Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 59935 

Subtitle VII, Aviation Programs, 

describes in more detail the scope of the 

agency’s authority. 

This rulemaking is promulgated 

under the authority described in 

Subtitle VII, Part A. Subpart I, Section 

40103. Under that section, the FAA is 

charged with prescribing regulations to 

assign the use of airspace necessary to 

ensure the safety of aircraft and the 

efficient use of airspace. This regulation 

is within the scope of that authority as 

it amends controlled airspace at 

Smithfield, NC. 

Lists of Subjects in 14 CFR Part 71 

Airspace, Incorporation by reference, 

Navigation (Air). 

Adoption of the Amendment 

■ In consideration of the foregoing, the 

Federal Aviation Administration 

amends 14 CFR Part 71 as follows: 

PART 71—DESIGNATION OF CLASS A, 

B, C, D, AND E AIRSPACE AREAS; AIR 

TRAFFIC SERVICE ROUTES; AND 

REPORTING POINTS 

■ 1. The authority citation for Part 71 

continues to read as follows: 

Authority: 49 U.S.C. 106(g); 40103, 40113, 

40120; E.O. 10854, 24 FR 9565, 3 CFR, 

1959–1963 Comp., p. 389. 

§ 71.1 [Amended] 

■ 2. The incorporation by reference in 

14 CFR 71.1 of Federal Aviation 

Administration Order 7400.9U, 

Airspace Designations and Reporting 

Points, dated August 18, 2010, and 

effective September 15, 2010, is 

amended as follows: 

Paragraph 6005 Class E Airspace Extending 

Upward From 700 feet or More Above the 

Surface of the Earth 

* * * * * 

ASO NC E5 Smithfield, NC [Amended] 

Johnston County Airport, NC 

(Lat. 35°32′27′′ N., long 78°23′25′′ W.) 

Johnston Memorial Hospital 

Point In Space Coordinates 

(Lat. 35°31′23′′ N., long 78°20′35′′ W.) 

That airspace extending upward from 700 

feet above the surface within a 6.5-mile 

radius of the Johnston County Airport and 

within 2 miles each side of the 023° bearing 

from the airport extending from the 6.5-mile 

radius to 10.2 miles northeast of the Johnston 

County Airport and within a 6-mile radius of 

the point in space (lat.35°31′23′′ N., long. 

78°20′35′′ W.) serving Johnston Memorial 

Hospital. 

Issued in College Park, Georgia, on 

September 17, 2010. 

Myron A. Jenkins, 

Acting Manager, Operations Support Group, 

Eastern Service Center, Air Traffic 

Organization. 

[FR Doc. 2010–24113 Filed 9–28–10; 8:45 am] 

BILLING CODE 4910–13–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 312 and 320 

[Docket No. FDA–2000–N–0108] (formerly 

Docket No. 00N–1484) 

RIN 0910–AG13 

Investigational New Drug Safety 

Reporting Requirements for Human 

Drug and Biological Products and 

Safety Reporting Requirements for 

Bioavailability and Bioequivalence 

Studies in Humans 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is amending its 

regulations governing safety reporting 

requirements for human drug and 

biological products subject to an 

investigational new drug application 

(IND). The final rule codifies the 

agency’s expectations for timely review, 

evaluation, and submission of relevant 

and useful safety information and 

implements internationally harmonized 

definitions and reporting standards. The 

revisions will improve the utility of IND 

safety reports, reduce the number of 

reports that do not contribute in a 

meaningful way to the developing safety 

profile of the drug, expedite FDA’s 

review of critical safety information, 

better protect human subjects enrolled 

in clinical trials, subject bioavailability 

and bioequivalence studies to safety 

reporting requirements, promote a 

consistent approach to safety reporting 

internationally, and enable the agency 

to better protect and promote public 

health. 

DATES: This rule is effective March 28, 

2011. 

FOR FURTHER INFORMATION CONTACT: 

For information on IND safety 

reporting for human drug products: 

Janet Norden, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 51, rm. 6324, 

Silver Spring, MD 20993–0002, 301– 

796–2500. 

For information on IND safety 

reporting for human biological products: 

Laura Rich, Center for Biologics 

Evaluation and Research, Food and 

Drug Administration,1401 Rockville 

Pike, suite 200N, Rockville, MD 20852– 

1448, 301–827–6210. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Background 

A. Rationale for Rulemaking 

B. The Proposed Rule 

II. Overview of the Final Rule 

A. Definitions 

B. Review of Safety Information 

C. Reporting Requirements 

III. Comments on the Proposed Rule 

A. Definitions—Proposed § 312.32(a) 

B. Review of Safety Information— 

Proposed § 312.32(b) 

C. IND Safety Reports (Requirement 

for Minimum Data Set)—Proposed 

§ 312.32(c) 

D. Serious and Unexpected SADR— 

Proposed § 312.32(c)(1)(i) 

E. Alternative Reporting 

Arrangements 

F. Unblinding 

G. Information Sufficient to Consider 

Product Administration Changes— 

Proposed § 312.32(c)(1)(ii) 

