Special Protocol 
Assessment 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2018 
Procedural 
 
Revision 1 
 
OMB Control Number 0910-0014 
Current expiration date available at https://www.reginfo.gov 
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See additional PRA statement in section XI of this guidance. 
   
Special Protocol 
Assessment 
Guidance for Industry 
 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
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Food and Drug Administration 
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Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
April 2018 
Procedural 
 
Revision 1 
 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  ELIGIBLE PROTOCOLS AND GENERAL INFORMATION .................................. 2 
A.  Eligible Protocols ........................................................................................................................... 2 
B.  General Information ...................................................................................................................... 3 
1. Meeting With FDA Before Submission of a Request ........................................................................ 3 
2. Reaching SPA Agreement With FDA ............................................................................................... 4 
IV.  PROCEDURES FOR SUBMISSION OF A REQUEST ............................................... 5 
A.  Notice of Intent ............................................................................................................................... 6 
B.  Timing of a Request ....................................................................................................................... 6 
C.  Format of a Request ....................................................................................................................... 6 
D.  Where to Send a Request .............................................................................................................. 6 
V.  CONTENT OF A REQUEST AND SUBMISSION MATERIALS ............................. 7 
A.  Animal Carcinogenicity Protocols ................................................................................................ 7 
B.  Drug Substance and Drug Product Stability Protocols .............................................................. 7 
C.  Animal Rule Efficacy Protocols .................................................................................................... 7 
D.  Clinical Trial Protocols .................................................................................................................. 8 
VI.  FDA ASSESSMENT PROCESS ................................................................................... 10 
A.  Determining Whether a Submission Is Appropriate for an SPA ............................................ 10 
B.  Assessment of the SPA Submission ............................................................................................ 12 
C.  Revisions During FDA Assessment ............................................................................................ 13 
D.  FDA Response to Sponsor ........................................................................................................... 13 
VII.  SPONSOR OPTIONS AFTER RECEIPT OF SPECIAL PROTOCOL 
ASSESSMENT  NO AGREEMENT LETTER ........................................................ 13 
VIII.  DOCUMENTATION ...................................................................................................... 14 
IX.  CHANGES IN OR RESCISSION OF SPECIAL PROTOCOL ASSESSMENT 
AGREEMENTS .............................................................................................................. 15 
A.  FDA and Sponsor Agreement on Changes in an SPA Agreement .......................................... 15 
B.  FDA Rescinding of an SPA Agreement ...................................................................................... 15 
X.  DISPUTE RESOLUTION ............................................................................................. 18 
XI.  PAPERWORK REDUCTION ACT OF 1995 .............................................................. 18 
GLOSSARY................................................................................................................................. 20 
REFERENCES ............................................................................................................................ 21 
i 
   
APPENDIX:  LEGAL BACKGROUND .................................................................................. 23 
 
ii 
  Contains Nonbinding Recommendations 
Special Protocol Assessment 
Guidance for Industry1 
 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance provides information on the procedures and general policies adopted by the Center 
for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and 
Research (CBER) for special protocol assessment (SPA). 
 
SPA is a process in which sponsors2 may ask to meet with FDA to reach agreement on the design 
and size of certain clinical trials, clinical studies, or animal studies3 (i.e., a Request for SPA 
(hereafter Request); see section III., Eligible Protocols and General Information) to determine if 
they adequately address scientific and regulatory requirements for a study that could support 
marketing approval.   
 
An SPA agreement indicates concurrence by FDA with the adequacy and acceptability of 
specific critical elements of overall protocol design (e.g., entry criteria, dose selection, endpoints, 
and planned analyses) for a study intended to support a future marketing application.  These 
elements are critical to ensuring that the trial conducted under the protocol can be considered an 
adequate and well-controlled study that can support marketing approval.4  Feedback on these 
issues provides the greatest benefit to sponsors in planning late-phase development strategy.  
However, an SPA agreement does not indicate FDA concurrence on every protocol detail, as 
described further in section III.B.2, Reaching SPA Agreement With FDA.   
 
 
1 This guidance has been prepared by the SPA Working Group in the Center for Drug Evaluation and Research in 
cooperation with the Center for Biologics Evaluation and Research at the Food and Drug Administration. 
2 For the purposes of this guidance, the term sponsor includes any sponsor or applicant interested in SPA. 
3 For the purposes of this guidance, the term trial includes clinical trials, clinical studies, or animal studies or trials 
discussed in the context of SPA. 
4 For the purposes of this guidance, the term approval refers to both approval of new drug applications and licensure 
of biologics license applications. 
  1  Contains Nonbinding Recommendations 
The existence of an SPA agreement does not guarantee that FDA will file (accept) a new drug 
application (NDA) or biologics license application (BLA),5 or that the trial results will be 
adequate to support approval.  Those issues are addressed during the review of a submitted 
application and are determined based on the adequacy of the overall submission.  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys 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.  
 
 
II.  BACKGROUND  
 
A summary of the statutory framework is provided in the Appendix. 
 
 
III.  ELIGIBLE PROTOCOLS AND GENERAL INFORMATION 
 
A.  Eligible Protocols 
 
Under section 505(b)(5)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the 
Prescription Drug User Fee Act (PDUFA) goals, and the Biosimilar User Fee Act (BsUFA) 
goals, the following protocols are eligible for a 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). 
 
 
5 See the draft guidance for industry Refuse to File:  NDA and BLA Submissions to CDER.  When final, this 
guidance will represent the FDAs current thinking on this topic.  For the most recent version of a guidance, check 
the FDA Drugs guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  See also MAPP 
6025.4 Good Review Practice:  Refuse to File (available at 
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProc
edures/default.htm) and SOPP 8404 Refusal to File Procedures for Biologics License Applications, New Drug 
Applications and Efficacy Supplements (available at 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/defau
lt.htm).  
  2  Contains Nonbinding Recommendations 
  Protocols for trials intended to form the primary basis of an efficacy claim.6  Protocols 
that meet this criterion can be submitted for an SPA, regardless of the product 
development phase (e.g., for products developed under accelerated approval (i.e., 21 CFR 
314.500, subpart H (for drugs), or 21 CFR 601.40, subpart E (for biological products)), 
such protocols might be phase 2 rather than phase 3).  In addition, protocols for clinical 
or animal trials of bioequivalence or bioavailability that will form the basis of an efficacy 
claim are considered to meet this criterion and are eligible for an SPA.   
 
  Protocols for any necessary clinical study or studies to prove biosimilarity and/or 
interchangeability (e.g., protocols for pharmacokinetic and pharmacodynamic studies, 
protocols for comparative clinical studies that will form the primary basis for 
demonstrating that there are no clinically meaningful differences between the proposed 
biosimilar biological product and the reference product, and protocols for clinical studies 
intended to support a demonstration of interchangeability).7  
 
B.  General Information 
 
1.  Meeting With FDA Before Submission of a Request 
 
The PDUFA and BsUFA goals letters state that protocols will qualify for the SPA program only 
if the sponsor has had an end-of-phase 2/pre-phase 3 meeting or end-of-phase 1 meeting, as 
appropriate,8,9 or biosimilar biological product development (BPD) Type 2 or Type 3 meeting, 
respectively.10  Therefore, before submitting a Request, the sponsor should meet with FDA to 
discuss the proposed trial and its regulatory context and to identify the particular questions of 
interest regarding the protocol.  If the proposed trial that will be the subject of a Request was not 
 
