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). 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s 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 Models—Essential 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/PostmarketingPhaseIVCommitments/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 

o	 A timetable for completion is a set of milestone dates by which we measure progress 

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: 

o 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 

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 

Agency’s 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. 

o	 Registries established with the primary purpose of enrolling patients to 

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. 

o	 A drug may be approved with a requirement for a registry that will 

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. 

o	 A sponsor may voluntarily create a registry to serve as a repository for 

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 requirement—efficacy 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 FDA’s 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 applicant’s 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 applicant’s 

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); 

16
 
 

 

 

Contains Nonbinding Recommendations 

(D) peer-reviewed biomedical literature; 

(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 

Authorities 

Postmarketing Commitment 

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