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Former FDA Reviewers Provide Answers to Key Questions

Nuventra’s consultants Gene Williams and Brian Furmanski spent a combined 23 years working for the FDA. In this new blog series, they will offer answers to key questions regarding regulatory interactions and strategy.

Q1: What are some questions to avoid when interacting with the FDA?

Avoid questions for which guidance exists and there are insufficient data to address the criteria the guidance specifies.  Unless such questions are a necessity, they should be delayed if the requisite data will be acquired during future development.

In early development, avoid requests for agreement on restrictive labeling and postmarketing requirements/commitments (PMRs/PMCs) to allow postponement of data acquisition until post-marketing.  Such questions are generally not answerable until the efficacy and safety profile, and metabolism and excretion in humans, are well understood.

Further, with the notable exception of accelerated approval, PMRs/PMCs are not intended to substitute for acquiring data during initial development. The intent of PMRs/PMCs is to address issues which are discovered during the review cycle which, while requiring data acquisition, do not preclude approval.

Q2: Can you provide tips for communicating with the Agency?

Send meeting minutes to the Agency as quickly as possible – there is potential that the FDA Project Manager will use these minutes as a source for writing the official FDA minutes.

The FDA has guidelines for best practices when communicating with the Agency. Requesting a clinical pharmacology specific meeting is an efficient and productive away to communicate your clinical pharmacology concerns to the Agency.

Q3: Are there clinical pharmacology studies that are often performed unnecessarily?

Bioavailability/bioequivalence studies of formulations that were unimportant in clinical development are often over-studied.  Unimportance is defined as, “the study will not contribute to the package insert.”  At times such studies may be desired for internal decision making by the sponsor, but often they are not a regulatory necessity.

QTc assessment for monoclonal antibodies can be over-emphasized. Large targeted proteins and monoclonal antibodies have a low likelihood of direct ion channel interactions and a thorough QT/QTc study is not necessary, unless the potential for proarrhythmic risk is suggested by mechanistic considerations or data from clinical or nonclinical studies. However, currently, peptides, oligonucleotides, and antibody-drug conjugates most often still require a thorough QT/QTc study.

Q4: What makes a submission frustrating or difficult for a reviewer?

It’s a hindrance when a submission requires excessive referencing to submissions outside the document being reviewed, especially when referencing is across multiple submissions or INDs. This makes the reviewer devote time to finding things rather than reviewing. This can be avoided by summarizing information within the document and providing a link/reference that is available if needed, but not essential for near-complete understanding.

Large and open-ended submissions that are tantamount to a fishing expedition for the FDA review team cause frustration.  The data dump strategy is ineffective in the age of electronic submissions:  a reviewer will use CTRL-F to quickly learn that relevant information is missing.

Having a clear and concise submission is critical for your message to the Agency. A sponsor is granted only a few meetings with the FDA per application and those meetings should not be wasted on clarifying misunderstandings that arose because a reviewer had to integrate information.  A sponsor is solely responsible for demonstrating that an investigational agent is safe and effective to the Agency. In other words, don’t organize the submission such that a reviewer must synthesize to make the case.

Chat with the Experts

Do you have additional questions for Gene or Brian? Let’s chat – contact us to schedule a complimentary 30-minute consultation.