6 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological 
Products.  (We update guidances periodically.  To make sure you have the most recent version of a guidance, check 
the FDA Drugs guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.)  For the purposes 
of this guidance, the term efficacy claim is defined by its use in the PDUFA goals letter; see note 8, supra.  
7 FDA has published several guidances related to biosimilarity and interchangeability.  See the Biosimilars guidance 
web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm.  
In addition, see section 744G(3) and (4) of the FD&C Act and section 351(i) of the Public Health Service Act for the 
statutory definition of biosimilar biological product, biosimilar biological product application, and definitions of 
selected terms used in this guidance.   
8 FDA first agreed to specific PDUFA goals for SPA in November 1997 in conjunction with PDUFA II, the 
reauthorization of PDUFA.  The PDUFA II goals are described in PDUFA Reauthorization Performance Goals and 
Procedures, an enclosure to a letter dated November 12, 1997, from the Secretary of Health and Human Services, 
Donna E. Shalala, to Senator James M. Jeffords 
(https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm143135.htm).  The program has been 
reauthorized every 5 years; the most recent goals letter is available on the FDA website at 
https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm149212.htm. 
9 See the BsUFA goals letter titled Biosimilar Biological Product Reauthorization Performance Goals and 
Procedures Fiscal Years 2018 Through 2022 available on the FDA website at 
https://www.fda.gov/downloads/forindustry/userfees/biosimilaruserfeeactbsufa/ucm521121.pdf.  The program is 
considered for reauthorization every 5 years; updated goals letters are posted on the FDA website at 
https://www.fda.gov/forindustry/userfees/biosimilaruserfeeactbsufa/default.htm. 
10 See the guidance for industry Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or 
Applicants.   
  3  Contains Nonbinding Recommendations 
previously discussed at a drug development meeting, a separate meeting may be appropriate to 
ensure understanding of the regulatory context (see section IV., Procedures for Submission of a 
Request, when an SPA meeting is requested, but an investigational new drug application (IND) 
has not been filed).  FDA strongly encourages sponsors to request such meetings to discuss such 
trials and the Request.  As provided in section 505(b)(5) of the FD&C Act, if a sponsor makes a 
reasonable written request for such a meeting, FDA will grant the meeting request.  In some 
cases (e.g., protocols to support submission of an efficacy supplement or a carcinogenicity 
study), FDA may already be familiar with the regulatory context, or it can be adequately 
described in the Request and supporting materials.  In such cases, some sponsors have decided 
not to submit a meeting request and FDA has accepted the Request for SPA without having had a 
prior meeting.   
 
Sufficient information should be provided in the meeting request to ensure that all relevant 
disciplines and offices that should participate are identified, to permit detailed discussion of the 
relevant issues, and to facilitate subsequent FDA review of an SPA submission.  These detailed 
discussions are especially important if the development plan will include trial elements with 
which there is little past experience (e.g., novel eligibility criteria or efficacy endpoints) or has 
complex design or analytic features (e.g., noninferiority, bioequivalence, adaptive designs, 
multiplicity considerations).  These discussions are also critically important for reaching 
consensus on the use of an appropriate animal model to support approval under the animal rule.11  
Discussions with FDA regarding the development of an appropriate animal model under the 
animal rule should begin early in the product development process so that the meeting before 
submission of a Request focuses on final consensus on the animal model, not an introduction of 
this topic (see section V.C., Animal Rule Efficacy Protocols). 
 
The need for consultation during an SPA review (e.g., by special government employees or by a 
different FDA office or center), described in section VI.B., Assessment of the SPA Submission, 
also should be considered and discussed at the meeting. 
 
2.  Reaching SPA Agreement With FDA 
 
As noted, FDA will review the protocol for the adequacy and acceptability of critical elements of 
overall protocol design and analysis and will respond to relevant questions posed by the sponsor.  
FDA will also provide advice on other important concerns identified during review, even in the 
absence of a specific question.  Although the goal of an SPA is to reach concurrence on the 
adequacy of protocol elements of a study intended to support a finding of safety and efficacy, an 
SPA agreement with FDA indicates concurrence with critical trial design concepts but does not 
imply that FDA has reviewed, or concurs with, protocol details that do not affect approvability.   
 
 
11 In 2002, FDA amended its regulations in the final rule New Drug and Biological Drug Products; Evidence 
Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible 
(67 FR 37995, May 31, 2002).  These regulations address approval of certain new products for ameliorating or 
preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic 
biological, chemical, radiological, or nuclear substances based on evidence of effectiveness from animal studies 
when human efficacy trials are not ethical or feasible.  
  4  Contains Nonbinding Recommendations 
Sponsors should make every effort to identify unusual or potentially problematic aspects of the 
protocol and submit specific questions in their Request (see section V., Content of a Request and 
Submission Materials).  FDAs review of the Request is facilitated by a description from the 
sponsor of its desired indication and development plan in the cover letter, including any protocol 
elements intended to support a potential statement in labeling.  The sponsor should identify 
potential labeling statements for discussion with FDA, with appropriate objectives and statistical 
analysis that are intended to support this claim.  Claims not agreed upon at the meeting, and not 
supported by appropriate prespecified objectives and appropriate control for multiplicity are 
unlikely to support inclusion in labeling.    
 
The presence of an SPA agreement does not guarantee that a marketing application will be filed 
or approved, even if the trial is conducted in accordance with the protocol.  When an application 
is submitted, FDA reviews the application to make a threshold determination that the application 
is sufficiently complete to permit a substantive review; the fact that a trial conducted pursuant to 
an SPA agreement forms the basis of an efficacy claim in the application does not mean that the 
application in its entirety meets the criteria in 21 CFR 314.101 (for NDAs) or in 21 CFR 601.2 
(for BLAs) with respect to filing the application.  After an application has been filed, FDA 
reviews it to evaluate whether the submitted evidence in the application as a whole meets the 
statutory standard for approval.  Although, as set forth in the SPA provisions in the FD&C Act, 
FDA will not change its position regarding the critical design elements agreed to as part of an 
SPA agreement unless a substantial scientific issue essential to determining the safety or 
effectiveness of the product has been identified after the trial begins and the sponsor is notified 
of such (see section IX., Changes in or Rescission of Special Protocol Assessment Agreements), 
the existence of an SPA agreement does not mean that the application as a whole will meet the 
statutory standard for approval.   
 
 
IV.  PROCEDURES FOR SUBMISSION OF A REQUEST  
 
A Request should be submitted to a sponsors existing IND for each protocol the sponsor wants 
reviewed under an SPA.  A Request should not include more than one protocol.  If there is no 
IND for the product, FDA will assign a pre-IND number so that a meeting to fully inform FDA 
of the overall development plan for the product can be scheduled (see section III.B.1., Meeting 
With FDA Before Submission of a Request).  The sponsor can subsequently open an IND after 
the meeting and then submit a Request to the IND. 
 
FDA encourages electronic submissions in electronic common technical document format.12  
Electronic submission enhances the receipt, processing, and review of an SPA submission, 
particularly in view of the multidisciplinary input required to complete the SPA.   
 
 
12 See the guidance for industry Providing Regulatory Submissions in Electronic Format  Certain Human 
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.  As is further 
described in that guidance, electronic submission of commercial INDs in electronic common technical document 
format will be required after May 5, 2018. 
  5  Contains Nonbinding Recommendations 
A.  Notice of Intent 
 
Informing FDA of an upcoming Request will facilitate efficient review by FDA, and may permit 
earlier feedback to the sponsor.  Notification can be communicated during a drug development 
meeting or as an informal fax or email to the regulatory project manager. 
 
B.  Timing of a Request 
 
To allow sufficient time for FDA review and comment, as well as for resolution of outstanding 
high-level issues before the initiation of the proposed trial,13 CDER and CBER generally 
recommend that a sponsor submit a Request and submission materials to FDA sufficiently in 
advance of the anticipated start of the trial, so that FDA assessment can be completed before the 
protocol is finalized and submitted to the investigational review board(s).  The protocol, 
including a planned statistical analysis that includes critical statistical components, should be 
complete (see section V., Content of a Request and Submission Materials).  An interactive 
process, to reach concurrence on major protocol design features during the 45-day review period, 
is desirable to avoid the need for resubmission.14  If only minor issues remain, sponsors can 
proceed with protocol implementation, recognizing that a subsequent protocol amendment may 
be needed after study initiation.  Protocols for trials that have already begun do not qualify for an 
SPA (see section VI.A., Determining Whether a Submission Is Appropriate for an SPA). 
 
