Guidance for Industry 
 
Postmarketing Studies and  
Clinical Trials  
Implementation of 
Section 505(o)(3) of the 
Federal Food, Drug, and 
Cosmetic Act  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 2011 
Drug Safety 
 
 
   
Guidance for Industry 
 
Postmarketing Studies and  
Clinical Trials  
Implementation of  
Section 505(o)(3) of the 
Federal Food, Drug, and 
Cosmetic Act 
 
Additional copies are available from: 
Office of Communications 
Division of Drug Information, HFD-240 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 51, Room 2201 
Silver Spring, MD  20993-0002 
(Tel) 301-796-3400 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 Office of Communication, Outreach, and Development, HFM-40  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
1401 Rockville Pike  
Rockville, MD  20852-1448 
(Tel) 800-835-4709 or 301-827-1800 
http://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 2011 
Drug Safety 
 
   
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Past Practice ................................................................................................................................... 2 
B.  New FDAAA Authority and Requirements ................................................................................. 3 
1. FDA May Require Applicants to Conduct Studies and Clinical Trials ........................................... 4 
2. Applicants Are Required to Report on the Status of Studies and Clinical Trials............................. 5 
 
III.  IMPLEMENTATION OF POSTMARKETING STUDY AND CLINICAL TRIAL 
REQUIREMENTS UNDER FDAAA ................................................................................. 6 
A.  Examples of Postmarketing Requirements (PMRs) Required Under Section 505(o) ............. 7 
B.  Examples of Postmarketing Commitments (PMCs) That Are Not Required Under Section 
505(o) ..................................................................................................................................................... 10 
 
IV.  PROCEDURES ............................................................................................................... 11 
V.  REPORTING .................................................................................................................. 12 
A.  PMR Reports ................................................................................................................................ 12 
B.  PMC Reports ................................................................................................................................ 13 
C.  Reports for Other Studies and Clinical Trials .......................................................................... 13 
D.  Reports in REMS Assessments ................................................................................................... 13 
E.  Summary ....................................................................................................................................... 14 
VI.  DISPUTE RESOLUTION ............................................................................................. 14 
VII.  ENFORCEMENT OF REQUIREMENTS FOR POSTMARKETING STUDIES 
AND CLINICAL TRIALS ............................................................................................. 14 
APPENDIX A:  GLOSSARY ..................................................................................................... 16 
APPENDIX B:  PMR AND PMC AUTHORITIES ................................................................. 18 
  Contains Nonbinding Recommendations 
Guidance for Industry1 
 
Postmarketing Studies and Clinical Trials  
Implementation of Section 505(o)(3) of the Federal Food, Drug, and 
Cosmetic Act  
 
 
 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
I.  INTRODUCTION  
 
This guidance provides information on the implementation of new section 505(o) of the Federal 
Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(o)), added by section 901 of the Food 
and Drug Administration Amendments Act of 2007 (FDAAA).  Section 505(o)(3) authorizes 
FDA to require certain postmarketing studies and clinical trials2 for prescription drugs approved 
under section 505 of the Act and biological products approved under section 351 of the Public 
Health Service Act (the PHS Act) (42 U.S.C. 262).3  This guidance provides information about 
the requirements for postmarketing studies and clinical trials under section 505(o)(3) of the Act.  
The guidance also describes the types of postmarketing studies and clinical trials that:  
 
  will generally be required under the new legislation (postmarketing requirements 

(PMRs)) and  
                                                 
1 This guidance has been prepared by the FDAAA Title IX Working Group, comprising staff from the Center for 
Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food 
and Drug Administration.  
 
2 FDAAA makes a new distinction between study and clinical trial.  Previous laws, regulations, and practice 
have generally used the terms studies and trials interchangeably.  For example, section 506B of the Act (21 U.S.C. 
356b) uses studies to describe the postmarketing commitments (PMCs) that must be reported annually, including 
clinical trials.  For purposes of implementing section 505(o)(3) of the Act, because FDAAA distinguishes between 
studies and clinical trials and section 505(o) provides criteria to determine which may be required (see section II.B 
of this guidance), we distinguish between studies and clinical trials for the purposes described in this document.   
 
3 For the purposes of this guidance, all references to drugs include both human drugs and biological drug products 
regulated by CDER and CBER unless otherwise specified.  
 
  Contains Nonbinding Recommendations 
  will generally be agreed-upon commitments (postmarketing commitments (PMCs)) 

because they do not meet the new statutory criteria for required postmarketing studies 
and clinical trials.   
 
Section 901 of FDAAA also created new sections 505-1 and 505(o)(4) of the Act, which 
authorize FDA, under certain circumstances, to require risk evaluation and mitigation strategies 
(REMS) to ensure that the benefits outweigh the risks of a drug and safety-related labeling 
changes (SLC) respectively.4  This guidance does not address REMS and SLC provisions.  FDA 
wishes to clarify that PMRs, REMS, and SLCs are required under separate sections of the Act 
and while all are intended to address serious safety risks, they are separate provisions that have 
different goals and must meet separately defined statutory criteria.  REMS are not a special type 
of PMR, nor are PMRs elements of a REMS.5 
 
This guidance does not apply to nonprescription drugs approved under a new drug application 
(NDA), nor does it apply to generic drugs approved under section 505(j) of the Act.  Section 
505(o) of the Act applies only to prescription drugs approved under section 505(b) of the Act and 
biological products approved under section 351 of the PHS Act.  See 505(o)(2)(B). 
 