H. Submission of Written Reports— 

Proposed § 312.32(c)(1)(iii) 

I. Telephone and Facsimile 

Transmission Safety Reports— 

Proposed § 312.32(c)(2) 

J. Investigations of Marketed Drugs— 

Proposed § 312.32(c)(4) 

K. Followup—Proposed § 312.32(d) 

L. Disclaimer—Proposed § 312.32(e) 

M. Annual Reports 

N. Investigator Reports—Proposed 

§ 312.64(b) 

O. Bioavailability and Bioequivalence 

Requirements—Proposed 

§ 320.31(d) 

P. Reports to Investigators and IRBs 

Q. Miscellaneous Comments 

R. Initial Analysis of Impacts and 

Paperwork Burden Estimates 

IV. Legal Authority 

V. Environmental Impact 

VI. Analysis of Impacts 

A. Need for the Regulation 

B. Costs of the Regulation (to Prepare 

and Submit Safety Reports) 

C. Benefits of the Regulation 

D. Final Regulatory Flexibility 

Analysis 

VII. Paperwork Reduction Act of 1995 

VIII. Executive Order 13132: Federalism 

IX. References 

I. Background 

In the Federal Register of March 14, 

2003 (68 FR 12406), FDA issued a 

proposed rule to revise its regulations 

governing pre- and postmarketing safety 


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59936 Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 

1For the purposes of this document, unless 

otherwise specified, all references to ‘‘drugs’’ or 

‘‘drug products’’ include human drug products and 

biological products that are also drugs. 

reporting for human drug and biological 

products1, which appear in parts 310, 

312, 314, 320, 600, 601, and 606 (21 

CFR parts 310, 312, 314, 320, 600, 601, 

and 606). The proposed revisions 

represented a major effort to clarify and 

integrate several safety reporting rules 

and guidance documents that had been 

issued by international organizations 

and by FDA dating back to the 1990s. 

The background for and description of 

these regulations and guidance 

documents are described in the 

preamble of the proposed rule (68 FR 

12406 at 12407 to 12410, Figure 1). The 

proposal called for the submission of 

comments by July 14, 2003. At the 

request of industry, and to provide all 

interested persons additional time to 

comment, the comment period was 

extended until October 14, 2003 (68 FR 

36527, June 18, 2003). 

FDA received numerous comments in 

response to the proposed rule, many of 

which stated that the proposal would 

not meet its stated goals and requested 

that the agency reevaluate specific 

aspects of the proposal. FDA agreed 

with some of these comments and has 

reevaluated and revised aspects of the 

proposal. To make the rulemaking 

process more manageable, FDA has 

decided to issue revisions to the 

premarketing and postmarketing safety 

reporting regulations in two separate 

rulemakings. By separating these rules, 

the agency has been able to reevaluate 

and refine each requirement in the 

premarketing and postmarketing 

settings to better ensure that the rules 

will achieve their goals. 

This rule finalizes revisions to the 

IND safety reporting regulations found 

in part 312 and the safety reporting 

requirements for bioavailability and 

bioequivalence studies found in part 

320. The agency is working on revisions 

to the postmarketing safety reporting 

regulations found in parts 310, 314, 600, 

601, and 606 separately, and will 

address these sections in a future rule. 

Therefore, revisions to and comments 

about postmarketing safety reporting 

requirements found in parts 310, 314, 

600, 601, and 606 are not addressed in 

this rulemaking. This document 

discusses information relevant to and 

comments about the proposed revisions 

found in parts 312 and 320. 

A. Rationale for Rulemaking 

In the proposed rule (68 FR 12406 at 

12412 to 12415), FDA described its 

goals for the proposed rulemaking. 

Many of the stated goals were primarily 

applicable to postmarketing safety 

reporting, but revising and clarifying the 

IND safety reporting requirements was 

also a critical component of FDA’s 

stated efforts to: (1) Improve the overall 

quality of safety reporting, thereby 

strengthening the agency’s ability to 

review critical safety information, (2) 

monitor the safety of human drug and 

biological products, and (3) harmonize 

safety reporting internationally. Each of 

these is discussed in turn in this 

document. 

First, the revisions to the IND safety 

reporting requirements will improve the 

overall quality of safety reporting and 

the agency’s ability to review critical 

safety information by ensuring that the 

information that FDA receives in an IND 

safety report is relevant and useful. 

Under former regulations, there may 

have been over-reporting of serious 

adverse events for which there was little 

reason to believe that the drug had 

caused the event, complicating or 

delaying FDA’s ability to detect a safety 

signal. In this final rule, FDA clarifies 

definitions, provides examples of the 

types of evidence that suggest a causal 

relationship for purposes of reporting a 

suspected adverse reaction to the IND 

and participating investigators, and 

revises the requirements for expedited 

reporting of serious and unexpected 

suspected adverse reactions to the IND. 

The final rule also allows sponsors to 

arrange alternative formats and/or 

frequencies for reporting and provides 

that study endpoints must not be 

submitted as IND safety reports except 

in unusual cases. These revisions not 

only have an impact on which reports 

are sent to FDA and participating 

investigators, but also affect the reports 

that are sent by investigators to 

Institutional Review Boards (IRBs). 