C.  Format of a Request 
 
When submitting to an IND, a sponsor should submit each protocol for an SPA as a separate 
amendment with Form FDA 1571 and a cover letter attached.  Paper submissions must be 
submitted in triplicate.15  The cover letter should identify the submission as a REQUEST FOR 
SPECIAL PROTOCOL ASSESSMENT in bolded block letters at the top and should state the 
type of protocol being submitted.  If a sponsor does not designate a submission as a Request, 
FDA may not immediately recognize it as such, resulting in a delay in the start and subsequent 
timeline of the review. 
 
D.  Where to Send a Request 
 
The Request should be submitted to the appropriate CDER or CBER division, using standard 
submission processes.  A copy of the cover letter should be sent via fax or secure email to the 
regulatory project manager for the application in the appropriate division. 
 
 
 
13 For example, when developing a timeline for an animal rule efficacy protocol SPA, the sponsor should consider 
the limited availability of laboratories capable of conducting studies employing chemical, biological, radiological, or 
nuclear agents. 
14 See the guidance for industry and review staff Best Practices for Communication Between IND Sponsors and 
FDA During Drug Development.   
15 See 21 CFR 312.23(d). 
  6  Contains Nonbinding Recommendations 
V.  CONTENT OF A REQUEST AND SUBMISSION MATERIALS 
 
The content of a Request and accompanying submission materials should be complete and the 
sponsor must provide information necessary for discussion and agreement on the design and size 
of the trial.16  Any areas of incomplete information should be identified and adequately justified 
by the sponsor.  Similarly, the sponsor should reference in the Request any relevant discussions 
and agreements with FDA on the phase 3 protocol based on previous meetings (e.g., an end-of-
phase 2/pre-phase 3 meeting, end-of-phase 1 meeting, or BPD Type 2 or Type 3 meeting).  
Relevant guidances that may be helpful to sponsors, both for supporting the trial design and for 
determining whether a Request is appropriate, are cited in References.  Sponsors are advised to 
consult the Drugs and Biologics guidance web pages for the most current lists of available 
guidances.17 
 
A.  Animal Carcinogenicity Protocols 
 
A sponsor should include relevant background information in addition to the complete protocol 
for CDER requests.18 
 
B.  Drug Substance and Drug Product Stability Protocols 
 
Generally, standard stability protocols should be based on the principles described in FDA and 
International Council for Harmonisation (ICH) guidances and do not need an SPA (see 
References). 
 
A Request can be submitted for a stability protocol that differs significantly from a standard 
stability protocol or that raises specific questions not addressed in existing guidance.  Before 
submitting a Request for a stability protocol, a sponsor should ensure that the product is in 
advanced clinical development and product characterization should be complete.  Manufacturing 
steps that can affect product stability should be identified.  The sponsor also should ensure that 
the manufacturing process, formulation, and container closure for the product described in the 
Request do not differ substantively from those for the product to be marketed and that the tests 
described will adequately qualify the product for use in the proposed protocol.  
 
C.  Animal Rule Efficacy Protocols 
 
Before submitting a Request, a sponsor should have FDA concurrence on the animal model 
proposed for use in the efficacy study (including, but not limited to, the species, the details of the 
challenge agent, and the conditions of exposure) and the method that will be used to extrapolate 
 
16 See section 505(b)(5)(B) of the FD&C Act. 
17 See https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, 
respectively.  
18 See the guidance for industry Carcinogenicity Study Protocol Submissions.  Additional information may be found 
in MAPP 7412.1 Rev. 2 Management of CDER Executive Carcinogenicity Assessment Committee and 
Communication of Committee Proceedings at 
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProc
edures/default.htm.  
  7  Contains Nonbinding Recommendations 
from the animal data to select an effective dose and regimen in humans.  The Request should 
include a detailed protocol and focused questions regarding the protocol such as study design, 
conduct, objectives, endpoints, data analysis, evaluation criteria, and the plan for ensuring data 
quality and integrity.  The sponsor should include background information, separate from the 
protocol, that describes in detail all relevant data (including clinical data), assumptions, and 
information that can assist FDA in evaluating the protocol and responding to the sponsors 
questions.  Although most of this information should have been discussed during previous 
interactions with FDA, this document should provide explanations of the scientific and 
regulatory basis for the study design, endpoints, statistical analysis plan, and the agreed-upon 
animal model.  In addition, the document should provide a detailed plan describing how the 
effective dose in animals will be translated to an appropriate dosing regimen in humans.  
Sponsors should consult the guidance for industry Product Development Under the Animal Rule 
when developing background documents. 
 
D.  Clinical Trial Protocols 
 
For protocols for clinical trials intended to form the basis for an efficacy claim (either under 
traditional or accelerated approval) a sponsor should describe in the submission how the protocol 
will fulfill the required essential data elements for an adequate and well-controlled trial (21 CFR 
314.126).  If the sponsor intends to rely on only one trial as part of its demonstration of 
substantial evidence of effectiveness, the sponsor should refer to the guidance for industry 
Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, and the 
protocol design should address the recommendations in the guidance.  However, the SPA review 
by FDA will focus on the submitted protocol; an SPA agreement should not be interpreted as 
concurrence on the sufficiency of one trial to support approval of a marketing application.  
Sufficiency of one trial to support approval is an appropriate topic for the end-of-phase 2 
meeting held before SPA submission. 
 
For protocols for clinical studies intended to support a demonstration of biosimilarity and/or 
interchangeability, a sponsor should describe in the submission how the protocol will support a 
demonstration of biosimilarity and/or interchangeability.19  
 
In addition, sponsors should review relevant FDA and ICH guidances for industry (see 
References).   
 
A sponsor should submit background information adequate to support critical design elements.  
This background information generally can be contained within the protocol, but also can be 
submitted as a separate document if the protocol does not provide a detailed and complete 
rationale, or if additional information is needed for FDA to address specific questions.  
Additional supporting documentation is especially important for consideration of novel 
endpoints to demonstrate clinical efficacy and any unusual design features.  The SPA agreement 
 
19 FDA has issued guidances related to the design of clinical studies intended to support a demonstration of 
biosimilarity and/or interchangeability in a BLA submitted under section 351(k) of the Public Health Service Act.  
These guidances are available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm. 
  8  Contains Nonbinding Recommendations 
describes concurrence on critical elements of the overall protocol design, but does not imply 
concurrence on these supportive documents.  The accompanying submission materials can: 
 
  Include information about the role of the trial in the overall development of the product. 
 
  Document and justify complex or novel eligibility criteria. 
 
  Consider the relevance of the population to be studied to the U.S. population in which the 
product is intended to be used, taking into account sex and age distribution20 and ethnic 
diversity reflective of the U.S. population.  If the population in the proposed trial is 
narrow, any plans to study the product in a broader, more diverse population should be 
described.  If the sponsor has feasibility information indicating that the trial will recruit 
the majority of enrollees from outside of the United States, the submission should include 
an explanation of why the results should be considered applicable to a U.S. population, 
and/or identify additional planned trials that will provide an adequate understanding of 
the benefits and risks of the therapy for the U.S. population, considering ethnic, genomic, 
standard of care, and other factors relevant to the specific therapy. 
 
  Provide adequate information to justify the critical design features of the trial, including, 
but not limited to: 
 
  Explaining reasons for dose selection, and, if applicable, justification for not 
including more than one dose. 
 
  Describing and explaining choice of trial endpoints, including identification of the 
primary and secondary endpoint(s), and plans for controlling overall type I error rate 
(false positive rate).   
 
