Regulatory Focus™ > News Articles > FDA Revises Guidance on Special Protocol Assessments

FDA Revises Guidance on Special Protocol Assessments

Posted 04 May 2016 | By Zachary Brennan 

FDA Revises Guidance on Special Protocol Assessments

The draft guidance on the special protocol assessment (SPA) process is an update on guidance from 2002 and delves into the meetings between pharmaceutical or biotech sponsors and the US Food and Drug Administration (FDA) to discuss plans for clinical trials.

Under the hopes that the SPA process will improve the quality of clinical trials, FDA has made significant changes from 2002 guidance, including:

  • Clarification on which protocols are eligible for SPA;
  • The addition of animal rule efficacy protocols intended to support approval for drugs and biologics;
  • The addition of protocols intended to support approval of a biosimilar;
  • And more detail about the content of an SPA submission, as well as clarification on the process for rescinding an SPA agreement.


SPA provides for the evaluation of protocols for trials that have not been initiated, meaning the existence of an SPA agreement does not guarantee that FDA will accept a new drug application (NDA) or biologics license application (BLA), or that the trial results will be adequate to support approval.

The following protocols are eligible for an SPA request:

  • Animal carcinogenicity protocols.
  • Drug substance and drug product stability protocols
  • Animal efficacy protocols for studies intended to provide primary evidence of effectiveness required for approval or licensure for products developed under the animal rule (animal rule efficacy protocols).
  • Protocols for trials intended to form the primary basis of an efficacy claim, and protocols for clinical or animal trials of bioequivalence or bioavailability that will form the basis of an efficacy claim.
  • Any necessary trials to prove biosimilarity and/or interchangeability (e.g., protocols for comparative clinical trials that will demonstrate no clinically meaningful differences between the proposed biosimilar and the reference product, and protocols for clinical trials intended to support a demonstration of interchangeability).

Protocols are reviewed by FDA “for the adequacy and acceptability of critical elements of overall protocol design and analysis” and the SPA process allows time for FDA to respond to relevant questions posed by the sponsor.

The agency says it understands that the efficiency of its review of the SPA submission, the completeness of FDA’s answers to sponsor questions, and the quality of the future NDA or BLA may be improved by holding such a meeting before a submission.

 “For example, an SPA agreement for a protocol might communicate to the sponsor that FDA agrees with the proposed primary endpoint or the sample size estimate, but might not include a detailed review of the case report form; it might address the adequacy of and final timing of a radiographic procedure used to measure the primary endpoint, but might not comment on the use of three versus four interim radiographs,” FDA says.

FDA calls on sponsors to make every effort to identify unusual or potentially problematic aspects of the protocol and submit specific questions in their SPA request.


In addition to offering details on procedures for submitting a request, the content of that request and submission materials, the guidance delves into FDA’s assessment process, which involves determining if a submission is appropriate, how to revise the protocol prior to the meeting and the obligations FDA has in responding to sponsors.

The draft also includes information on the options a sponsor has if FDA does not agree to a meeting, how to initiate a trial without an SPA agreement and how to discuss any such disagreements.

Special Protocol Assessment Guidance for Industry


© 2021 Regulatory Affairs Professionals Society.

Regulatory Focus newsletters

All the biggest regulatory news and happenings.