FDAs guidance documents, including this guidance, 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 
 
On September 27, 2007, the President signed FDAAA (Public Law 110-85) into law.  Section 
901 of Title IX of FDAAA amended the Act by adding new section 505(o).  Section 505(o)(3) 
authorizes FDA to require certain postmarketing studies and clinical trials for prescription drugs 
approved under section 505(b) of the Act and biological products approved under section 351 of 
the PHS Act. 
 
A.  Past Practice 
 
In the past, FDA has used the term postmarketing commitment (PMC) to refer to certain studies 
(including clinical trials), conducted by an applicant after FDA has approved a drug for 
marketing or licensing, that were intended to further refine the safety, efficacy, or optimal use of 
a product or to ensure consistency and reliability of product quality.  These PMCs were generally 
                                                 
4 See the guidance for industry on Format and Content of Proposed Risk Evaluation and Mitigation Strategies 
(REMS), REMS Assessments, and Proposed REMS Modifications, at 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM184128.pdf. 
5 See section V.D of this document for information on the requirement for REMS assessments to include 
information about the status of PMRs, PMCs, and studies and/or trials otherwise undertaken by the applicant to 
investigate a safety issue. 
 
 
2  Contains Nonbinding Recommendations 
agreed upon by FDA and the applicant.  Prior to the passage of FDAAA, FDA required 
postmarketing studies or clinical trials only in the situations described below: 
  
  Subpart H and subpart E accelerated approvals for products approved under 505(b) of the 
Act or section 351 of the PHS Act, respectively, which require postmarketing studies to 
demonstrate clinical benefit (21 CFR 314.510 and 601.41, respectively);  
  Deferred pediatric studies, where studies are required under section 505B of the Act (21 
CFR 314.55(b) and 601.27(b));6 and 
  Subpart I and subpart H Animal Efficacy Rule approvals, where studies to demonstrate 
safety and efficacy in humans are required at the time of use (21 CFR 314.610(b)(1) and 
601.91(b)(1), respectively).7 
 
Section 130(a) of the Food and Drug Administration Modernization Act of 1997 (the 
Modernization Act) amended the Act by adding a new provision requiring reports of certain 
postmarketing studies for human drug and biological products (section 506B of the Act (21 
U.S.C. 356b)).  Section 506B of the Act provides FDA with additional authority to monitor the 
progress of a PMC by requiring the applicant to submit a report annually providing information 
on the status of the PMC, which was defined to include agreed-upon commitments and required 
studies (including clinical trials).8  This report must also include the reasons, if any, for failure to 
complete the commitment.  This provision is implemented at 21 CFR 314.81(b)(2)(vii) and 
601.70. 9  Under section 506B(b) and (c), FDA is required to track these PMCs and report on 
them annually in the Federal Register.10 
 
 
B.  New FDAAA Authority and Requirements   
 
                                                 
6 See the FDA guidance for industry on How to Comply with the Pediatric Research Equity Act.  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the CDER guidance 
page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatory Information/Guidances/default.htm. 
 
7 See the FDA guidance for industry on Animal ModelsEssential Elements to Address Efficacy Under the Animal 
Rule, http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
 
8 See the guidance for industry on Reports on the Status of Postmarketing Study Commitments  Implementation of 
Section 130 of the Food and Drug Administration Modernization Act of 1997 (guidance on the status of PMCs), 
available on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ 
Guidances/default.htm.   
 
9 In addition, new drug application (NDA) applicants are required by 21 CFR 314.81(b)(2)(viii) to report annually to 
FDA on postmarketing studies or trials that are not 506B studies or trials.  Such studies or trials are not required, and 
they include chemistry, manufacturing, and controls (CMC) studies that applicants have agreed with FDA to 
conduct (CMC commitments), and all product stability studies that applicants have agreed with FDA to conduct 
(stability studies).  The reporting requirement at 21 CFR 314.81(b)(2)(viii) also includes any postmarketing study 
not included under [ 314.81](b)(2)(vii) . . . that is being performed by, or on behalf of, the applicant.  Reports on 
the status of these types of studies are not reports required under section 506B.  
 
10 Available on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-
marketingPhaseIVCommitments/default.htm. 
 
 
 
3  Contains Nonbinding Recommendations 
1.  FDA May Require Applicants to Conduct Studies and Clinical Trials 
 
Section 505(o)(3) of the Act authorizes FDA to require postmarketing studies or clinical trials at 
the time of approval or after approval if FDA becomes aware of new safety information.11  
Section 505-1(b)(3) of the Act defines new safety information to include data about a serious 
risk, or an unexpected serious risk associated with use of the drug (see Appendix A for the 
complete definition).  Even if a serious risk is known at the time of approval of the drug, more 
may be learned after approval about its frequency or severity that can be considered new safety 
information.   
 