These revisions and clarifications will 

minimize reports that do not contribute 

to FDA’s understanding of the 

developing safety profile of the drug and 

decrease the number of uninterpretable 

reports (so-called ‘‘noise’’) in the system. 

In addition, the revisions and 

clarifications will help to make clear 

under what circumstances the study 

blind should be broken and when 

unblinding is unnecessary. Ultimately, 

these revisions and clarifications should 

contribute toward more useful adverse 

reaction information and more effective 

monitoring of clinical trials. 

Second, by requiring expedited 

reports of certain safety information that 

was not reported expeditiously under 

former IND safety reporting 

requirements or bioavailability or 

bioequivalence requirements, the final 

rule will help FDA monitor the safety of 

human drug and biological products 

and better protect human subjects 

enrolled in clinical trials. Under the 

final rule, FDA will receive expedited 

reports of: 

• Findings from clinical studies, 

epidemiological studies or pooled 

analyses of multiple studies that suggest 

a significant risk in humans exposed to 

the drug, 

• Serious suspected adverse reactions 

that occur at an increased rate than 

listed in the protocol or investigator 

brochure, and 

• Serious adverse events from 

bioavailability and bioequivalence 

studies. 

By receiving these reports 

expeditiously, FDA will be better able to 

monitor and evaluate the drug’s safety. 

Finally, FDA had proposed certain 

revisions to its IND safety reporting 

requirements to harmonize the 

regulations with recommendations by 

the International Conference on 

Harmonisation of Technical 

Requirements for Registration of 

Pharmaceuticals for Human Use (ICH) 

and by the World Health Organization’s 

Council for International Organizations 

of Medical Sciences (CIOMS), and 

which have been adopted by the 

European Union (EU) (Ref. 1). In the 

preamble to the proposed rule (68 FR 

12406 at 12415, table 4), FDA detailed 

the specific proposed revisions to the 

definitions and reporting standards 

based on international 

recommendations in the ICH guidance 

‘‘E2A Clinical Safety Data Management: 

Definitions and Standards for Expedited 

Reporting’’ (60 FR 11284, March 1, 1995) 

(ICH E2A guidance). FDA received 

numerous comments, described in more 

detail in section III of this document, 

stating that certain of FDA’s proposed 

revisions were inconsistent with how 

the provisions are interpreted and 

implemented in other member ICH 

nations. After reviewing the comments 

and after discussions with our ICH 

partners, FDA has revised the 

definitions and reporting standards to 

be as consistent as possible with 

international definitions and standards, 

recognizing that there may be 

inconsistencies within ICH documents 

and among the other member ICH 

nations’ interpretations of these 

definitions and standards. 

B. The Proposed Rule 

The following describes the proposed 

revisions to the requirements in parts 

312 and 320. FDA proposed the 

following revisions to § 312.32 on IND 

safety reports: 

• Replace the defined phrase 

‘‘associated with the use of the drug’’ 


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Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 59937 

with the term ‘‘suspected adverse drug 

reaction (SADR),’’ 

• Require submission of expedited 

reports of ‘‘information sufficient to 

consider product administration 

changes,’’ 

• Make it clear that safety reports of 

overall findings or data in the aggregate 

must be submitted in a narrative format, 

• Permit the determination that an 

SADR is life-threatening to be based on 

the opinion of either the investigator or 

sponsor (as opposed to only the 

investigator), 

• Require that the sponsor notify FDA 

and all participating investigators of 

each SADR that is both serious and 

unexpected, based on the opinion of 

either the investigator or sponsor (as 

opposed to only the sponsor), 

• Require a ‘‘‘‘minimum data set’’ for 

each report of an SADR submitted to 

FDA, and 

• Clarify the sources of information 

that sponsors must review for safety 

surveillance and reporting purposes. 

FDA proposed the following revision 

to § 312.64(b): 

• Make it clear that the investigator 

must report to the sponsor any serious 

SADR immediately and any other SADR 

promptly, unless otherwise specified in 

the protocol or investigator’s brochure. 

FDA proposed the following revision 

to § 320.31(d): 

• Make bioavailability and 

bioequivalence studies subject to IND 

safety reporting requirements. 

II. Overview of the Final Rule 

This final rule amends parts 312 and 

320 of FDA regulations by revising the 

requirements for IND safety reporting 

and for bioavailability and 

bioequivalence studies. This final rule 

reflects revisions the agency made in 

response to comments on the March 

2003 proposal (addressed in detail in 

section III of this document) and other 

revisions, including editorial changes to 

clarify provisions and support the 

agency’s plain language initiative 

(addressed in this section). 

A. Definitions 

The definitions section for the IND 

safety reporting regulations (§ 312.32(a)) 

now includes the following five terms: 

• Adverse event, 

• Life-threatening adverse event or 

life-threatening suspected adverse 

reaction, 

• Serious adverse event or serious 

suspected adverse reaction, 

• Suspected adverse reaction, and 

• Unexpected adverse event or 

unexpected suspected adverse reaction. 