  Describing choice of trial design (e.g., dose-response, superiority, add-on, 
noninferiority, equivalence) and control (e.g., placebo, best supportive care, active 
control).  If the trial is a noninferiority trial, the choice of active control and the 
noninferiority margin derived from the estimated treatment effect of the active control 
should be identified and justified.  If the protocol includes adaptive features, then 
decision rules for adaptations while controlling overall type I error rate and 
operational bias should be justified.  Enrichment designs, if considered, should be 
based on scientific rationale and the design should take prevalence of the disease into 
consideration.  
 
  If a sponsor submits a protocol for a single-arm trial for an SPA, justifying why a 
concurrently controlled trial is not feasible or cannot be conducted ethically. 
 
  Describing and explaining duration of therapy. 
 
 
20 See the guidance for industry Guideline for the Study and Evaluation of Gender Differences in the Clinical 
Evaluation of Drugs. 
  9  Contains Nonbinding Recommendations 
  Describing methods of endpoint assessment. 
 
  Justifying the use of novel biomarkers if used to select the population, monitor drug 
response or safety, or as an endpoint to support a labeling claim. 
 
  Describing procedures to minimize bias at all stages (e.g., randomization, blinding, 
endpoint assessment committee). 
 
  Describing the statistical approach, including a planned statistical analysis that 
includes critical statistical components and plans for reducing and imputing missing 
data.  Any planned interim analyses should be described, with the level of 
significance allocated for the planned interim analyses. 
 
Sponsors should submit specific questions for FDA response regarding critical protocol features 
such as expected accrual populations, primary efficacy and safety endpoints, dose range, analysis 
plans, and potential limitations of the proposed trial to achieve its regulatory goals. 
 
In codevelopment programs (i.e., development of a drug and a companion diagnostic device) 
where a sponsor requests an SPA for the drug, the sponsor should include as part of an SPA 
agreement drug-related questions and responses, including a devices effect on interpretation of 
drug data.  Device questions and responses directed toward aspects of the devices performance 
(i.e., device data collection that is independent of the drug) are inappropriate for inclusion in an 
SPA agreement, as noted in the Appendix under Statutory Framework.  Sponsors should direct 
questions about companion diagnostic protocols to the Center for Devices and Radiological 
Health.21  
 
 
VI.  FDA ASSESSMENT PROCESS 
 
A.  Determining Whether a Submission Is Appropriate for an SPA 
 
After receiving a Request and submission materials (SPA submission), the decision to accept the 
Request is made by the division director in consultation with the appropriate reviewers and team 
leaders.  If the division director concludes that the submission is not appropriate for an SPA, the 
division will notify the sponsor as soon as practicable about the determination and the specific 
reasons for the decision.  Generally, a rapid form of communication will be followed by a letter. 
 
 
21 See the guidance for industry and Food and Drug Administration staff Requests for Feedback on Medical Device 
Submissions:  The Pre-Submission Program and Meetings with Food and Drug Administration Staff.  This guidance 
is available on the FDA Medical Devices/Cross-Center Final Guidance web page at 
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm081752.htm. 
  10  Contains Nonbinding Recommendations 
An SPA submission may not be appropriate for such assessment if:  
 
  It contains a request to evaluate more than one protocol.  In such a case, FDA will ask the 
sponsor to submit separate requests for each protocol.  This process may delay the 
initiation of the SPA reviews. 
 
  It contains a protocol for an ongoing trial.22,23 
 
  It contains a protocol for which evaluation and critical features are adequately described 
by existing guidance (e.g., conventional stability study).  (See section V.B., Drug 
Substance and Drug Product Stability Protocols, for further explanation.)  
 
  It does not provide sufficient content and detail as described in section V., Content of a 
Request and Submission Materials, including: 
 
  A detailed protocol 
 
  Specific questions for FDA to address  
 
  Adequate background documents to support the critical elements of the trial design, 
or to determine whether it can adequately address scientific and regulatory 
requirements for the purpose identified by the sponsor 
 
  Prior FDA concurrence has not been obtained for the animal model to be used in the 
proposed animal rule efficacy study (see section V.C., Animal Rule Efficacy Protocols). 
 
  As stated in the PDUFA and BsUFA goals, the sponsor has not had a meeting (e.g., end-
of-phase 2/pre-phase 3 meeting (or end-of-phase 1 meeting, if applicable) or a BPD Type 
2 or Type 3 meeting) with the review division at which the regulatory context for the 
study or trial that is the subject of the SPA was discussed (where the trial is intended to 
support efficacy or trials to prove biosimilarity and/or interchangeability).24  
 
 
22 For the purposes of this guidance, the study initiation date for an animal rule efficacy study is defined as the first 
date on which an animal is assigned to the study protocol.  For a clinical trial, it begins when subject screening or 
enrollment begins.  For carcinogenicity studies, it is the first day of dosing.  For stability studies, FDA recommends 
that, where possible, an SPA be submitted before the study begins or the first measurement point is reached.  FDA 
accepts stability study SPAs after study initiation, because most are submitted when ICH recommendations prove to 
be infeasible and FDA advice is needed. 
23 See note 11, supra. 
24 See notes 8 and 9, supra.  As discussed in section III.B.1., Meeting With FDA Before Submission of a Request, in 
some cases (e.g., protocols to support submission of an efficacy supplement), FDA may already be familiar with the 
regulatory context, or it can be adequately described in the Request and supporting materials.  In such settings, some 
sponsors have decided not to submit meeting requests, and FDA has granted the Requests without having had a prior 
meeting.   
  11  Contains Nonbinding Recommendations 
B.  Assessment of the SPA Submission 
 
For each SPA submission accepted for assessment, FDA will respond to the sponsors questions 
focusing on protocol design, trial conduct and execution, data analysis, and labeling implications.  
FDAs review is intended to focus on critical protocol design features, rather than a line-by-line 
assessment of the protocol.  FDAs responses are based primarily on the information provided by 
the sponsor and relevant FDA policies and guidances; FDA also considers publicly available 
information as appropriate.  Sponsors should ensure that the data submitted in support of 
proposed protocols are current, complete, and accurate, because any change in the underlying 
data, assumptions, and information could affect the assessment of protocols and the resulting 
recommendations and/or SPA agreements. 
 
For animal carcinogenicity protocols submitted to CDER, review staff will present their 
assessments to the Executive Carcinogenicity Assessment Committee (ECAC).  The ECAC 
renders a final judgment on a protocols acceptability.  Concurrence with the general protocol 
design, documented in writing as described below, constitutes an SPA agreement.  If the ECAC 
does not agree with the sponsors proposed protocol design but the SPA submission contains 
adequate supporting data, FDA may propose specific protocol recommendations (e.g., dose, trial 
design) that, if followed by the sponsor, are considered by FDA to constitute an SPA agreement.  
For cases in which the ECAC does not agree with the proposed protocol design and the SPA 
submission does not provide adequate data to support recommendations for protocol design 
changes, the ECAC will consider the SPA status to be nonagreement.  The sponsor can resubmit 
the Request after deficiencies in the supporting information are resolved, or continue without 
formal FDA agreement. 
 
Comments from the ECAC regarding carcinogenicity protocols, including recommendations and 
conclusions (i.e., agreement or nonagreement), will be sent as minutes of the ECAC meeting, 
attached to the FDA Response to the Sponsor (see section VI.D., FDA Response to Sponsor). 
 
Occasionally, FDA divisions determine that input obtained from advisory committee review or 
consultants (internal, including internal regulatory meetings, or external) is critical to the review 
of any type of SPA submission.  FDA can seek advisory committee review or advice from 
advisory committee members, other special government employees, or other external 
consultants, and will consider the advice provided.  Advisory committee discussion of protocols 
submitted for SPA generally will not be open to the public.  FDA will follow standard procedures 
to protect confidentiality of commercial trade secret information.  For some animal rule efficacy 
protocols and certain novel clinical trial protocols, complex issues may arise requiring one or 
more internal consultant reviews and one or more internal meetings among multiple centers 
and/or multiple offices within FDA.   
 