In some cases, FDA may be concerned about a risk and believe that it is serious, but may not 
know enough about the risk to determine how to address the risk in labeling and what 
information would be appropriate to include.  In such a case, FDA can require a postmarketing 
study or clinical trial to obtain more information.  See purposes set forth in 505(o)(3)(A) below. 
 
If there is information on chemically-related or pharmacologically-related drugs, FDA may 
consider this drug class safety information when requiring a study or clinical trial.  See 
505(o)(3)(A). 
 
Section 505(o)(3)(A) states that postmarketing studies and clinical trials may be required for any 
or all of three purposes listed in section 505(o)(3)(B): 
 
  To assess a known serious risk related to the use of the drug 
  To assess signals of serious risk related to the use of the drug 
  To identify an unexpected serious risk when available data indicates the potential for a 
serious risk 
 
For the purposes of implementing section 901 of FDAAA,12 clinical trials and studies are 
defined as follows: 
  Clinical trials are any prospective investigations in which the applicant or investigator 
determines the method of assigning the drug product(s) or other interventions to one or 
more human subjects.   
  Studies are all other investigations, such as investigations with humans that are not 
clinical trials as defined above (e.g., observational epidemiologic studies), animal studies, 
and laboratory experiments.  
 
Clinical trials are one type of clinical investigation, as defined at 21 CFR 312.3(b).  For the 
purposes of this guidance, FDA has separately defined these terms as listed above because 
statutory provisions below from section 505(o)(3) of the Act differentiate between studies and 
clinical trials. 
 
                                                 
11 Defined at section 505-1(b)(3) of the Act (see Appendix A, Glossary). 
 
12 These definitions of postmarketing clinical trial and study do not affect whether the trials or studies are subject to 
the requirements of Title VIII of FDAAA (Clinical Trial Databases) and section 402(j) of the PHS Act (42 U.S.C. 
282(j)).   
 
 
4  Contains Nonbinding Recommendations 
STATUTORY PROVISIONS 
 
Under section 505(o)(3)(D)(i), before requiring a postmarketing study, FDA must find that 
adverse event reporting under section 505(k)(1) of the Act and the new pharmacovigilance 
system that will be established under section 505(k)(3) of the Act will not be sufficient to 
meet the purposes described in section 505(o)(3)(B). 
 
Under section 505(o)(3)(D)(ii), before requiring a postmarketing clinical trial, FDA must 
find that a postmarketing study will not be sufficient to meet the purposes described in section 
505(o)(3)(B). 
 
 
2.  Applicants Are Required to Report on the Status of Studies and Clinical Trials 
 
The applicant is required to provide certain information to FDA with regard to required 
postmarketing studies and clinical trials (section 505(o)(3)(E)(ii)).  Under section 
505(o)(3)(E)(ii), this information must include: 
 
  For all required postmarketing studies and clinical trials, a timetable for completion  
 
  A timetable for completion is a set of milestone dates by which we measure progress 
o
of studies and clinical trials and compliance with requirements.  These goal dates 
generally include, but are not limited to, final protocol submission date, study or 
clinical trial completion date, and final report submission date.  FDAAA does not 
include provisions to amend or change milestone dates for purposes of reporting as 
required under 21 CFR 314.81(b)(2)(vii)(a)(8)(ii-iii) and 21 CFR 601.70(b)(8)(ii-iii).  
Therefore, status reporting under these regulations will remain based on the original 
schedule. 
 
  For each study required under section 505(o)(3), periodic reports on the status of the 
study, including whether any difficulties in completing the study have been encountered 
 
  For each clinical trial required under section 505(o)(3), periodic reports on the status of 
the clinical trial, including: 
 
  whether enrollment has begun,  
o
  the number of participants enrolled, 
o
  the expected completion date, 
o
  whether any difficulties completing the clinical trial have been encountered, and 
o
  registration information with respect to the clinical trial under section 402(j) of the 
o
PHS Act (42 U.S.C. 282(j)) 
 
In addition, FDAAA requires that applicants report on each study and clinical trial 
otherwise undertaken by the applicant to investigate a safety issue (see section 
505(o)(3)(E)(ii)).  Reports on these studies and clinical trials would previously have been 
required under 21 CFR 314.81(b)(2)(viii).  
 
 
5  Contains Nonbinding Recommendations 
 
 
III.  IMPLEMENTATION OF POSTMARKETING STUDY AND CLINICAL TRIAL 
REQUIREMENTS UNDER FDAAA13   
 
Under section 505(o)(3) of the Act, FDA will require applicants to conduct a postmarketing 
study or studies or clinical trial(s) when the following conditions are met: 
 
1.  When the decision to require a postmarketing study or clinical trial is based on scientific data 
deemed appropriate by FDA, including information regarding chemically-related or 
pharmacologically-related drugs; and   
 
2.  When FDA has found  
 
a.  before requiring a postmarketing study, that adverse event reporting under section 
505(k)(1) of the Act and the new pharmacovigilance system that will be established 
under section 505(k)(3) will not be sufficient to meet the purposes described in condition 
3 below; and  
b.  before requiring a postmarketing clinical trial, that a postmarketing study will not be 
sufficient to meet the purposes in condition 3 below; and 
  
3.  When the purposes of the study or clinical trial, as described in section 505(o)(3)(B), are one 
or more of the following: 
 
  To assess a known serious risk related to the use of the drug 
  To assess signals of serious risk related to the use of the drug 
  To identify an unexpected serious risk when available data indicates the potential for a 
serious risk  
 
When these conditions are met, the Agency intends to require the study or clinical trial as a 
postmarketing requirement (PMR). 
 