FDA has revised and clarified terms 

and definitions that were in the 

proposed rule. First, as discussed in 

detail in section III of this document, 

the two terms ‘‘adverse event’’ and 

‘‘suspected adverse reaction’’ replace the 

proposed definition of ‘‘suspected 

adverse drug reaction (SADR).’’ The 

definitions ‘‘adverse event’’ and 

‘‘suspected adverse reaction’’ also 

replace the phrase ‘‘associated with the 

use of the drug’’ defined in former 

§ 312.32(a). The definitions of the terms 

‘‘adverse event’’ and ‘‘suspected adverse 

reaction’’ make clear a distinction in the 

degree of evidence of a causal 

relationship between the drug and the 

adverse event within these terms. 

Second, the final rule requires that the 

determination for reporting purposes 

about whether an adverse event or 

suspected adverse reaction is ‘‘lifethreatening’’ or ‘‘serious’’ be based on the 

opinion of either the investigator or 

sponsor. FDA had proposed this 

revision for the definition of ‘‘lifethreatening SADRs,’’ and the agency 

decided that the determination about 

whether an adverse event or suspected 

adverse reaction is ‘‘serious’’ is 

comparable to the determination of 

whether it is life-threatening. Therefore, 

FDA revised the definition ‘‘serious 

adverse event or serious suspected 

adverse reaction’’ to specify that the 

determination of seriousness be based 

on the opinion of either the investigator 

or sponsor. In addition, FDA eliminated 

the definition of ‘‘disability’’ as a 

separate term and includes the meaning 

of the term in the definition of ‘‘serious 

adverse event or serious suspected 

adverse reaction.’’ 

Third, the final rule makes clear what 

adverse events or suspected adverse 

reactions are considered unexpected. 

The proposed definition of ‘‘unexpected 

SADR’’ included the following sentence 

from the then-current definition for 

‘‘unexpected adverse drug experience’’ 

(with minor clarification): ‘‘‘Unexpected’ 

as used in this definition, refers to an 

SADR that has not been previously 

observed (e.g., in the investigator 

brochure); it does not refer to an SADR 

that might be anticipated from the 

pharmacological properties of the drug 

product.’’ To this clarification, FDA 

proposed to add the following new 

sentence: ‘‘SADRs that are mentioned in 

the investigator’s brochure as occurring 

with a class of drugs but not specifically 

mentioned as occurring with the 

particular drug are considered 

unexpected.’’ In this final rule, FDA 

combined these proposed sentences to 

read as follows: ‘‘‘Unexpected,’ as used 

in this definition, also refers to adverse 

events or suspected adverse reactions 

that are mentioned in the investigator 

brochure as occurring with a class of 

drugs or as anticipated from the 

pharmacological properties of the drug, 

but are not specifically mentioned as 

occurring with the particular drug under 

investigation.’’ This revision makes clear 

that adverse events that have not been 

previously observed with the drug 

under investigation, but are predicted to 

occur based on the class of the drug or 

pharmacological properties of the drug 

are considered ‘‘unexpected’’ for 

reporting purposes. 

B. Review of Safety Information 

The final rule clarifies what safety 

information must be reviewed under 

§ 312.32(b). The proposal would have 

required sponsors to review ‘‘reports 

from foreign regulatory authorities that 

have not been previously reported to 

FDA by the sponsor.’’ FDA has deleted 

the phrase ‘‘that have not been 

previously reported to FDA by the 

sponsor,’’ because it confuses the review 

with the reporting requirements. FDA 

expects sponsors to review all 

information, but to avoid duplicate 

reporting to the agency. In addition, the 

final rule clarifies the agency’s 

expectations for analysis of previous, 

similar reports (§ 312.32(c)(1)). 

C. Reporting Requirements 

In § 312.32(c), the final rule clarifies 

how and when to submit IND safety 

reports to FDA and participating 

investigators, including the requirement 

in § 312.32(c)(1)(v) that certain reports 

be submitted in a narrative format 

(proposed § 312.32(c)(1)(iii)). It provides 

examples of the kinds of evidence that 

suggest a causal relationship between 

the drug and the adverse event when 

determining whether a serious and 

unexpected adverse event qualifies for 

expedited reporting (§ 312.32(c)(1)(i)). 

The final rule also requires that 

sponsors submit expedited reports of 

findings from clinical studies, 

epidemiological studies, or pooled 

analyses of multiple studies that suggest 

a significant risk in humans 

(§ 312.32(c)(1)(ii)); findings from animal 

or in vitro testing that suggests a 

significant risk in humans 

(§ 312.32(c)(1)(iii)); and reports of an 

increased rate of occurrence of serious 

suspected adverse reactions over that 

listed in the protocol or investigator 

brochure (§ 312.32(c)(1))(iv)). The final 

rule also provides for alternative 

reporting arrangements (§ 312.32(c)(3)) 

and provides that study endpoints not 

be reported except in unusual cases 

(§ 312.32(c)(5)). 