If such input is needed, FDAs response may be delayed.  If such a delay occurs, FDA should 
inform the sponsor as soon as practicable, but no later than 45 calendar days of receipt of the 
Request, generally by fax or email followed by a mailed letter.  The communication will include 
the reason for the delay, the anticipated date of FDAs response, and an overview of the specific 
issues that will be reviewed. 
 
  12  Contains Nonbinding Recommendations 
After additional input has been obtained, FDA intends to send an SPA letter to the sponsor, 
which will include comments from the review team that result from consideration of advice from 
internal or external consultants, as soon as practicable, but no later than 45 calendar days of the 
advisory committee meeting or consultant review of the protocol. 
 
C.  Revisions During FDA Assessment 
 
FDA should communicate with the sponsor regarding deficiencies or problems with the protocol 
to allow for potential resolution as soon as possible and before issuing a Special Protocol 
Assessment  No Agreement letter.  FDA will make every effort to incorporate timely 
responses addressing easily correctable deficiencies into the 45-day review timeline.  If a sponsor 
submits additional questions, unsolicited revisions to the protocol, or a lengthy or complex 
response to an FDA question, or amends original submission materials with new information for 
any reason, FDA ordinarily will not respond to the original questions and will consider the 
original SPA submission withdrawn.  If FDA considers the SPA withdrawn, the division will 
notify the sponsor, followed by a letter that includes the rationale for the action.  FDA will 
consider submission of a revised protocol, or revised or additional supporting materials, to be a 
new SPA submission with a new 45-day timeline for response. 
 
D.  FDA Response to Sponsor 
 
Under PDUFA and BsUFA goals, FDA committed to sending an SPA letter (see sections VIII., 
Documentation, and VI.B., Assessment of the SPA Submission) to the sponsor within 45 
calendar days of receipt of the SPA submission.  This letter includes agreements, nonagreements, 
ECAC minutes (where applicable), and comments from the review team.  If FDA believes that 
meeting with a sponsor could facilitate resolution of outstanding issues, the letter may include a 
recommendation to request a Type A or BPD Type 1 meeting.25  The division will mail the letter 
to the sponsor, even if the letter was first sent by fax or email.   
 
 
VII.  SPONSOR OPTIONS AFTER RECEIPT OF SPECIAL PROTOCOL 
ASSESSMENT  NO AGREEMENT LETTER 
 
Sponsors should note that, despite additional communications in writing and/or additional Type 
A or BPD Type 1 meetings, sponsors and FDA may not reach agreement on all aspects of the 
protocols and specific questions posed.  A Special Protocol Assessment  No Agreement letter 
may identify areas in which FDA concurs with the sponsors proposal, even if a Special Protocol 
Agreement letter cannot be issued.  The following options are available to sponsors after 
receiving Special Protocol Assessment  No Agreement letters: 
 
  Initiate Trial Without SPA Agreement  Sponsors can initiate trials after receipt of 
Special Protocol Assessment  No Agreement letters.  FDA agreement is not required 
before proceeding with trials intended to form primary evidence of effectiveness, and 
 
25 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (when final, this guidance will represent FDAs current thinking on this topic) and the guidance for 
industry Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants.  
  13  Contains Nonbinding Recommendations 
FDA reviews marketing applications on the basis of submitted data, regardless of 
whether FDA previously agreed with protocol designs in SPA agreements.  If the results 
from a trial are submitted in a marketing application, FDA will review the results and 
determine whether they support the approval of the application.  Applications that meet 
the statutory standards will result in approval. 
 
  Do Not Initiate Trial and Respond in Writing to Address Nonagreement  Sponsors 
can respond in writing to amend protocols or provide additional supporting information 
to address the reasons for the nonagreement expressed by FDA.  This amendment and 
response will be considered an SPA resubmission, not a new SPA submission under 
PDUFA and BsUFA performance goals, and FDA will make every effort to complete the 
subsequent review within 45 days.  In some cases, changes to the protocol included in the 
SPA resubmission may not require the full additional review period, and FDA will make 
every effort to complete the review as soon as practicable.   
 
Resubmissions should be complete and should address outstanding critical protocol 
issues.  As previously mentioned, an SPA is intended to provide feedback on critical 
protocol design issues rather than minor protocol details that would be well managed by 
sponsors.  SPA resubmissions should address specific issues identified in Special 
Protocol Assessment  No Agreement letters and should not address or introduce new 
issues or items for discussion.  Introducing significant new material alters the 
developmental context and may warrant a meeting to discuss the new information. 
 
  Request a Type A or BPD Type 1 Meeting to Discuss Nonagreement  Sponsors can 
request Type A or BPD Type 1 meetings with the divisions to discuss nonagreement 
issues.  If FDA believes that meeting with a sponsor is the best way to resolve 
outstanding issues regarding an SPA, FDA can suggest in the Special Protocol 
Assessment  No Agreement letter that the sponsor request such a meeting.  Type A and 
BPD Type 1 meeting requests are handled according to PDUFA or BsUFA goals for 
meeting management, respectively.26  At a Type A or BPD Type 1 meeting, FDA and the 
sponsor should discuss remaining issues and uncertainties regarding the protocol but may 
not necessarily come to final agreement on all remaining issues.  If the issues of concern 
are resolved, SPA agreement could be documented in the meeting minutes in advance of 
FDA issuing a Special Protocol Agreement letter. 
 
 
VIII.  DOCUMENTATION 
 
All agreements between FDA and the sponsor regarding an SPA must be documented in writing 
(section 505(b)(5)(C) of the FD&C Act).  FDA will also document nonagreements and FDA 
responses to the sponsors questions and issues identified by FDA.  The primary documentation 
 
26 See notes 8 and 9, supra.  See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or 
Applicants of PDUFA Products (when final, this guidance will represent FDAs current thinking on this topic) and 
the guidance for industry Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or 
Applicants.  
  14  Contains Nonbinding Recommendations 
should consist of an SPA letter that includes agreement, nonagreement, comments or questions 
to the sponsor, and ECAC minutes (if applicable).   
 
 
IX.  CHANGES IN OR RESCISSION OF SPECIAL PROTOCOL ASSESSMENT 
AGREEMENTS 
 
Section 505(b)(5)(C) of the FD&C Act states that any SPA agreement shall not be changed 
after the testing begins, except   
 
(i)  with the written agreement of the sponsor or applicant; or 
 
(ii) pursuant to a decision, made in accordance with subparagraph (D) by the director of the 
reviewing division that a substantial scientific issue essential to determining the safety or 
effectiveness of the drug has been identified after the testing has begun. 
 
The PDUFA and BsUFA goals letters further describe changes in SPA agreements:   . . . having 
agreed to the design, execution, and analyses proposed in protocols reviewed under this process, 
the Agency will not later alter its perspective on the issues of design, execution, or analyses 
unless public health concerns unrecognized at the time of protocol assessment under this process 
are evident.27   
 
Therefore, SPA agreements will not be changed at any time except as described below. 
 
A.  FDA and Sponsor Agreement on Changes in an SPA Agreement 
 
Under section 505(b)(5)(C) of the FD&C Act, a documented SPA agreement can be modified 
after testing begins if FDA and the sponsor agree in writing to modify the agreement.  Generally, 
such a modification is intended to improve the trial.  An SPA agreement modified in this manner 
is binding on the division in the same manner as the original SPA agreement.28  In general, 
requests to modify an SPA agreement will be reviewed as soon as practicable and will include 
discussion with the sponsor as appropriate.  FDA will make every effort to complete its review 
and amend the agreement within 45 days of receipt.  More substantial or complex changes may 
require additional input (see section VI.B., Assessment of the SPA Submission) or longer review 
times. 
 