We believe that the authority to require a responsible person to conduct a postapproval study or 
studies or clinical trial(s) of the drug includes the authority for FDA to describe the study or trial 
to be conducted, including how the study or trial is to be done and the population and indication.  
In other words, we can require a study or clinical trial that is well-designed and adequate to 
address the serious safety concern.   
 
Examples of studies or clinical trials that meet criteria for PMRs are provided later in this 
document, and definitions of new safety information and serious risk are included in the 
Glossary at the end of this guidance document.  The new safety information that prompts the 
postmarketing study or clinical trial after approval of a drug product will be described in the 
Agencys letter to applicants notifying them of the requirement. 
                                                 
13 Applicants conducting postmarketing studies and clinical trials must continue to comply with 21 CFR part 312 
and 21 CFR part 58 when applicable, and Health and Human Services (HHS) and FDA human subject protection 
regulations at 45 CFR part 46 and 21 CFR parts 50 and 56 when applicable. 
 
 
6  Contains Nonbinding Recommendations 
  
The purposes outlined in section 505(o)(3)(B) are all related to drug safety.  Although almost any 
study or clinical trial might be broadly construed to evaluate safety, FDA does not intend to 
consider all postmarketing studies and clinical trials as PMRs.  We will generally require PMRs 
for all studies and clinical trials with purposes that meet the criteria for assessing or identifying a 
serious risk as described above.  FDA also recognizes that many postmarketing studies and 
trials agreed upon as PMCs before FDAAA was enacted meet current standards for required 
safety studies and clinical trials under FDAAA.  However, FDA does not intend to convert these 
PMCs to PMRs, unless new safety information relevant to a delayed PMC emerges. 
 
Since FDAAA, the terms PMR and PMC are used as follows: 
 
  The term postmarketing requirement or PMR is used to describe all required postmarketing 
studies or clinical trials, including those required under FDAAA and those required under 
subpart H of 21 CFR part 314, subpart E of 21 CFR part 601, the Pediatric Research Equity 
Act, and the Animal Efficacy Rule. 
  The term postmarketing commitment or PMC is used to describe studies and clinical trials 
that applicants have agreed to conduct, but that will generally not be considered as meeting 
the statutory purposes in 505(o)(3)(B) and so will not be required.  
 
Appendix B summarizes these authorities. 
 
Described below in section III.A are the categories of postmarketing studies and clinical trials 
that will generally be considered as meeting the conditions described above for PMRs.  Section 
III.B outlines the categories of studies and clinical trials that will generally not be required by 
statute or regulation, but may be PMCs. 
 
A.  Examples of Postmarketing Requirements (PMRs) Under Section 505(o)   
 
PMRs under FDAAA generally would include, but not be limited to, the following:   
 
  Observational pharmacoepidemiologic studies are generally studies designed to assess a 
serious risk associated with a drug exposure or to quantify risk or evaluate factors that affect 
the risk of serious toxicity, such as drug dose, timing of exposure, or patient characteristics.  
To facilitate interpretation of the findings, the studies should always have a protocol, should 
include a control group, and should test prespecified hypotheses.  However, control groups 
may be omitted when there is a scientifically valid reason to exclude controls.  For a solely 
descriptive study, instead of a prespecified hypothesis, the protocol for a descriptive study 
may include clearly stated objectives for describing the safety issue, including a defined 
upper bound for detectable risk, if applicable.  Data sources for observational studies could 
include administrative health care claims data, electronic medical records, registries, 
prospectively collected observational data, or other sources of observational information. 
 
  Registries may be designed with different goals.   
  Registries established with the primary purpose of enrolling patients to 
o
mitigate a serious risk associated with a drug would be required as part 
 
 
7  Contains Nonbinding Recommendations 
of a REMS under section 505-1(f)(3)(F).  When part of a REMS, they 
are an element necessary for the safe use of the drug, and are not 
designed as a study with completion dates.  These types of registries 
would not be required as a PMR and are not described further in this 
guidance.   
  A drug may be approved with a requirement for a registry that will 
o
collect data to be analyzed in a study required as a PMR (under section 
505(o)(3)), outside of a REMS (section 505-1(f)(3)(F)).  When a 
pharmacoepidemiologic study using registry data meets the statutory 
criteria for a PMR described above in section III, the registry and the 
study will be required as a PMR. 
  A sponsor may voluntarily create a registry to serve as a repository for 
o
clinical data, such as an outcomes registry. Such a registry is not 
required as part of a PMR (section 505(o)(3)).  However, if FDA 
becomes aware of new safety information in the post approval setting, 
the sponsor could be required to conduct a PMR study, which may 
utilize the registry data.  
 