Furthermore, FDA has made it clear 

in § 312.32(c)(1)(v) that the period of 

time for submitting additional data 

requested by the agency is 15 calendar 


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59938 Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 

days (i.e., the same period of time that 

is allowed for submitting followup 

information under § 312.32(d)(3)). In 

addition, the agency revised several 

provisions to allow for electronic 

submission of reports. First, in 

§ 312.32(c)(1)(v) ‘‘Submission of IND 

safety reports,’’ FDA renamed and 

revised proposed § 312.32(c)(1)(iii) 

‘‘Submission of written reports.’’ 

Second, FDA revised proposed 

§ 312.32(c)(2) ‘‘Telephone and facsimile 

transmission safety reports’’ to eliminate 

the specificity that unexpected fatal or 

life-threatening reports be submitted 

only by telephone or facsimile 

transmission so that other means of 

rapid communication (e.g., e-mail) may 

be accepted in the future. FDA also 

renamed the provision to ‘‘Unexpected 

fatal or life-threatening suspected 

adverse reaction reports.’’ Last, in 

§ 320.31(d)(3), FDA revised the 

proposed requirement for submission of 

IND safety reports and unexpected fatal 

or life-threatening reports from 

bioavailability and bioequivalence 

studies to mirror these revisions. 

The final rule allows for alternative 

reporting arrangements, as provided in 

former § 312.32(c)(3). However, the 

agency revised the statement, ‘‘FDA may 

request a sponsor to submit IND safety 

reports in a format or at a frequency 

different than that required under this 

paragraph’’ by replacing the word 

‘‘request’’ with ‘‘require’’ to reflect the 

existing process. In addition, the final 

rule clarifies the reporting requirements 

for clinical investigations of drug 

products that are marketed in the 

United States (§ 312.32(c)(4)). 

The final rule makes minor editorial 

changes to § 312.32(d)(2) to clarify the 

followup reporting requirements. In 

addition, the agency eliminated the 

redundant submission requirements for 

information amendments and annual 

reports under § 312.32(d)(4) because 

they are already contained in §§ 312.31 

and 312.33. 

The final rule clarifies the 

requirements for investigators to submit 

reports of serious adverse events to the 

sponsor and clarifies the requirement 

for reporting study endpoints that are 

serious adverse events (§ 312.64(b)). 

Finally, the final rule requires that 

applicants submit to FDA reports of 

serious adverse events from 

bioavailability and bioequivalence 

studies. Proposed § 320.31(d) would 

have required that these studies be 

subject to the proposed IND safety 

reporting requirements, thereby 

requiring all reports under proposed 

§ 312.32 (e.g., reports of serious and 

unexpected SADRs, reports of 

information sufficient to consider 

product administration changes). FDA 

has tailored the rule to require only 

those reports that FDA believes would 

be most informative (i.e., reports of all 

serious adverse events). FDA also 

revised this provision to make it 

consistent with the final revisions for 

submission of IND safety reports and 

reports of any fatal or life-threatening 

adverse event. The final rule requires 

that reports must be submitted to the 

Office of Generic Drugs. 

Table 1 of this document identifies 

the changes from the proposed rule in 

the IND safety reporting requirements 

that the agency made in this final rule. 

TABLE 1—CHANGES MADE BY THE FINAL RULE FROM THE PROPOSED RULE

21 CFR Section in Final Rule Description of Change See comment or section of this document (identified in parentheses) 

for more detailed information regarding the change. 

312.32(a) Adverse event • Added definition for ‘‘adverse event’’ (1) 

312.32(a) Life-threatening adverse event or lifethreatening suspected adverse reaction • Made minor editorial revisions for clarity, including language changes to accommodate deletion of ‘‘SADR’’ definition and use of alternative terminology (2) 

312.32(a) Serious adverse event or serious suspected adverse reaction • Changed language to accommodate deletion of ‘‘SADR’’ definition and use of alternative 

terminology (6) 

• Incorporated the definition from former § 312.32(a) of ‘‘disability’’ within the definition of 

‘‘serious’’ (III.A.2) 

• Revised so that the seriousness determination is based on the opinion of either the sponsor or investigator (6) 

312.32(a) Suspected adverse reaction • Replaced the term ‘‘SADR’’ with the term ‘‘suspected adverse reaction,’’ clarifying the 

meaning of ‘‘reasonable possibility’’ within the definition (1) 

312.32(a) Unexpected adverse event or unexpected suspected adverse reaction • Revised to make clear that ‘‘unexpected’’ adverse events or suspected adverse reactions 

include those that may be anticipated from the pharmacological properties of the drug, or 

that occur with members of the drug class, but that have not previously been observed 

with the drug under investigation (8) 

312.32(b) Review of safety information • Made minor editorial changes for clarity and deleted the phrase ‘‘that have not been previously reported to FDA by the sponsor’’ (II) 

312.32(c)(1) IND safety reports • Withdrew the proposed requirement for each report of an SADR to contain a minimum 

data set and to maintain records of efforts to obtain a minimum data set (5, 13, and 14) 

312.32(c)(1)(i) Serious and unexpected suspected adverse reactions • Clarified agency’s expectation for analysis of previous, similar reports or any other relevant 

information (16) 

• Withdrew the requirement that the causality assessment be based on the opinion of the investigator or the sponsor (15) 

• Provided examples of the types of evidence that suggest a causal relationship between 

the drug and the adverse event (18 to 21) 

312.32(c)(1)(ii) Findings from other studies • Revised proposed reports of ‘‘Information sufficient to consider product administration 

changes’’ to clarify agency expectations of reports from clinical studies, epidemiological 

studies or pooled analyses of multiple studies that suggest a significant risk in humans (23 

to 25) 


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TABLE 1—CHANGES MADE BY THE FINAL RULE FROM THE PROPOSED RULE—Continued 

21 CFR Section in Final Rule Description of Change See comment or section of this document (identified in parentheses) 

for more detailed information regarding the change. 