B.  FDA Rescinding of an SPA Agreement 
 
In rare cases, FDA may rescind an SPA agreement.  Since the Food and Drug Administration 
Modernization Act of 1997 was enacted through 2016, CDER has issued more than 1,000 SPA 
agreements; less than 1 percent of those SPAs have been rescinded. 
 
FDA recognizes that the written agreements reached as part of the SPA process are important to 
the product development process.  Written agreements on the design and size of a trial described 
 
27 See notes 8 and 9, supra. 
28 Because of CBERs organizational structure, SPAs are binding on the product office rather than the division. 
  15  Contains Nonbinding Recommendations 
in section 505(b)(5)(B) of the FD&C Act are based on the best scientific information available at 
the time of the agreement.  However, newly available scientific knowledge in the form of data or 
other information, or a reevaluation or improved understanding of relevant scientific knowledge, 
may challenge or cause the scientific community and FDA to question or reject previously held 
assumptions or beliefs supporting an earlier decision and agreement on an SPA.   
 
FDA may rescind an SPA agreement when the division director or senior management 
determines that a substantial scientific issue essential to determining the safety or efficacy of the 
product has been identified after the trial has begun (section 505(b)(5)(C)(ii) of the FD&C Act).  
A substantial scientific issue essential to determining the safety or efficacy of the product may 
include, but is not limited to: 
 
  Identification of data that would call into question the clinical relevance of previously 
agreed-upon efficacy endpoints 
 
  Identification of safety concerns related to the product or its pharmacological class 
 
  Paradigm shifts in disease diagnosis or management recognized by the scientific 
community and FDA   
 
  The relevant data, assumptions, or information provided by the sponsor in the SPA 
submission are found to be false statements or misstatements, or are found to omit 
relevant facts, such that the clinical relevance of critical components of trial design is 
called into question, or appropriate safety monitoring and human subject protection are 
affected 
 
Note that if the sponsor fails to follow the protocol that was agreed upon with FDA consistent 
with the SPA agreement, or makes substantive changes in the protocol without agreement with 
FDA (e.g., change in endpoint or population), then FDA will consider the results from the study 
as a review issue; FDA will not, however, be bound by the SPA agreement because the study 
conducted was not within the agreed terms of the SPA.  Note that minor changes to protocols 
(e.g., changes in noncritical conduct of the trial or editorial changes) typically would not affect 
the SPA agreement.  Although failure of the sponsor to follow the protocol may not preclude 
approval of the product based on review of the submitted data, it can form the basis for rescission 
of the SPA agreement.     
 
Although the process under section 505(b)(5)(B) of the FD&C Act does not apply to devices, 
some alterations to a device used in a codevelopment program may affect the type or 
interpretation of the data collected in the drug trial.29  For example, device alterations might 
change the characteristics of the enrolled patient population or could alter the threshold for a 
positive outcome used as a primary endpoint.  If a device is altered or replaced with a different 
technology after the trial has begun, such a change may be considered a substantial scientific 
issue if it negatively affects the ability to interpret the trial results.  
 
 
29 Such alterations might include, for example, changed cut-off values, an altered scoring system, or addition of 
analytes.  Changes in the performance characteristics of the device could affect sensitivity or specificity. 
  16  Contains Nonbinding Recommendations 
Given that each SPA agreement is unique to the product, product development plan, patient 
population, and/or proposed indication, decisions concerning whether to rescind an SPA 
agreement are made on a case-by-case basis after review of the substantial scientific issue that 
has been identified after a trial has begun, and the evaluation of its effect on the ability to 
interpret the safety or effectiveness of the product.  The rare occurrence of rescission reflects the 
diligence with which FDA performs an SPA review, and FDAs appreciation of the significance 
of a rescission decision.  Such an action is taken only after consideration and input from 
appropriate staff.  FDA views rescission as part of its mandate to protect the public health by 
ensuring that human subjects are not enrolled in clinical trials that cannot meet their regulatory 
objectives and to ensure that FDA advice to sponsors developing products for approval is based 
on the most current scientific knowledge. 
 
If a decision to rescind an SPA agreement is being considered, the division director will notify 
the sponsor in writing.  The notice will include the rationale for the potential action and offer an 
opportunity for a Type A or BPD Type 1 meeting under the PDUFA or BsUFA goals, 
respectively.  The purpose of the meeting will be to allow the sponsor to submit relevant data, 
analyses, or information to address the scientific concerns and discuss their potential effects on 
the protocol.  In some cases, FDA may seek advice from external experts, which may include 
discussing the SPA submission and the substantial scientific issue at an FDA advisory committee 
meeting, before the review division decides whether to rescind the agreement.  Standard FDA 
procedures to protect confidentiality will be followed. 
 
If, after review of any additional submitted material, consultation with internal or external 
experts (as appropriate), and discussions with the sponsor, the division director concludes that 
the SPA agreement should be rescinded, he or she will issue a Special Protocol Rescind 
Agreement letter that details the data and information that support that decision.  As stated in 
section 505(b)(5)(D) of the FD&C Act, if the division director makes such a determination, the 
sponsor will be given an opportunity for a meeting, regardless of whether the sponsor met with 
FDA before receiving the Special Protocol Rescind Agreement letter, at which the division 
director will discuss the scientific issue involved.  This meeting will be a Type A or BPD Type 1 
meeting under the PDUFA or BsUFA goals, respectively.  This post-action meeting provides the 
possibility to reach agreement on a developmental path forward, even if the agreement is outside 
of an SPA agreement. 
 
If after receiving the Special Protocol Rescind Agreement letter the sponsor disagrees, it can 
follow the formal dispute resolution procedures (see section X., Dispute Resolution).  Generally, 
a sponsor should have had a post-action meeting before initiating the formal dispute resolution 
procedures. 
 
FDA should convey its decision to rescind an SPA agreement as early as possible during the 
product development and/or application review process, recognizing that the timing of the 
decision will depend on when FDA receives information about or becomes aware of the 
substantial scientific issue.  FDA will also strive to identify other SPAs that could be affected by 
the information or substantial scientific issue and notify the relevant sponsors (if any) as soon as 
possible.  FDA anticipates that these cases will continue to be rare, prompted by significant 
changes in medical science that undermine the basis for the prior agreements.  
  17  Contains Nonbinding Recommendations 
 
FDA is committed to keeping current with scientific and medical innovation, and will, to the best 
of its ability, communicate important changes in science that affect regulatory aspects of product 
development to sponsors in the course of formal meetings and responses to submissions as soon 
as practicable.  Such changes could include evolving understanding of protocol design, 
knowledge of ongoing clinical trials, or the accrual of data regarding other product development 
programs in the same, or a related, pharmacological class.  FDA makes every effort throughout 
the product development process to communicate to sponsors any concerns regarding relevant 
new information that may affect FDAs thinking regarding an SPA agreement as soon as it is 
appropriate and feasible to do so.  However, sponsors are responsible for continued product 
development and they should review the results of published scientific investigations and other 
sources of data and information and ascertain whether these affect ongoing investigations, 
including trials conducted under SPAs.  Sponsors should notify the appropriate review division 
as soon as they are aware of a scientific finding that might affect their SPA agreements. 
 
 
X.  DISPUTE RESOLUTION 
 
If, after being notified of the FDA action (e.g., nonagreement or rescission) by the division, the 
sponsor disagrees with the FDA action, the sponsor should first try to resolve the matter with the 
division.  If the sponsor is not satisfied with FDAs response, the sponsor can follow FDA 
procedures for formal dispute resolution, as described in regulations (21 CFR 10.75, 312.48, and 
314.103), the PDUFA goals letter,30 the BsUFA goals letter,31 and the guidance for industry and 
review staff Formal Dispute Resolution:  Sponsor Appeals Above the Division Level.  As part of 
the formal dispute resolution process, FDA may decide, either on its own initiative or at the 
request of the sponsor, to seek input from an advisory committee, irrespective of whether FDA 
obtained input from an advisory committee before entering into the SPA agreement.  
 