Examples of observational studies include pharmacoepidemiologic studies designed to: 
 
  Estimate the risk of a serious adverse event or toxicity associated with use of a 
drug 
  Provide estimates of absolute risk (e.g., incidence rates) for a serious adverse 
event or toxicity  
  Obtain long-term clinical outcome data, including information about potentially 
rare serious adverse events, in patients taking the drug compared to patients not 
exposed to the drug 
  Identify risk factors (e.g., patient characteristics, duration of drug use) associated 
with the occurrence of adverse events among patients exposed to specified drugs. 
  Compare pregnancy incidence, pregnancy outcomes, and/or child outcomes after 
patient drug exposure compared to patients who did not receive the drug    
 
  Meta-analyses may be designed to evaluate a safety endpoint by statistical analysis of data 
from completed studies or clinical trials.  A meta-analysis should use a prospectively 
designed study protocol and analysis plan with a comprehensive selection of relevant studies 
or clinical trials and appropriate statistical methodology.   
 
  Perform a meta-analysis of the occurrence of all-cause mortality, cardiovascular 
death, and cancer incidence and identify potential predictive factors in patients 
treated with the drug compared to control therapies in all completed randomized 
clinical trials that include the drug 
 
  Clinical trials with a safety endpoint evaluated with prespecified assessments and adequately 
powered to analyze the serious risk identified by FDA under section 505(o)(3) would be 
considered PMRs.  Although efficacy endpoints may also be evaluated, the trial should be 
 
 
8  Contains Nonbinding Recommendations 
powered to adequately assess the safety concern that gives rise to the requirement.  Examples 
include clinical trials designed to:   
 
  Evaluate the occurrence of asthma exacerbations associated with an irritative 
component of inhalation treatments for asthma in a controlled clinical trial, where 
the increased risk of drug-related exacerbation has the potential to offset the 
effectiveness of the inhaled drug 
  Determine the incidence of myocardial infarction in patients treated with the 
approved drug in a follow-on trial after approval, using the original randomized 
population 
  Evaluate differences in safety outcomes between patients withdrawn from 
treatment after some period of treatment and patients who remain on the treatment 
(randomized withdrawal trial) 
  Evaluate the potential for Q-T prolongation in a thorough Q-T clinical trial 
  Measure growth and neurocognitive function in pediatric patients treated 
chronically with the drug14 
  Evaluate safety in a particular racial or ethnic group or vulnerable population such 
as the immunocompromised14  
  Evaluate the safety of the drug in pregnant women14 
  Evaluate drug toxicity in patients with hepatic or renal impairment14 
  Evaluate long-term safety of cell and gene therapy products depending on the type 
of vector used and the inherent risk of integration 
  Evaluate the safety of a drug in patients with HIV-1 co-infected with hepatitis C 
or B14 
 
  Safety studies in animals investigating specific end-organ toxicities, including, but not 
limited to carcinogenicity and reproductive toxicity studies.  Although in most instances 
these studies are completed prior to marketing approval, they may be conducted postapproval 
for certain drugs  for example, products intended to treat serious and life-threatening 
diseases.15  If conducted postapproval, these studies would be required under 505(o).  
Examples include studies designed to: 
 
  Assess carcinogenic potential in appropriate species (e.g., mice and rats) 
  Assess the potential for reproductive toxicology in appropriate species (e.g., 
monkeys or rabbits) 
 
  Examples of in vitro laboratory safety studies that would qualify as PMRs would be studies 
designed to: 
 
                                                 
14 Patients are treated with the drug at a dose and schedule specified in the clinical trial protocol. 
 
15 See the ICH S1A guidance for industry on The Need for Long Term Rodent Carcinogenicity Studies of 
Pharmaceuticals, 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065007.htm.  
 
 
9  Contains Nonbinding Recommendations 
  Assess certain receptor affinities for any circulating or major metabolites, 
including conjugates, to evaluate the potential for off-target binding and resulting 
serious risk 
  Determine whether resistance to a drug has developed in those organisms specific 
to the labeled indication, resulting in increased serious risk 
  Define the mechanism of drug resistance for certain organisms 
  Assess the risk of cross-contamination between products that could result from 
sharing product-contacting equipment and parts 
  Validate the accuracy, precision, sensitivity, specificity, and robustness of an 
immunogenicity assay for a drug or biological product to assess an immunologic 
safety concern 
 
  Pharmacokinetic studies or clinical trials that would be PMRs include those to evaluate the 
pharmacokinetics of the drug in the labeled population or in a subpopulation at potential risk 
for high drug exposures that could lead to toxicity.  Examples include studies or clinical trials 
designed to:   
 
  Determine the optimal dose for maintenance therapy in patients with chronic renal 
disease, a population at risk for drug accumulation 
  Study the pharmacokinetic profile in a rodent model of hepatic dysfunction in 
order to evaluate the potential for toxicity in patients with liver impairment 
 
  Studies or clinical trials designed to evaluate drug interactions or bioavailability when there 
are scientific data that indicate the potential for a serious safety risk.  Examples include 
studies or clinical trials to: 
 
  Assess in vitro whether products are p-glycoprotein substrates and therefore could 
lead to increased drug concentrations and toxicity  
  Assess potential interactions of an approved drug with a frequently concomitantly 
prescribed medication 
  Evaluate whether multiple doses of an approved drug alter the metabolism of a 
sensitive CYP2C9 substrate 
  Evaluate bioavailability of an oral drug in the presence of food 
 