312.32(c)(1)(iii) Findings from animal or in vitro 

testing 

• Revised proposed reports of ‘‘Information sufficient to consider product administration 

changes’’ to clarify agency expectations of reports from animal or in vitro testing that suggests a significant risk in humans (26 to 29) 

312.32(c)(1)(iv) Increased rate of occurrence of 

serious suspected adverse reactions 

• Added the requirement for reports of any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure 

(32) 

312.32(c)(1)(v) Submission of IND safety reports • Revised to allow for electronic submission of IND safety reports and clarified time period 

for reporting additional data or information requested by FDA (II) 

312.32(c)(2) Unexpected fatal or life-threatening 

suspected adverse reaction reports 

• Revised to eliminate the specificity that unexpected fatal or life-threatening suspected adverse reaction reports be submitted only by telephone or facsimile transmission and renamed the requirement (II) 

312.32(c)(3) Reporting format or frequency • Replaced ‘‘request’’ with ‘‘require’’ (20) 

312.32(c)(4) Investigations of marketed drugs • Clarified requirements for investigations of marketed drugs (31) 

312.32(c)(5) Reporting study endpoints • Added requirement that study endpoints (e.g., mortality or major morbidity) must be reported according to the protocol instead of as IND safety reports except when there is evidence suggesting a causal relationship between the drug and the event (19 and 21) 

312.32(d) Followup • Deleted provision that required safety information to be submitted in an information 

amendment or annual report and made minor editorial changes for clarity (III.K) 

312.64(b) Investigator reports • Clarified requirements for investigator reports (35 and 36) 

320.31(d) Applicability of requirements regarding 

an ‘‘Investigational New Drug Application’’ 

• Revised to require that persons conducting bioavailability and bioequivalence studies report all serious adverse events (II) 

• Revised to make consistent with requirements for submission of IND safety reports and reports of any fatal or life-threatening adverse event (II) 

III. Comments on the Proposed Rule 

The agency received 110 comments in 

the docket for the March 14, 2003, 

proposed rule on premarket and 

postmarket safety reporting revisions. 

Comments were received from 

prescription and nonprescription drug 

manufacturers and related companies; 

trade organizations representing drug 

manufacturers and other interested 

parties; blood banks and transfusion 

facilities; international organizations 

and non-U.S. agencies; professional 

associations and organizations; 

consultants; contract research 

organizations; academic institutions; 

health care and consumer advocacy 

organizations, individual physicians, 

pharmacists, and consumers; and 

others. 

To make it easier to identify 

comments and our responses, the word 

‘‘Comment,’’ in parentheses, appears 

before the comment’s description, and 

the word ‘‘Response,’’ in parentheses, 

appears before our response. We have 

numbered each comment to help 

distinguish between different 

comments. Similar comments are 

grouped together under the same 

number. The number assigned to each 

comment is purely for organizational 

purposes and does not signify the 

comment’s value or importance or the 

order in which it was received. 

Comments addressing the proposed 

requirements for IND safety reporting 

and bioavailability and bioequivalence 

studies and the agency’s responses 

follow: 

A. Definitions—Proposed § 312.32(a) 

1. Suspected Adverse Drug Reaction 

(SADR) 

FDA proposed to add the term 

‘‘suspected adverse drug reaction 

(SADR)’’ and define the term as follows: 

‘‘A noxious and unintended response to 

any dose of a drug product for which 

there is a reasonable possibility that the 

product caused the response. In this 

definition, the phrase ‘a reasonable 

possibility’ means that the relationship 

cannot be ruled out.’’ 

(Comment 1) Nearly all of the 

comments overwhelmingly opposed the 

agency adopting the proposed definition 

of SADR and strongly encouraged the 

agency to abandon the proposed 

definition for many reasons, including 

the following: 

• Many comments did not agree that 

‘‘reasonable possibility’’ should be 

defined as ‘‘the relationship cannot be 

ruled out.’’ Most comments stated that 

this interpretation makes the definition 

overly broad and will lead to reporting 

almost every serious, unexpected 

adverse event because no event could 

ever be completely ruled out. 