 
XI.  PAPERWORK REDUCTION ACT OF 1995 
 
This guidance contains information collection provisions that are subject to review by the Office 
of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520).   
 
The time required to complete this information collection is estimated to average 8 hours to 
prepare a notice of intent to request SPA of a carcinogenicity protocol and 15 hours to prepare a 
request for SPA, including the time to review instructions, search existing data resources, gather 
the data needed, and complete and review the information collection.  Send comments regarding 
this burden estimate or suggestions for reducing this burden to:  Office of Regulatory Policy, 
Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Silver Spring, MD  20993-0002. 
 
 
30 See note 8, supra. 
31 See note 9, supra. 
  18  Contains Nonbinding Recommendations 
This guidance also refers to previously approved collections of information found in FDA 
regulations.  The collections of information for FDA Form 1571 have been approved under 
OMB control number 0910-0014.   
 
An agency may not conduct or sponsor, and a person is not required to respond to, a 
collection of information unless it displays a currently valid OMB control number.  The 
OMB control number for this information collection is 0910-0014.  The current expiration 
date is available at https://www.reginfo.gov (search ICR and enter OMB control number). 
 
 
  19  Contains Nonbinding Recommendations 
GLOSSARY 
 
Notice of Intent:  An informal notice that a sponsor plans to submit a Request. 
 
Request for SPA (Request):  The letter from a sponsor to FDA asking for a special protocol 
assessment (SPA). 
 
SPA Agreement:  Concurrence with the adequacy and acceptability of specific critical elements 
of protocol design and analysis. 
 
SPA Letter:  FDAs action letter in response to an SPA submission.  Indicates agreement or 
nonagreement with specific critical elements of design and analysis of the proposed protocol and 
provides responses to a sponsors questions, as appropriate. 
 
SPA Review:  FDAs review of all material submitted by a sponsor pertaining to a Request (i.e., 
FDAs review of the SPA submission). 
 
SPA Submission:  A Request plus accompanying supportive materials and protocol. 
 
Special Protocol Assessment (SPA):  A process by which a sponsor asks FDA to evaluate a 
protocol to determine whether it adequately addresses scientific and regulatory requirements for 
the purpose identified by the sponsor.  As part of the process, sponsors generally submit specific 
questions about protocol designs and scientific and regulatory requirements.  FDA completes the 
review of the SPA submission and any internal and/or external consultations.  FDA then sends an 
SPA letter to the sponsor to close out the process.  The term special protocol assessment, for the 
purposes of this guidance, refers to the processes and procedures that begin when a sponsor 
notifies FDA of its intent to submit a Request or its submission of a Request, and end with FDA 
issuing an SPA letter.  
 
Special Protocol Rescind Agreement Letter:  FDAs action letter when it has determined that 
it will rescind an existing SPA agreement based on the fact that a substantial scientific issue 
essential to determining the safety or effectiveness of the product has been identified after testing 
began. 
 
  20  Contains Nonbinding Recommendations 
REFERENCES 
 
The following guidances provide additional information for section V., Content of a Request and 
Submission Materials, of the guidance. 
 
Drug Substance and Drug Product Stability Protocols 
 
ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products 
 
ICH guidance for industry Q1B Photostability Testing of New Drug Substances and Products 
 
ICH guidance for industry Q1C Stability Testing for New Dosage Forms 
 
ICH guidance for industry Q1D Bracketing and Matrixing Designs for Stability Testing of New 
Drug Substances and Products 
 
ICH guidance for industry Q1E Evaluation of Stability Data  
 
ICH guidance for industry Q5C Quality of Biotechnological Products:  Stability Testing of 
Biotechnological/Biological Products 
 
Clinical Trial Protocols 
 
Draft guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics32  
 
Draft guidance for industry Considerations in Demonstrating Interchangeability With a 
Reference Product33  
 
Guidance for industry Clinical Pharmacology Data to Support a Demonstration of Biosimilarity 
to a Reference Product 
 
Guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and 
Regulatory Applications 
 
Guidance for industry Non-Inferiority Clinical Trials 
 
Guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference 
Product 
 
ICH guidance for industry E3 Structure and Content of Clinical Study Reports 
 
ICH guidance for industry E4 Dose-Response Information to Support Drug Registration 
 
ICH guidance for industry E9 Statistical Principles for Clinical Trials 
 
32 When final, this guidance will represent the FDAs current thinking on this topic. 
33 When final, this guidance will represent the FDAs current thinking on this topic. 
  21  Contains Nonbinding Recommendations 
 
ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials 
 
ICH guidance for industry M4 Organization of the CTD  
 
  22  Contains Nonbinding Recommendations 
APPENDIX:  LEGAL BACKGROUND 
 
Statutory Framework 
 
Section 119(a) of the Food and Drug Administration Modernization Act of 1997 (FDAMA) 
amended section 505(b) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 
355(b)) and directed FDA to meet with sponsors who request to meet, provided certain 
conditions are met, to reach agreement on the design and size of the well-controlled clinical trials 
intended to form the primary basis for a demonstration of effectiveness in a marketing 
application submitted under section 505(b) of the FD&C Act or section 351 of the Public Health 
Service Act (PHS Act) (42 U.S.C. 262).34  These provisions subsequently were amended in 
section 7002(d)(1) of the Biologics Price Competition and Innovation Act of 2009 to include any 
necessary clinical study or studies for biosimilar biological product applications under section 
351(k) of the PHS Act.   
 
In 2013, the Pandemic and All Hazards Preparedness Reauthorization Act of 2013 (PAHPRA) 
further amended the special protocol assessment (SPA) provisions to provide for SPA 
agreements regarding animal and associated clinical trials conducted in support of applications 
for products developed under 21 CFR part 314, subpart I, and 21 CFR part 601, subpart H (the 
animal rule).35  The amendments in section 301 of PAHPRA provided for the use of the SPA 
process with respect to studies conducted in support of product development in the case where 
human efficacy studies are not ethical or feasible, of animal and any associated clinical trials 
which, in combination, are intended to form the primary basis of an effectiveness claim.  These 
revisions to the SPA provisions are consistent with FDAs previous approach to interpreting the 
SPA provisions broadly; most products developed under the animal rule will be used as medical 
countermeasures for serious events that require rapid distribution and deployment, and would be 
approved and ready for use in advance of such an event. 
 
As set forth in the current SPA provisions in section 505(b)(5)(B) and (C) of the FD&C Act, if a 
sponsor makes a reasonable written request to meet with FDA to reach agreement on the design 
and size of a trial covered by the statute, FDA will grant the request.  If FDA and the sponsor 
reach an agreement, FDA will put the agreement in writing and make it part of the administrative 
record (see the User Fee Acts section in this Appendix for a discussion of FDAs performance 
goals for review).  Neither FDA nor the sponsor may change an agreement after the trial begins 
except:  (1) with the written consent of the sponsor; or (2) if the FDA division director 
determines that a substantial scientific issue essential to determining the safety or effectiveness 
 
34 Section 119(b) of FDAMA also amended section 505(j) of the FD&C Act, and directed FDA to meet with 
sponsors and applicants, provided certain conditions are met, to reach agreement on the design and size of 
bioavailability and bioequivalence trials needed to support applications submitted under section 505(j) of the FD&C 
Act (i.e., abbreviated new drug applications).  Adequacy of trial design to support 505(j) applications is outside the 
scope of this guidance.   
35 In 2002, FDA amended its regulations in the final rule New Drug and Biological Drug Products; Evidence 
Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible 
(67 FR 37995, May 31, 2002).  These regulations address approval of certain new products for ameliorating or 
preventing serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic 
biological, chemical, radiological, or nuclear substances based on evidence of effectiveness from animal studies 
when human efficacy trials are not ethical or feasible. 
  23  Contains Nonbinding Recommendations 
of the drug has been identified after the testing has begun.36  Should it be necessary for FDA to 
change or rescind an SPA agreement, FDA will first give the sponsor the opportunity for a 
meeting at which the FDA division director will be present and at which the director will 
document the scientific issue involved.  This process is discussed in greater detail in section IX., 
Changes in or Rescission of Special Protocol Assessment Agreements, of the guidance.    
 