B.  Examples of Postmarketing Commitments (PMCs) That Are Not Required Under 
Section 505(o)(3) 
 
Generally, the following types of studies or clinical trials would not meet the statutory purposes 
for PMRs, but might be considered for agreed-upon PMCs: 
 
  Drug and biologic quality studies, including manufacturing, stability, and immunogenicity 
studies that do not have a s primary safety endpoint, such as studies designed to:  
 
  Develop an optical rotation test, collect data on commercial batches, and use the 
data to update drug substance specification standards 
 
 
10  Contains Nonbinding Recommendations 
  Evaluate immune response to concomitant vaccination(s) that are a part of routine 
U.S. immunization practice  
 
  Pharmacoepidemiologic studies designed to examine the natural history of a disease or to 
estimate background rates for adverse events in a population not treated with the drug that is 
the subject of the marketing application.  
 
  Studies and clinical trials conducted with vaccines, such as surveillance and observational 
pharmacoepidemiologic  studies when data do not suggest a serious risk or signals of serious 
risk related to the use of the vaccine and when available data do not indicate the potential for 
serious risk, such as: 
 
  A surveillance study of cases of the infectious disease targeted by the approved 
vaccine occurring in vaccinated populations; conduct product-specific surveys and 
calculate product-specific rates of infectious disease within the monitored population 
  A clinical trial conducted with vaccines in which the objective is a further 
characterization of the safety profile and the primary endpoint is not related to a 
serious risk identified by FDA under section 505(o) of the Act 
 
  Clinical trials in which the primary endpoint is related to further defining efficacy, designed 
to: 
 
  Evaluate long-term effectiveness or duration of response16 
  Evaluate efficacy using a withdrawal design 
  Evaluate efficacy in a subgroup 
 
IV.  PROCEDURES 
 
As outlined in section X.B of the Prescription Drug User Fee Act (PDUFA) Reauthorization 
Performance Goals and Procedures, FY 2008-2012,17 FDA plans to inform the applicant of the 
planned target date for communication of feedback from the review division to the applicant 
regarding PMRs and PMCs in a letter sent within 14 days of the 60-day filing date of the 
marketing application.  Generally, the designated planned target date will be no later than 1 
month prior to the PDUFA goal date.   
 
FDA plans to communicate a list of potential PMRs and PMCs, clearly delineated as to which 
are required and which may be agreed upon, to the applicant near the target date along with a 
brief rationale for why FDA thinks these studies and clinical trials are necessary.  The list will 
also include a request for a proposed timetable for completion.  
 
                                                 
16 Not related to a subpart H requirementefficacy trials that are not required as part of accelerated approval (AA).  
Clinical trials required under AA are PMRs. 
 
17 Attachment to Letter to Chairman Dingell from Michael O. Leavitt, Secretary HHS, September 27, 2007,   
http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119243.htm. 
 
 
 
11  Contains Nonbinding Recommendations 
The applicant will have the opportunity to discuss the design and conduct of the PMRs and 
PMCs, as well as the overall goal, with the FDA review team.  The applicant should provide 
prompt feedback and engage in discussion as needed with the FDA review team to facilitate 
completion of clearly written and well-designed PMRs and PMCs.  The applicant should also 
provide a timetable for completion of the study or clinical trial for the PMRs and a schedule for 
milestone submissions and final reports for PMCs.18  For PMRs and PMCs, the first milestone is 
generally the final protocol submission date.  Final implies that the applicant has submitted a 
protocol, the FDA review team has sent comments to the applicant, and the protocol has been 
revised as needed to meet the goal of the study or clinical trial.  Thus, the date for this milestone 
should be selected to allow for the discussion period needed to create a well-designed study or 
clinical trial.  As described in section II.B.2 of this guidance, public status of PMRs and PMCs is 
based on the original schedule, so appropriate and realistic dates should be proposed. 
 
The FDA review team will (1) review the potential study or clinical trial designs to make sure 
they will serve the purposes of the study or clinical trial and (2) assess whether the proposed 
timetable will be realistic and will provide for timely completion of the study or clinical trial. 
 
FDAAA gives FDA the authority to require PMRs without prior agreement from the applicant.    
For PMCs, the applicant should submit a written agreement to conduct the PMCs.  The PMRs 
and PMCs, and their milestones and dates, will be included in the action letter issued at the 
completion of the application review. 
 
 
V.  REPORTING 
 
Except when otherwise provided, an applicant may satisfy its obligation to periodically report 
on the status of PMRs and other studies and clinical trials undertaken to investigate a safety issue 
by submitting the annual status reports required under 21 CFR 314.81 or 601.70 if the required 
elements of information about the status of the PMR information, set forth in section 
505(o)(3)(E)(ii), are accurately and completely provided in that report.  Therefore, applicants 
will be able to report on both PMRs and PMCs at the same time and use the format 
recommended in the guidance on the status of PMCs,19 as long as the applicant includes the 
required PMR status information, which is described below.  On a case-by-case basis, a PMR 
may impose an additional obligation to periodically report at specified milestones.  
 
A REMS assessment also must include information about the status of PMRs, PMCs, and studies 
and/or trials otherwise undertaken by the applicant to investigate a safety issue.  See section 505-
1(g)(3).  This requirement is discussed below.  
 