• Many comments stated that 

although the proposed definition was 

similar to the definition contained in 

the ICH E2A guidance, the agency’s 

interpretation was inconsistent with the 

guidance. The ICH E2A guidance makes 

clear that a causality assessment is 

required for clinical investigations and 

that a ‘‘reasonable causal relationship’’ is 

meant to convey in general that there 

are facts (evidence) or arguments to 

suggest a causal relationship. The 

comments expressed concern that the 

agency’s interpretation of ‘‘reasonable 

possibility’’ would lead to 

inconsistencies in globally conducted 

studies and reports. 

• Many comments asserted that the 

significantly increased numbers of 

expedited reports that could result from 

the proposed definition might dilute 

real safety signals, making them harder 

to detect. The lengthy in depth 

investigations needed to rule out the 

increased number of false positive 

associations would take away resources 

from other safety surveillance efforts 

and potentially lead to a delay in 

identification of real signals. 


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59940 Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 

• Several comments expressed 

concern that the proposed definition 

would have a negative impact on the 

conduct of clinical trials. In addition to 

sharply increasing the number of reports 

of cases from clinical trials that would 

need to be sent to FDA in an expedited 

manner, sponsors and investigators 

would have to break the blind for nearly 

all subjects with serious, unexpected 

SADRs because the relationship 

between drug and the event could not 

definitively be ruled out. Increased 

unblinding would compromise the 

integrity of well-regulated clinical 

investigations, lead to fewer patients 

completing a trial, necessitate larger 

patient enrollment, and lengthen the 

timeline for new product development, 

possibly leading to higher costs for 

marketed drugs. One comment 

expressed concern that, to minimize 

unblinding, studies would be designed 

to exclude patients with serious medical 

conditions who are likely to experience 

serious adverse events during the study 

period, thereby limiting the 

applicability of study results. 

Many comments also stated that the 

proposed definition would result in 

significant increases in meaningless 

individual expedited reports being sent 

to already overburdened IRBs and 

investigators. The comments pointed 

out that an unintended effect of the 

increase in volume of reports may be to 

reduce an investigator’s and IRB’s 

vigilance in detecting adverse events. 

• Several comments expressed 

concern that the proposed definition 

would dilute the utility of drug product 

labeling because many more events 

would be regarded as ‘‘drug related’’ 

even though the likelihood of a true 

causal relationship is minimal. 

• Several comments stated that the 

‘‘S’’ abbreviation for ‘‘suspected’’ in 

SADR could be confused with the ‘‘S’’ 

abbreviation for ‘‘serious’’ in SAE 

(serious adverse event). 

The majority of the comments 

recommended that reporting adverse 

events from clinical trials should be 

based on a scientific or medical 

judgment that there is a possible causal 

relationship between the drug and the 

event, rather than simply being unable 

to unequivocally exclude a drug’s role. 

The comments suggested several 

alternatives to the agency’s proposed 

definition, including the following: 

• Several comments recommended 

that the definition of an adverse reaction 

encompass all of the concepts presented 

within the ICH E2A guidance, which are 

supported by CIOMS and presented in 

the European Union Clinical Trial 

Directive. Comments recommended that 

the definition of reasonable possibility 

be technically consistent with the ICH 

E2A guidance definition and clearly 

delineate the concept of ‘‘reasonable 

causal relationship’’ as conveying in 

general that there are facts (evidence) or 

arguments to suggest a causal 

relationship. 

• Some comments supported 

retaining FDA’s former definition of 

‘‘associated with the use of the drug’’ as 

‘‘there is a reasonable possibility that the 

experience may have been caused by the 

drug.’’ 

Three comments supported adopting 

the proposed definition because they 

considered it an inclusive, conservative 

approach to adverse event reporting. 

(Response) Based on the comments, 

and on review of definitions and 

terminology used in the ICH E2A 

guidance and in former § 312.32, the 

agency has decided not to adopt the 

proposed definition for ‘‘suspected 

adverse drug reaction (SADR).’’ The 

agency agrees with the comments 

stating that there should be a causality 

assessment applied and that the 

threshold for reporting should be that 

there is a ‘‘reasonable possibility’’ that 

the drug caused the adverse event. The 

agency also believes that it is important 

to use definitions that are clear and 

consistent, and in harmony with those 

used internationally. 

The agency believes that the 

comments raised legitimate concerns 

that the proposed definition was too 

broad and could have a negative impact 

on clinical trials, IRBs, investigators, 

signal detection, and drug labeling. 

Instead of adopting the proposed 

definition, the agency has adopted the 

terms for ‘‘adverse event’’ and 

‘‘suspected adverse reaction’’ in the 

definition section of this final rule, 

which addresses these concerns. The 

definitions of these terms should 

contribute to harmonization of safety 

reporting to regulatory authorities 

worldwide because they are consistent 

with the concepts and definitions 

adopted by the ICH E2A guidance and 

CIOMS. The terms are defined as 

follows: 

• ‘‘Adverse event’’ means any 

untoward medical occurrence 

associated with the use of a drug in 

humans, whether or not considered 

drug related. (For the purposes of this 

definition, ‘‘untoward’’ means 

unfavorable, negative, or harmful). 

‘‘Suspected adverse reaction’’ means 

any adverse event for which there is a 

reasonable possibility that the drug 

caused the adverse event. For the 

purposes of IND safety reporting, 

‘‘reasonable possibility’’ means there is 

evidence to suggest a causal relationship 

between the drug and the adverse event. 

