With over twenty years in pre- and post-approval regulatory affairs CMC in large and small molecules products, Marilyn Julien comes to Bracken with a strong background in drug lifecycle management, comparability assessments, and FDA/EMA planning and advising meetings. With a BA in chemistry from Rutgers University, Marilyn worked as a research and analytical chemist before moving into regulatory affairs, most recently serving as the Director for Global Regulatory Affairs CMC - Biologics Early Development at BeiGene.
Regulatory Affairs Chemistry, Manufacturing, and Controls (Reg CMC)—long name, huge role in drug development, approval, and life-cycle management. But unless you live in the Reg CMC world full-time, you may not have a clear picture of the critical role Reg CMC plays in pharma. To find out, we sat down with Bracken Senior Partner and Global Regulatory CMC Consultant Marilyn Julien to get the skinny on Reg CMC and the benefits of working with a stellar consultant. In this post, we’ve distilled Marilyn’s knowledge into a pint-size roundup of 5 regulatory takeaways sure to make your Reg CMC process that much smoother.
First, a quick rundown of Reg CMC from Marilyn Julien:
Reg CMC is an integral part of drug advancement. We work with the development, process, analytical, and QA units to ensure regulatory documents are adequate to gain approval. Reg CMC is also a critical part of the change review procedure. We see the long-term effects of certain changes and review the experimentation proposed. It’s our job to understand the regulatory landscape and sometimes inform the project lead on which functional areas should be involved in the discussion. Really, we consider ourselves the “heart” of the pharmaceutical industry.
1. Timing is key. The type of FDA1 submission will determine the amount of time to wait before proceeding. If it's an initial investigational new drug (IND) submission, we must wait 30 calendar days after official FDA receipt, prior to initiation of the clinical trial. If it's an IND amendment, it depends—if the sponsor has done their due diligence and is sure about the change being implemented, they can release the investigational drug to the clinic as soon as they get the official receipt from FDA. For biologics, we usually recommend waiting about 60 - 90 days to implement a complex change or 30 days for a simple change. Since there’s no PDUFA date (review period end date) for investigational drugs, this gives the agency time to actually look at the submission before we release the material impacted by the change to the clinic for patient dosing.
2. Form strong FDA partnerships. While it’s not a requirement, we want the reassurance of FDA clearance, especially for a major change to an investigational biologic drug. So, for a complex change, at about the 45-day mark, we’ll contact the FDA regulatory project manager and ask for an update. We would usually ask, “Do the reviewers have any questions on the amendment?” and/or, “In order to keep to our project development timelines, we were planning to distribute the affected drug on MM-DD- YYYY, could the reviewers please provide any comments by MM-DD-YYYY?” The FDA regulatory project manager is usually very understanding, and they will contact the FDA reviewers to give us an answer, usually before the implementation date. If you build a good relationship with your FDA regulatory project manager, it's okay to make those calls, but don’t nag them—nobody likes that.
3. Communicate. Sometimes in the post-approval world, the technical folks make changes to processes, packaging/labeling sites, or analytical methods without informing Reg CMC. Then they get annoyed when they are handed an FDA 483 (a notice of inspectional observations) or Warning Letter. Reg CMC is the owner of the quality (M3) information that FDA reviews, so if we don’t have the current information, how do we answer questions during FDA inspections?
All proposed changes must go through the change management system to ensure that the correct regulatory disposition is made and the change is appropriately submitted to FDA. In the investigational world, a similar situation exists. When process/analytical changes are made, they must be assessed by Reg CMC and tracked. FDA not being aware of changes made to the process/product/control could jeopardize the clinical data collected using the affected material.
4. Stay current. A Reg CMC professional must remain current on new and changing
regulations. With over 20 years in the pharmaceutical world, when I am asked a question, I usually start by recalling from my personal experiences, then I check the global guidances to determine if there have been any changes. From there, I cite the regulatory reason for my counsel.
5. Do the work. If you're a good scientist, you know the data that you need to include in a report and how to formulate a conclusion based on that data. Likewise, if you're a good Reg CMC professional, you know what FDA will usually request. So if you include that in your regulatory documentation, there's no reason for the FDA to put you on clinical hold or delay an approval.
A Reg CMC professional knows what is required—as Nike reminds us, “Just do it!” Nobody wants to get CMC questions in a phase 1 IND. That usually means that you didn’t do what you were supposed to do. Of course, sometimes an FDA Study May Proceed letter will include a “phase inappropriate” request. A Reg CMC consultant will help formulate an appropriate response to such questions.
Lastly, Marilyn’s advice on working with a Reg CMC consultant:
Drug developers should not be penny wise and dollar foolish; they have to do it right the first time. The prime reason is the patients. We do not work for the healthy; we work for the sick and dying. The former head of Global Technical Operations at Celgene Corp once told me, “None of us matter. The only people who matter are the patients. We do what we have to do to get the drugs to the patients.” This is gospel! If Reg CMC is not consulted and a clinical hold or other negative regulatory outcome is garnered, yes, shareholders will be affected, but this is nothing compared to the disappointment of a patient who cannot get a much-needed, potentially lifesaving drug. So do it right—get the needed regulatory help, avoid the health authority questions, and aim for success.
Contact us today to learn more about working with Marilyn and Bracken’s team of expert consultants.
1 Although “FDA” is used throughout, all regulatory health authorities are included in these statements, as appropriate. Ex-US health authorities have their own review/approval timelines that differ from FDA and should be considered individually.