A.  PMR Reports 
 
                                                 
18 Milestone dates are a series of goal dates (e.g., final protocol submission, study or clinical trial completion date, 
final report submission) by which we measure progress of studies and clinical trials and compliance with 
requirements. 
 
19 The guidance on the status of PMCs will be updated to reflect FDAAA-related changes.  
 
 
12  Contains Nonbinding Recommendations 
For each PMR required under FDAAA, the applicant must periodically report on the status of the 
study or clinical trial (see section 505(o)(3)(E)(ii)).  For clinical trials, the report must also 
include whether enrollment has begun, the number of participants enrolled, the expected 
completion date, whether any difficulties completing the clinical trials have been encountered, 
and registration information as required under section 402(j) of the PHS Act (see section 
505(o)(3)(E)(ii)).  We recognize that some of the information required for clinical trial reporting 
is also relevant to observational pharmacoepidemiologic studies, and FDA will interpret the 
requirement to include this information as applicable to all studies or clinical trials performed in 
humans.  Registration information for clinical trials should include documentation that the PMR 
is registered in accordance with Title VIII of FDAAA.20  
 
B.  PMC Reports 
 
For each PMC under section 506B of the Act, applicants are required to report annually on the 
status of the studies or clinical trials (21 U.S.C. 356b(a); 21 CFR 314.81(b)(2)(vii) and 
601.70(b)).  The recommendations regarding compliance with section 506B may be found in the 
guidance on the status of PMCs. 
 
C.  Reports for Studies and Clinical Trials Otherwise Undertaken 
 
For studies or clinical trials otherwise undertaken by the applicants to investigate a safety issue, 
the applicant must report to FDA under section 505(o)(3)(E)(ii) of the Act and 21 CFR 
314.81(b)(2)(viii).  These studies or clinical trials are neither required by FDA nor agreed upon 
between FDA and the applicant.  They may include investigations initiated by an applicant for 
many reasons without prior discussion with or notification to FDA.  These studies and clinical 
trials must be summarized in a section of the annual report (drugs) or annual status report 
(biologics). 
 
D.  Reports in REMS Assessments 
 
In addition, section 505-1(g)(3) of the Act at paragraphs (B) and (C) (21 U.S.C. 355-1(g)(3)(B) 
and (C)) requires that risk evaluation and mitigation strategy (REMS) assessments include the 
status of postapproval studies and clinical trials required under section 505(o) and those that are 
otherwise undertaken to investigate a safety issue.  PMRs are not part of REMS and are not 
submitted as part of the REMS, but must be described in REMS assessments.  Applicants can 
satisfy these requirements in their REMS assessments by referring to relevant information 
included in the most recent annual report required under section 506B of the Act and 21 CFR 
314.81(b)(2)(vii) or 21 CFR 601.70, and including any material or significant updates to the 
status information since the annual report was prepared.  Failure to comply with the REMS 
assessment provisions in section 505-1(g) could result in enforcement action.  
 
                                                 
20 See FDAs guidance on Compliance with Section 402(j) of The Public Health Service Act, Added By Title VIII of 
The Food and Drug Administration Amendments Act of 2007, available on the Internet at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
 
 
 
13  Contains Nonbinding Recommendations 
E.  Summary 
 
Applicants may generally report on PMRs, PMCs, and studies or clinical trials undertaken by the 
applicant to investigate a safety issue in periodic reports (e.g., annually) that are already required 
by our regulations.  On a case-by-case basis, a PMR may impose an additional obligation to 
periodically report at specified milestones.  In addition, although most PMRs and PMCs will 
be conducted under the IND for a drug, annual reports are required under the NDA/BLA.  When 
multiple related applications exist (e.g., several formulations of the same drug with the same 
applicant), unified reporting, consistent with past practice, may be considered.  An applicant who 
proposes unified reporting should discuss the proposal with the review division.  REMS 
assessments, submitted under the NDA/BLA, are required under separate schedules.  While the 
REMS assessments may reference the annual report for the required PMR reporting, the annual 
report does not replace the REMS assessment. 
 
 
VI.  DISPUTE RESOLUTION 
 
The applicant may appeal a requirement to conduct a postmarketing study or clinical trial using 
the usual dispute resolution procedures (see the guidance for industry on Formal Dispute 
Resolution:  Appeals Above the Division Level)21 (see section 505(o)(3)(F) of the Act). 
 
 
VII.  ENFORCEMENT OF REQUIREMENTS FOR POSTMARKETING STUDIES 
AND CLINICAL TRIALS 
 
The new amendments to the Act give FDA authority to enforce the section 505(o)(3)(E)(ii) 
requirements for postmarketing studies and clinical trials.22  An applicants failure to comply 
with the timetable, periodic report submissions, and other requirements of section 
505(o)(3)(E)(ii) will be considered a violation unless the applicant demonstrates good cause for 
the noncompliance.  Under section 505(o)(3)(E)(ii) of the Act, FDA is authorized to determine 
what constitutes good cause.  In addition, under section 505(p)(2), failure to conduct a 
postmarketing study or trial required under subparts H and E (21 CFR 314.510 and 601.41) may 
result in enforcement action. 
 
