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Former FDA Reviewers Provide Answers to Key Questions: Part 2

Nuventra’s Gene Williams, Ph.D., has 25 years of experience in clinical pharmacology, 20 of which occurred at the FDA, first as a FDA Primary Reviewer and subsequently as a FDA Team Leader. In Part 1 of this blog series, Gene provided insider tips about communicating with the FDA and some keys to creating a reviewer-friendly submission. Here in Part 2, Gene is back to address more common questions regarding regulatory interactions and strategy.

Q1: Do I have to follow the guidance?

This is a very common question from our clients. Some people are under the impression that guidances must be followed to the letter, while others see guidances more as suggestions or best practices. In truth, guidance documents exist to guide drug developers and other stakeholders along an acceptable path, but they are not legally binding like statutes. They also do not necessarily outline the only path to success. This can ring especially true for innovative medical products, rare diseases, and other cases where some unique aspect makes conforming to guidance recommendations difficult or suboptimal.

While we do not advocate dismissing guidance recommendations, there are times when straying somewhat from established guidances can make sense. In these instances, it is important to communicate all relevant information to the FDA reviewers in briefing documents explaining why your suggested approach is a reasonable one to ensure the acceptability of your approach. To this point, consider that all guidances documents include the following (or very similar) text:

“This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes and regulations…”

“FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.”

These statements are not mere legalities. Rather, they reflect the Agency’s actual approach. While guidances are not trivial, the Agency appreciates that there may be nuances to a drug development program that make an approach that deviates from guidances the most prudent one. Remember, an approval decision by the FDA is based upon an overall benefit-risk assessment rather than being an exercise in applying guidance recommendations.

Q2: How do I time clinical pharmacology studies within my drug development program?

During drug development, the most important purpose of pharmacokinetics (PK) and pharmacodynamics (PD) data is to inform dose regimen selection, whether it is during Phase 1, 2, or 3. In programs where there is a well understood relationship between plasma concentrations, target occupancy, and clinical outcomes, clinical pharmacology data may be valuable for GO/NO GO decision making and is critical to study design. For these programs, PK data should be collected as early and comprehensively as possible. In other programs where dose regimen selection is more empirical, full or sparse PK sampling should still be performed during Phase 1 and throughout development, where possible, to describe any exposure-response relationships for safety, and if possible, for efficacy. However, when dose regimen selection is more empirical, acquisition of PK/PD data is a secondary endpoint resulting in greater flexibility regarding study design.

For some indications (i.e., disease states) and compounds, patients often receive co-medications with high drug interaction potential. Similarly, impairment of an organ of elimination (i.e., kidney or liver) may be related to the disease process of interest or an important co-morbidity. In such cases, a quantitative understanding of the drug interaction potential of the new drug, or of the effect(s) of organ impairment(s) on the drug, may be needed relatively early in development to allow for appropriate dose adjustments for extrinsic and intrinsic patient factors during efficacy and safety studies. In other cases, Sponsors may decide to restrict trial enrollment in efficacy and safety studies and to postpone determining quantitative pharmacokinetic differences until proof of concept has been established.

Q3: What is the FDA’s Model Informed Drug Development program and how do I apply?

Model-Informed Drug Development (MIDD) is a key tool that utilizes mathematical models and simulations to ensure the most appropriate dosage regimen and study design, to predict the likelihood of success for the drug, to extrapolate to new indications including pediatrics, and to optimize benefit-risk in the indicated population and specific sub-populations (e.g. drug interactions, hepatic impairment).

The FDA’s MIDD program is an initiative with the goal of accelerating drug development by modeling existing pharmacokinetic, biological, and other related metrics. Although any idea is welcome, the preferred topics outlined by the FDA are dose selection or estimation, clinical trial simulation, and predictive or mechanistic safety evaluation. While the program can be utilized with standard milestone meetings (e.g., Pre-IND, End-of-Phase, and Pre-NDA/BLA), one advantage of participating in this program is that it can grant a Sponsor the opportunity to speak with the FDA outside of a standard milestone meeting.

Applying to the program is straightforward and the FDA has outlined specific instructions for how to request a meeting. Per the FDA MIDD website:

Meeting requests should be submitted electronically to the relevant application (i.e., PIND, IND) with “MIDD Pilot Program Meeting Request for CDER” (CDER applications) or “MIDD Pilot Program Meeting Request for CBER” (CBER applications) in the subject line. Information about providing regulatory submissions in electronic format is available at: Electronic Common Technical Document (eCTD) or on our blog post: eCTD Regulatory Submissions: Hints & Common Mistakes to Avoid

In addition, please send an email to MIDD@FDA.HHS.GOV providing notification that your meeting request has been submitted to the relevant application. Refer to the FDA website for further information regarding the content and format of the MIDD package.

Q4: How do I contact the FDA outside of an Investigational New Drug (IND) milestone meeting?

The primary contact for application-specific, technical, and scientific questions is the regulatory project manager (RPM) assigned to the IND. The RPM will direct questions to the appropriate review division member(s). The FDA strongly discourages Sponsors from directly contacting an FDA reviewer, although direct contact may occur on a case-by-case basis after approval by FDA management.

The Enhanced Communication Team (ECT) serves as a second point of contact with the FDA. The ECT can answer general questions about the drug development process and provide clarification on which review division to contact for submission of the IND. The ECT also provides a secondary point of communication for Sponsors who are unable to contact the review division or who seek management of disagreements when communicating with review teams. Below is the email address for the ECT as well as other groups that may be contacted based on their specific expertise.

For further information, the FDA has a guidance entitled, “Best Practices for Communication Between IND Sponsors and FDA During Drug Development,” that describes best practices and procedures for communications between IND Sponsors and the FDA. We have also summarized key considerations for communicating with the FDA in a separate blog post.


Every drug development program is unique, and for certain products the most appropriate path may be the one less traveled. Understanding how to balance FDA’s guidance recommendations with the realities of your own program is an important first step. Clear and concise communication with the FDA is essential for reaching agreement for efficient clinical development. Finally, knowing where opportunities lie and where to turn for advice can go a long way toward achieving success.

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Communicating with FDA Toolkit

Clear communication with the FDA can greatly increase the chances of getting your drug approved. In this toolkit, you will find essential resources to improve your communication with the FDA. You will also benefit from first-hand experience and advice from Nuventra consultants, Gene Williams and Iftekhar Mahmood, who both spent over 20 years as clinical pharmacology reviewers at the FDA. Follow the link below to have our toolkit emailed directly to you.

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