Guidance for Industry and Investigators Safety Reporting equirement

Guidance for Industry

and Investigators

Safety Reporting Requirements

for INDs and BA/BE Studies-

Small Entity Compliance Guide

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)

December 2012

Drug Safety

Guidance for Industry

and Investigators

Safety Reporting Requirements

for INDs and BA/BE Studies-

Small Entity Compliance Guide

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or

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/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/

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)

December 2012

Drug Safety

Contains Nonbinding Recommendations

TABLE OF CONTENTS

I. 1

II. 1

III. QUESTIONS 2

Contains Nonbinding Recommendations

Guidance for Industry and Investigators1

Safety Reporting Requirements for INDs and BA/BE Studies-

Small Entity Compliance Guide

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 is intended to help small businesses understand and comply with FDA’s safety

reporting regulations for human drug and biological products that are being investigated under an

investigational new drug application (IND) and for drugs that are the subjects of bioavailability

(BA) and bioequivalence (BE) studies that are exempt from the IND requirements. The FDA has

prepared this guidance in accordance with section 212 of the Small Business Regulatory

Enforcement Fairness Act (Public Law 104-121).

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

In the Federal Register of September 29, 2010,2 FDA published a final rule that revised the IND

safety reporting requirements for human drug and biological products under 21 CFR part 312,

and added safety reporting requirements for persons conducting BA and BE studies under 21

CFR part 320. The final rule revised the definitions used for safety reporting and made clear

when to submit expedited safety reports. FDA issued a guidance for industry and investigators,

entitled Safety Reporting Requirements for INDs and BA/BE Studies that is intended to help

sponsors and investigators comply with the revised requirements for IND safety reporting (21

CFR 312.32 and 312.64(b)) and safety reporting for BA/BE studies (21 CFR 320.31(d)).3 This

This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research

(CDER) in conjunction with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug

Administration.

2 75 FR 59935, September 29, 2010.

3 FDA guidance for industry and investigators on Safety Reporting Requirements for INDs and BA/BE Studies,

/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/.

1

Contains Nonbinding Recommendations

Small Entity Compliance Guide is intended to complement that guidance and provide further

clarification to small businesses by answering several frequently asked questions from

investigators and sponsors regarding the amended safety reporting requirements.

III. QUESTIONS AND ANSWERS

Question: Do the amended safety reporting requirements for INDs and BA/BE studies

apply to small entities?

Answer: Yes, small entities are required to follow the safety reporting regulations for INDs

under 21 CFR 312.32, 312.64(b), and for BA/BE studies under 21 CFR 320.31(d)(3).

Question: What is a sponsor-investigator? Do these safety reporting regulations apply to

sponsor-investigators?

Answer: A sponsor-investigator, as defined in § 312.3, is ‘‘an individual who both initiates

and conducts an investigation, and under whose immediate direction the

investigational drug is administered or dispensed. The term does not include any

person other than an individual. The requirements applicable to a sponsor-investigator under this part [312] include both those applicable to an investigator and

a sponsor.’’ Therefore, the amended IND safety reporting requirements under §§

312.32 and 312.64(b) apply to a study conducted by a sponsor-investigator (often

called an investigator-initiated study).

Question: How do I comply with the safety reporting requirements if I am a sponsor or

sponsor-investigator conducting one trial and do not have access to all of the

safety data from other entities (e.g., a commercial sponsor)?

Answer: For IND safety reporting, the Agency recognizes that a sponsor or sponsor-investigator may not have access to the complete safety data maintained by a

commercial sponsor, but sponsors and sponsor-investigators are required to evaluate

all safety information that is available to them to determine whether the information

qualifies for reporting (21 CFR 312.32). For example, sponsors and sponsor-investigators should examine reports in the scientific literature and perform literature

searches to actively seek new safety information about the drug under investigation.

To protect human subjects, the Agency recommends that entities that provide drug to

or receive drug from other entities share safety information with each other.

Question: The regulations require reporting in an IND safety report when an aggregate

analysis of specific events observed in a clinical trial indicates those events occur

more frequently in the drug treatment group than in a control group (21 CFR

312.32(c)(1)(i)(C)). How do sponsors comply with this aggregate reporting

requirement?

Answer: For IND safety reporting in general, sponsors should have a predefined safety

monitoring plan that includes processes and procedures for the review, evaluation,

2

Contains Nonbinding Recommendations

and management of safety information. For reporting events in the aggregate,

sponsors should perform an aggregate analysis of specific events both for individual

studies and across all studies, including across INDs of the drug, to determine

whether they meet the criteria for expedited reporting under 21 CFR

312.32(c)(1)(i)(C) or 312.32(c)(1)(iv). As discussed in the previous question, the

sponsor should perform these analyses on the data available to them.

Question: Does this final rule change how sponsors report safety information in the IND

annual report (21 CFR 312.33)?

Answer: No, the revised IND safety reporting requirements did not make any changes to the

IND annual report requirements.

Question: Does this final rule change what investigators report to their institutional review

board (IRB)?

Answer: No, the final rule did not change the reporting requirements to IRBs. FDA’s

guidance on Adverse Event Reporting to IRBs – Improving Human Subject

Protection provides recommendations on reporting to IRBs.4

Question: Where can I find additional information on the safety reporting requirements

for INDs and BA/BE studies?

Answer: For information on the safety reporting requirements for INDs and BA/BE studies,

see FDA’s guidance for industry and investigators on Safety Reporting Requirements

for INDs and BA/BE Studies.5

Question: If I have questions about how to comply with this rule, who should I contact at

FDA?

Answer: For IND safety reporting, you should contact the review division in the Center for

Drug Evaluation and Research or Center for Biologics Evaluation and Research that

has responsibility for review of the IND. For BA/BE safety reporting, you should

contact OGD-PremarketSafetyReports@.

4

Guidance for clinical investigators, sponsors, and IRBs on Adverse Event Reporting to IRBs – Improving Human

Subject Protection, /Drugs/GuidanceComplianceRegulatoryInformation/Guidances/.

5 See footnote 3 for the link to that guidance.

3