sounds easy, but for some it also sounds threatening. What if the regulatory authority wants much more to be done than is currently scheduled? What impact would that have on the corporate-determined marketing submission date? Senior management must understand that it is not about a company believing that it knows more about its process and product than the regulatory authority; it is about involving the regulatory authority as a team player. Since the regulatory authority ultimately controls the drug product’s fate, it can only be an advantage for a company to ensure that the reviewer dearly understands the science behind the manufacturing process and product.
You need a reality check for your CMC regulatory compliance strategy at this transition from Phase 2 to Phase 3, and the regulatory authorities can provide it. Both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) see the value of CMC-focused End-of-Phase 2 (EOP2) meetings with companies; they consider these meetings a “critical interaction” and “particularly important” for expedited programs, respectively.
3) Seek agreement that the data package is adequate to support the approach while understanding that the FDA must review the actual NDA or BLA submission to come to a final determination
Deadlines are set and publicly announced, and then the pressure is on for the CMC team to meet the timeline for submission of the marketing application. Talk about pressure! All too often, there is a rush to submit, with the expected negative consequences.
The FDA product approval system permits the agency to issue a “refusal to file” letter declining to review a submission if there are major gaps in CMC information (such as the lack of full description of the manufacturing methods or uncorrected deficiencies that were dearly communicated to the applicant before submission of the application).
Even if a rushed submission passes this first gauntlet, it does not mean there will not be major trouble ahead. What was gained by rushing the submission filing, only to experience extensive delays in obtaining market approval?
A premature submission may meet a corporate target, but it can lead to significantly longer review times. One FDA CMC senior reviewer offered this advice on knowing whether your company is ready to file: “If you have to ask, ‘Can we submit the [fill in the blank] section of the application [fill in the length of time) after we submit the application?’, you are not ready!” A premature submission may meet a preset corporate target, but it can lead to longer review times in the end. The Sponsor’s goal should not be the application filing date but the market approval date.