How Phase 3 Trials Support Accelerated Approvals and Fast Track Designations

Understanding Expedited Regulatory Pathways

As drug development becomes more focused on serious, life-threatening, and rare diseases, regulatory agencies have established expedited approval pathways to make promising therapies available faster. Two such pathways are the Accelerated Approval Program and the Fast Track Designation, primarily managed by the FDA.

Though these pathways are often associated with early-phase trials, Phase 3 studies still play a critical role—either by confirming earlier findings, serving as the basis for accelerated approval, or fulfilling post-marketing commitments.

Key Definitions: Fast Track vs Accelerated Approval

• Fast Track Designation: A process to facilitate the development and expedite the review of drugs that treat serious conditions and address unmet medical needs. It allows for:
  • More frequent meetings and written communication with the FDA
  • Eligibility for Rolling Review
  • Accelerated Approval and Priority Review eligibility
• Accelerated Approval: Allows earlier approval of drugs based on a surrogate endpoint that is reasonably likely to predict clinical benefit. Requires confirmatory post-marketing trials (often Phase 3).

These programs are not mutually exclusive—a product may be designated Fast Track and receive Accelerated Approval simultaneously.

When Do Phase 3 Trials Fit into These Pathways?

There are three major scenarios where Phase 3 trials intersect with expedited programs:

• Scenario 1: A single Phase 3 trial serves as the basis for full approval
• Scenario 2: A Phase 2 trial is used for Accelerated Approval, with a Phase 3 trial as a confirmatory study
• Scenario 3: Phase 3 trials are part of a rolling review submission supported by Fast Track designation

In all these cases, robust Phase 3 planning, endpoint selection, and regulatory consultation are crucial.

Examples of Phase 3 Trials in Expedited Approvals

1. Osimertinib (Tagrisso) – NSCLC with EGFR T790M Mutation

Initial approval was granted under Accelerated Approval based on Phase 2 data, but the full approval came after results from the Phase 3 AURA3 trial, which showed superiority over chemotherapy.

2. Aducanumab (Aduhelm) – Alzheimer’s Disease

Controversially approved via Accelerated Approval using a surrogate biomarker (amyloid-beta reduction). Post-marketing Phase 3 trials were required to confirm clinical benefit.

3. Bedaquiline (Sirturo) – Multi-Drug Resistant Tuberculosis

Approved via Accelerated Approval with Phase 3 confirmatory requirements due to life-threatening nature and lack of alternatives.

Design Considerations for Phase 3 Trials in Expedited Pathways

When planning Phase 3 trials for drugs under Fast Track or Accelerated Approval, sponsors must account for several design-specific factors:

• Surrogate Endpoints: If using a surrogate marker (e.g., viral load, biomarker reduction), it must be justified with historical or scientific evidence
• Adaptive Designs: Interim analyses, early stopping rules, or seamless Phase 2/3 trials may be approved under regulatory flexibility
• Small Sample Sizes: In rare diseases, Phase 3 trials may enroll fewer patients, relying on real-world data to supplement
• Accelerated Timelines: Phase 3 trials may be conducted concurrently with regulatory submission activities

Regulatory Expectations for Phase 3 in Accelerated Approval

• FDA: Requires post-marketing confirmatory trials (usually Phase 3) to verify clinical benefit. If the confirmatory study fails, the product can be withdrawn.
• EMA: Offers Conditional Marketing Authorization (CMA), which may use Phase 3 trials for confirmatory evidence in a defined timeframe
• CDSCO: Under NDCTR 2019, India allows expedited review if Phase 3 data is available from other regions but requires local bridging trials

Agencies often require pre-submission meetings to finalize trial design and confirm whether the selected endpoints and statistical analysis plans are acceptable.

Communication Benefits from Fast Track Designation

Fast Track designation doesn’t just expedite timelines—it also facilitates closer communication. Sponsors can engage with the FDA early and often, reducing the likelihood of submission failure. For Phase 3 trials, this means:

• Faster protocol feedback and alignment on endpoints
• Preemptive discussion on biomarker qualification
• Advance planning for integrated summaries and label text

Such collaboration leads to higher submission quality and fewer review delays.

Case Study: Ebola Vaccine (rVSV-ZEBOV)

Approved under accelerated pathways based on a single Phase 3 ring-vaccination trial conducted in Guinea. Key lessons included:

• Strong international collaboration (WHO, FDA, EMA)
• Trial conducted during outbreak—adaptive design permitted
• Accelerated filing followed by CMA in EU and Breakthrough Designation in U.S.

This example demonstrates how Phase 3 can be both pivotal and confirmatory in life-threatening, time-sensitive conditions.

Post-Approval Commitments and Phase 4 Planning

When Accelerated Approval is granted based on surrogate endpoints, confirmatory Phase 3 (or real-world Phase 4) studies become mandatory. Sponsors should:

• Define post-marketing study timelines in advance
• Align global trial sites with regulatory expectations
• Plan for withdrawal mechanisms in case confirmatory studies fail

Agencies like the FDA are now more active in enforcing timelines for confirmatory trials, especially following criticism of the Aducanumab approval.

Best Practices for Phase 3 Trials in Accelerated Pathways

• Engage early: Use pre-IND and Type B meetings to clarify trial expectations
• Justify surrogate endpoints: Provide data, literature, or precedent to support use
• Document clearly: Ensure CSR, SAP, and datasets trace all clinical benefit claims
• Integrate medical affairs: Begin communication planning with patients and providers early

Final Thoughts

Phase 3 trials remain essential even in the era of expedited approvals. Whether as the basis for approval or as post-approval confirmation, they validate that a drug truly benefits patients in the real world. Understanding their role in Fast Track and Accelerated Approval pathways is key for designing efficient, successful programs that balance speed with scientific rigor.

At ClinicalStudies.in, learning how to align Phase 3 strategies with regulatory pathways equips you for impactful roles in clinical development, regulatory affairs, and strategic trial planning.