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GOOD REGULATORY PRACTICES · 02

Good Regulatory Practices #2: Understanding How FDA Reviews Your IND

Understand FDA review priorities and communicate more effectively with your review division.

Dr. Leona Saunders, IRSG · 7 min read

Introduction

One of the most valuable things I learned during my regulatory career wasn't about regulations, it was about reviewers.

FDA reviewers are scientists and clinicians with demanding workloads, limited time, and clear priorities. When you understand how they approach your submission, you can structure your communications to align with their process rather than fighting against it.

Too many sponsors treat FDA as a black box. They submit documents and wait, hoping for the best. But the review process isn't random. The extent and type of clinical review and the nature of FDA's communication with you follows a predictable logic based on specific factors.

Understanding this logic doesn't just reduce anxiety. It helps you write better submissions, prepare more effectively for interactions, and build a more productive relationship with your review division.

What Determines the Depth of FDA Review?

Not all IND submissions receive the same level of scrutiny. FDA calibrates its review intensity based on several key factors:

1. Novelty of the Drug

High scrutiny: First-in-class compounds, novel mechanisms of action, new modalities (gene therapy, cell therapy, RNA-based therapeutics)

Lower scrutiny: Well-characterized molecule classes with established safety profiles, follow-on compounds in a crowded therapeutic space

Why it matters: If FDA has never seen anything like your drug, they have no historical context to draw from. They'll examine everything more carefully because they're establishing precedent, not just for you, but for future sponsors with similar products.

Your move: For novel products, anticipate more questions and longer review times. Be thorough in your rationale, cite relevant scientific literature, and don't assume reviewers share your assumptions about the science.

2. FDA's Familiarity with the Drug Class

High scrutiny: First or early entrant in a new therapeutic class

Lower scrutiny: Well-established drug classes with multiple approved products (e.g., ACE inhibitors, PD-1 inhibitors, GLP-1 agonists)

Why it matters: When FDA has reviewed dozens of similar products, they know what to expect. They've seen the common safety signals, they understand the typical development path, and they can review more efficiently.

Your move: If you're in a well-established class, reference the regulatory history. Show you understand the class-wide considerations. If you're early in a new class, expect to educate the reviewer and be prepared for more conservative requests.

3. Potential Safety Concerns

High scrutiny: Known class effects (e.g., cardiotoxicity, hepatotoxicity, immunogenicity), vulnerable populations (pediatrics, pregnant women), narrow therapeutic index, high-risk route of administration

Lower scrutiny: Established safety profiles, wide therapeutic margins, well-tolerated drug classes

Why it matters: Patient safety is FDA's primary mandate. Anything that raises safety flags will receive disproportionate attention. This isn't obstruction, it's the agency doing its job.

Your move: Address safety concerns proactively and comprehensively. Don't make reviewers dig for information. If there's a known class risk, explain your mitigation strategy upfront. Vague or incomplete safety sections invite clinical holds.

4. Stage of Development

High scrutiny: Original IND (first-in-human), Phase 3 protocols, pivotal trial designs

Lower scrutiny: Routine amendments, minor protocol modifications, annual reports

Why it matters: Original INDs and pivotal trials have the highest stakes. An error in your Phase 1 protocol could expose patients to unnecessary risk. A flawed Phase 3 design could waste years and render your data unapprovable.

Your move: Invest proportionally. Your original IND and pivotal trial protocols deserve senior review, regulatory strategy input, and possibly a Pre-IND or End-of-Phase 2 meeting. Routine amendments can be handled more efficiently.

5. Seriousness of the Disease

High scrutiny (but with flexibility): Life-threatening or severely debilitating conditions, diseases with no approved therapies, conditions with high unmet medical need

Lower scrutiny (but with rigor): Less serious conditions, well-served therapeutic areas

Why it matters: This is nuanced. Serious diseases don't mean less rigorous review, they mean FDA may be more flexible on certain requirements while maintaining high standards on others. Accelerated pathways exist for a reason, but they come with their own complexity.

Your move: If you're developing a drug for a serious condition, understand the available expedited pathways (Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review) and engage early with FDA about your strategy. Don't assume flexibility, request it with justification.

How FDA Prioritizes Within Limited Resources

Here's something sponsors often don't appreciate: FDA review divisions have finite staff reviewing a continuous flow of submissions. They can't give everything equal attention, so they prioritize.