Enforcement action could include one or more of the following: 
 
  Charges under section 505 of the Act.  A responsible person23 may not introduce or deliver 
into interstate commerce the drug involved if the applicant is in violation of section 505(o) 
                                                 
21 Available on the Internet at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ 
Guidances/default.htm. 
 
22 FDA has the authority to review records upon inspection of postmarketing studies and clinical trials, including 
underlying data and source documents (see section 505(k) of the Act). 
 
23 Defined at section 505(o)(2)(A) of the Act. 
 
 
14  Contains Nonbinding Recommendations 
(postmarketing study and clinical trial requirements) (see section 505(o)(1) of the Act) or 
505(p)(2) (certain postmarketing studies).   
 
  Misbranding charges.  A drug is misbranded under section 502(z) of the Act (21 U.S.C. 
332(z)) if the applicant for that drug violates postmarketing study or clinical trial 
requirements, including those outlined in section V above.   
 
  Civil monetary penalties.  Under section 303(f)(4)(A) of the Act (21 U.S.C. 333(f)(4)(A)), 
an applicant that violates postmarketing study or clinical trial requirements may be subject 
to civil monetary penalties of up to $250,000 per violation, but no more than $1 million for 
all violations adjudicated in a single proceeding.  These penalties increase if the violation 
continues more than 30 days after FDA notifies the applicant of the violation.  The penalties 
double for the following 30-day period and continue to double for subsequent 30-day 
periods, up to $1 million per period and $10 million for all violations adjudicated in a single 
proceeding.  In determining the amount of a civil penalty, FDA will consider the applicants 
efforts to correct the violation (see section 303(f)(4)(B) of the Act).  
 
   
 
 
15  Contains Nonbinding Recommendations 
APPENDIX A 
 
GLOSSARY 
 
The following definitions of terms are from section 505-1(b) of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 355-1(b)). 
 
Adverse drug experience includes an adverse event occurring in the course of the use of the 
drug in professional practice. 
 
New safety information with respect to a drug, means information derived from a clinical trial, 
an adverse event report, a postapproval study (including a study under section 505(o)(3)), or 
peer-reviewed biomedical literature; data derived from the postmarket risk identification and 
analysis system under section 505(k); or other scientific data deemed appropriate by the 
Secretary (of Health and Human Services) about   
(A) a serious risk or unexpected serious risk associated with use of the drug that the 
Secretary has become aware of (that may be based on a new analysis of existing 
information) since the drug was approved, since the risk evaluation and mitigation 
strategy was required, or since the last assessment of the approved risk evaluation 
and mitigation strategy for the drug; or 
(B) the effectiveness of the approved risk evaluation and mitigation strategy for the 
drug obtained since the last assessment of such strategy. 
 
Serious adverse drug experience is an adverse drug experience that  
(A) results in  
(i) death; 
(ii) an adverse drug experience that places the patient at immediate risk of 
death from the adverse drug experience as it occurred (not including an adverse 
drug experience that might have caused death had it occurred in a more severe 
form); 
(iii) inpatient hospitalization or prolongation of existing hospitalization; 
(iv) a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions; or 
(v) a congenital anomaly or birth defect; or  
(B) based on appropriate medical judgment, may jeopardize the patient and may 
require a medical or surgical intervention to prevent an outcome described under 
subparagraph (A).   
 
Serious risk means a risk of a serious adverse drug experience. 
 
Signal of a serious risk means information related to a serious adverse drug experience 
associated with use of a drug and derived from  
    (A) a clinical trial; 
    (B) adverse event reports; 
    (C) a postapproval study, including a study under section 505(o)(3);  
    (D) peer-reviewed biomedical literature; 
 
 
16  Contains Nonbinding Recommendations 
    (E) data derived from the postmarket risk identification and analysis system under 
section 505(k)(4); 
    (F) other scientific data deemed appropriate by the Secretary. 
 
Unexpected serious risk means a serious adverse drug experience that is not listed in the labeling 
of a drug, or that may be symptomatically or pathophysiologically related to an adverse drug 
experience identified in the labeling, but differs because of greater severity, specificity, or 
prevalence. 
 
FDA interprets these definitions to include safety information related to a class effect, not 
apparently limited to a single member of the class for structural, mechanistic, or other reasons.  
 
 
 
 
17  Contains Nonbinding Recommendations 
APPENDIX B 
 
PMR AND PMC AUTHORITIES 
 
Postmarketing Requirement  Postmarketing Commitment 
Authorities  Authority 
Pediatric Research under Section 505B of the  Agreed Upon Postmarketing Studies and 
Act:  Clinical Trials: 
   
  21 CFR 314.55(b) (drugs)    21 CFR 312.85 
  21 CFR 601.27(b) (biologics)   
 
Accelerated Approval regulations:   
 
  21 CFR 314.510, Subpart H (drugs) 
  21 CFR 601.41, Subpart E (biologics) 
 
Animal Rule:   
 
  21 CFR 314.610(b)(1), Subpart I 
(drugs) 
  21 CFR 601.91(b)(1), Subpart H 
(biologics) 
   
FDAAA, Section 901:   
  Section 505(o)(3) of the FDCA 
 
 
 
 
18