If a sponsor and FDA meet regarding the design and size of a trial under section 505(b)(5)(B) of 
the FD&C Act and the parties cannot agree that the trial design is adequate to meet the stated 
goals of the trial, FDA will state the reasons for the nonagreement in a Special Protocol 
Assessment  No Agreement letter to the sponsor.  Potential paths forward after receipt of this 
letter are described in section VII., Sponsor Options After Receipt of Special Protocol 
Assessment  No Agreement Letter, of the guidance. 
 
The SPA process does not apply to marketing applications for devices or to device protocols, 
including protocols for the development of companion diagnostic devices.  Sponsors can submit 
a Request for a protocol for the drug or biological product, but sponsors should direct questions 
about companion diagnostic protocols to the Center for Devices and Radiological Health.  
Questions about the device portion of a combination product are managed through the lead 
center using standard processes, but are not included in the SPA.37 
 
User Fee Acts 
 
Prescription Drug User Fee Act 
 
In conjunction with the reauthorization of the prescription drug user fee program in FDAMA 
(Prescription Drug User Fee Act (PDUFA) II), FDA agreed to specific performance goals 
(PDUFA goals) for SPA.38  According to the PDUFA goals letter, protocols that qualify for the 
SPA program include carcinogenicity protocols, stability protocols, and Phase 3 protocols for 
clinical trials that will form the primary basis of an efficacy claim.39  The goals letter further 
states, For products that will be using Subpart E or Subpart H development schemes [for 
accelerated approval], the Phase 3 protocols . . . should be construed to mean those protocols for 
trials that will form the primary basis of an efficacy claim no matter what phase of drug 
 
36 See section 505(b)(5)(C)(ii) of the FD&C Act. 
37 See Staff Manual Guide 4101 
(https://www.fda.gov/aboutfda/reportsmanualsforms/staffmanualguides/default.htm) and Rappel MJ, Hunter NL, 
Alexandrow AL, et al., 2017, Case Study for Lean Management in the Public Section:  Improving Combination 
Product Review at the Food and Drug Administration, Clin Transl Sci., epub ahead of print January 12, 2017, doi: 
10.1111/cts.12441. 
38 FDA first agreed to specific PDUFA goals for SPA in November 1997 in conjunction with PDUFA II, the 
reauthorization of the Prescription Drug User Fee Act of 1992.  The PDUFA II goals are described in PDUFA 
Reauthorization Performance Goals and Procedures, an enclosure to a letter dated November 12, 1997, from the 
Secretary of Health and Human Services, Donna E. Shalala, to Senator James M. Jeffords 
(https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm143135.htm).  The program has been 
reauthorized every 5 years; the most recent goals letter is available on the FDA website at 
https://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm149212.htm. 
39 Ibid. 
  24  Contains Nonbinding Recommendations 
development in which they happen to be conducted.40  The PDUFA goals regarding clinical 
protocol review and assessment are wider in scope than section 505(b)(5)(B) of the FD&C Act.  
Both the noted statutory requirements and the PDUFA goals apply to protocols for clinical trials 
intended to form the primary basis of an efficacy claim in original and supplemental 
applications.  However, the PDUFA goals also apply to animal carcinogenicity protocols and 
final product stability protocols, whereas the statutory section does not.   
 
Under the PDUFA goals, the sponsor may submit a Request for qualifying protocols (see section 
III., Eligible Protocols and General Information, in the guidance) that should include a limited 
number of specific questions about protocol design and scientific and regulatory requirements.41  
As set out in the PDUFA goals letter, for a protocol to qualify for SPA, the sponsor must have 
had a  . . . meeting with the review division so that the division is aware of the developmental 
context in which the protocol is being reviewed and the questions being answered.42  For the 
Requests that FDA accepts (see section VI., FDA Assessment Process, in the guidance), the goal 
is to complete 90 percent of SPA reviews within 45 days.  SPA reviews may not always be 
completed within 45 days, as further described in section VI.B., Assessment of the SPA 
Submission, of the guidance.  
 
Biosimilar User Fee Act 
 
In conjunction with the Biosimilar User Fee Act of 2012 (BsUFA), enacted as part of the Food 
and Drug Administration Safety and Innovation Act of 2012 (FDASIA),43 FDA agreed to 
specific performance goals for SPA.44,45  These goals were later updated, in conjunction with the 
Biosimilar User Fee Amendments of 2017.  The updated BsUFA goals letter states that [u]pon 
specific request by a sponsor (including specific questions that the sponsor desires to be 
answered), the Agency will evaluate certain protocols and related issues to assess whether the 
design is adequate to meet scientific and regulatory requirements identified by the sponsor, and 
further specifies which protocols qualify for an SPA.  They include any necessary clinical study 
or studies to prove biosimilarity and/or interchangeability (e.g., protocols for pharmacokinetic 
and pharmacodynamic studies, protocols for comparative clinical studies that will form the 
primary basis for demonstrating that there are no clinically meaningful differences between the 
 
40 For the purposes of this Appendix, the term efficacy claim is defined by its use in the PDUFA goals letter; see 
note 38, supra.  Subpart E or Subpart H refers to applications submitted in accordance with 21 CFR 601.40 and 
314.500, respectively. 
41 See note 38, supra. 
42 Ibid. 
43 See sections 401408 of FDASIA, adding sections 744G, 744H, and 744I to the FD&C Act. 
44 See the BsUFA goals letter titled Biosimilar Biological Product Reauthorization Performance Goals and 
Procedures Fiscal Years 2018 Through 2022 available on the FDA Web site at 
https://www.fda.gov/downloads/forindustry/userfees/biosimilaruserfeeactbsufa/ucm521121.pdf.  The program is 
considered for reauthorization every 5 years; updated goals letters are posted on the FDA website at 
https://www.fda.gov/forindustry/userfees/biosimilaruserfeeactbsufa/default.htm.  
45 For the statutory definition of biosimilar biological product, biosimilar biological product application, and 
definitions of selected terms used in this Appendix, see section 744G(3) and (4) of the FD&C Act, section 351(i) of 
the PHS Act, and the Glossary in the guidance for industry Scientific Considerations in Demonstrating Biosimilarity 
to a Reference Product.  We update guidances periodically.  To make sure you have the most recent version of a 
guidance, check the FDA Drugs guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
  25  Contains Nonbinding Recommendations 
proposed biosimilar biological product and the reference product, and protocols for clinical 
studies intended to support a demonstration of interchangeability).   
 
In accordance with the BsUFA goals letter, a sponsor may submit a Request for qualifying 
protocols (see section III., Eligible Protocols and General Information, in the guidance) and 
should include a limited number of specific questions about protocol design and scientific and 
regulatory requirements.  As set out in the BsUFA goals letter, for a protocol to qualify for 
SPA, the sponsor must have had a biosimilar biological product development Type 2 or Type 3 
meeting.  Of the Requests that FDA accepts, the goal is to complete 90 percent of SPA reviews 
within 45 days.  SPA reviews may not always be completed within 45 days, as further described 
in section VI.B., Assessment of the SPA Submission, of the guidance.  
 
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