The two main factors driving prioritization:

1. Relative Importance to Patient Safety

Submissions with immediate safety implications go to the top of the queue:

  • Clinical holds (stopping unsafe trials)
  • Serious adverse event reports
  • Safety-related protocol amendments
  • IND safety reports

Conversely, submissions with limited safety impact may wait longer:

  • Administrative amendments
  • Minor manufacturing changes
  • Information requests that don't affect ongoing trials

Your move: Don't treat every submission as urgent. If you flood the division with expedite requests for routine amendments, you burn goodwill and potentially delay the submissions that actually matter.

2. Context of the Sponsor's Development Plan

FDA reviewers aren't just evaluating individual submissions, they're tracking your overall development program. They prioritize based on where you are in development and what's at stake:

  • A Phase 3 protocol amendment blocking patient enrollment gets attention
  • An investigator brochure update with no immediate trial impact can wait
  • A pre-submission for an upcoming meeting needs timely review
  • Annual reports are reviewed as time permits

Your move: Provide context. If a submission is time-sensitive, explain why in your cover letter. "This protocol amendment is required before we can enroll patients at Site 23, and our enrollment timeline requires implementation by [date]." Reviewers are more likely to prioritize when they understand the practical impact.

Practical Implications for Sponsors

Understanding FDA's review logic should change how you approach submissions and communications:

Structure Submissions for Efficient Review

Reviewers are busy. Make their job easier:

  • Lead with the most important information
  • Use clear section headers and summaries
  • Highlight safety-relevant information prominently
  • Provide rationale, not just data
  • Cross-reference rather than repeat

A well-organized submission gets reviewed faster and more favorably than a disorganized one with the same content.

Calibrate Your Expectations

If you're filing an original IND for a first-in-class gene therapy, expect a thorough review with multiple questions. If you're filing a routine protocol amendment for a Phase 2 trial of a well-characterized small molecule, expect minimal feedback.

Misaligned expectations create frustration. Understanding what drives review intensity helps you plan timelines and allocate resources appropriately.

Communicate Strategically

Not every question requires a formal amendment. Not every concern requires a Type A meeting. Match your communication approach to the situation:

  • Minor clarifications: Email or phone call with the project manager
  • Scientific questions: Information request response
  • Significant changes: Formal amendment
  • Strategic decisions: Pre-scheduled meeting

Over-formalizing routine communications wastes everyone's time. Under-formalizing significant issues creates problems.

Build the Relationship

FDA reviewers aren't adversaries; they're scientific colleagues with a different mandate. The sponsors who navigate development most efficiently treat it as a collaboration:

  • Be responsive and professional
  • Follow through on commitments
  • Admit when you don't know something
  • Provide complete, honest information
  • Respect their time constraints

A good relationship with your review division is an asset that compounds over the life of your program.

When to Engage Regulatory Expertise

Consider bringing in experienced regulatory support when:

  • You're unfamiliar with your review division's expectations - Different divisions have different cultures and preferences
  • Your product has multiple factors driving high scrutiny - Novel, safety concerns, serious disease, first IND
  • You've received unexpected feedback - A clinical hold, refuse-to-file, or extensive information requests
  • You're preparing for a high-stakes FDA meeting - Pre-IND, End-of-Phase 2, Pre-BLA/NDA
  • You need to prioritize competing submissions - Multiple amendments, limited internal resources

An experienced regulatory consultant has seen how different divisions operate, what triggers scrutiny, and how to communicate effectively. That pattern recognition is hard to build if you're only developing one or two products.

The Bottom Line

FDA review isn't arbitrary. The depth of review, the nature of communication, and the timeline for feedback all follow a logic based on novelty, safety, development stage, and disease context.

When you understand that logic, you stop feeling like you're at the mercy of an unpredictable process. You can structure your submissions for efficient review, calibrate your expectations appropriately, communicate strategically, and build a productive relationship with your review division.

The sponsors who navigate FDA most effectively aren't the ones with the most aggressive approach. They're the ones who understand how the agency thinks and align their process accordingly.

About This Series

Good Regulatory Practices is an educational series designed to share practical regulatory knowledge that helps sponsors navigate drug development more effectively. Topics are drawn from real-world experience and address the strategic questions that make the difference between efficient development and costly delays.

Dr. Saunders is the Founder and CEO of Innovative Regulatory Science Group (IRSG), a regulatory consulting firm with over 25 years of FDA regulatory experience. She also serves as adjunct faculty at Northeastern University, teaching regulatory strategy for product development.

She is the Founder and CEO of tBrexa Bio, a woman- and minority-owned next-generation CDMO specializing in biologics, gene therapies, and AI-enabled manufacturing. Through tBrexa, she integrates regulatory intelligence, CMC strategy, and advanced bioprocessing to support innovators from IND planning to commercial readiness.

Educational planning content, not regulatory advice. Program-specific decisions require qualified quality, manufacturing and regulatory review.