Suspected adverse reaction implies a 

lesser degree of certainty about causality 

than adverse reaction, which means any 

adverse event caused by a drug. 

These definitions reflect the varying 

degrees of certainty that are part of a 

causality assessment. For example: 

• An adverse event (also referred to as 

an ‘‘adverse experience’’) is any event 

observed or reported that is associated 

with the use of the drug, without regard 

to causality. 

• A suspected adverse reaction is a 

subset of all adverse events in which 

there is a reasonable possibility that the 

drug caused the event. 

• An adverse reaction, described 

within the definition, is a subset of all 

suspected adverse reactions for which 

there is reason to conclude that the drug 

caused the event. 

With this change from the proposed 

definition, the basis that the agency has 

established for assessing the degree of 

certainty about causality between a drug 

and an adverse event for the purposes 

of expedited IND safety reporting has 

not changed from former § 312.32(c). 

The sponsor must continue to evaluate 

the evidence and use its judgment to 

determine whether an adverse event 

meets the definition of suspected 

adverse reaction and qualifies for 

expedited reporting under § 312.32(c). 

The agency has also clarified the 

requirements for reporting a serious and 

unexpected suspected adverse reaction 

under § 312.32(c)(1)(i) to assist sponsors 

with making this determination (see 

Comment 18 of this document). 

Finally, the agency has concluded 

that abbreviations are potentially 

confusing (e.g., the ‘‘S’’ abbreviation for 

‘‘suspected’’ in SADR could be mistaken 

for an abbreviation of the term 

‘‘serious’’). Although the agency has 

retained the term ‘‘suspected’’ in 

‘‘suspected adverse reaction,’’ our 

preferred approach is to avoid use of 

any abbreviation (e.g., ‘‘SAR’’ for 

‘‘suspected adverse reaction’’). The 

agency believes that sponsors are 

familiar with the term ‘‘suspected’’ and 

its use by the European Commission 

and CIOMS (e.g., the acronym ‘‘SUSAR’’ 

means ‘‘suspected, unexpected, serious 

adverse reaction’’ in guidance 

documents and working group reports 

(for example, see Ref. 1)). 

Because the agency is not adopting 

the proposed definition of ‘‘suspected 

adverse drug reaction (SADR),’’ other 

proposed definitions (e.g., ‘‘serious 

SADR,’’ ‘‘life-threatening SADR’’) and 

requirements that used this terminology 

have been revised in this final rule to 

use the terms ‘‘adverse event’’ or 

‘‘suspected adverse reaction’’ as 

appropriate. 


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Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 59941 

2 Draft and final guidances for the Center for Drug 

Evaluation and Research (CDER)-related 

information are posted on the Internet at http:// 

www.fda.gov/Drugs/GuidanceCompliance

RegulatoryInformation/Guidances/default.htm. The 

Center for Biologics Evaluation and Research 

(CBER)-related information is posted at http:// 

www.fda.gov/BiologicsBloodVaccines/Guidance

ComplianceRegulatoryInformation/Guidances/ 

default.htm (21 U.S.C. 371(h), 21 CFR 10.115). 

2. Disability 

The proposed rule included a 

definition of the term ‘‘disability’’ to 

mean a substantial disruption of a 

person’s ability to conduct normal life 

functions. Because the term ‘‘disability’’ 

appeared only within the definition of 

‘‘serious SADR’’ in the proposed rule, 

the agency eliminated the definition of 

‘‘disability’’ as a separate term in this 

final rule. Instead, the agency revised 

the definition of ‘‘serious adverse event 

or serious suspected adverse reaction’’ 

in this final rule to incorporate the 

definition of ‘‘disability’’ by replacing 

the phrase ‘‘a persistent or significant 

disability/incapacity’’ with ‘‘a persistent 

or significant incapacity or substantial 

disruption of the ability to conduct 

normal life functions.’’ Thus, in the final 

rule, the term disability is replaced by 

the proposed definition in the one place 

where it appeared, and the definition 

itself has been deleted. 

3. Life-Threatening Suspected Adverse 

Drug Reaction (SADR) 

FDA proposed the term ‘‘lifethreatening suspected adverse drug 

reaction (SADR)’’ to mean any SADR 

that, in the view of the investigator or 

sponsor, places the patient or subject at 

immediate risk of death from the SADR 

as it occurred. It does not include an 

SADR that, had it occurred in a more 

severe form, might have caused death. 

(Comment 2) Several comments 

agreed with FDA’s proposal to add the 

term ‘‘or sponsor’’ to the definition of 

life-threatening SADR. SADRs would be 

reported as life-threatening if either the 

investigator or sponsor considered them 

to be life-threatening. However, several 

comments expressed concern with 

FDA’s proposal. The comments stated 

that a trained investigator is most 

qualified to make the sometimes 

subjective assessment of whether an 

event is life-threatening and that this 

determination often is best made by the 

health-care professional or the reporter 

who is in direct contact with the 

patient. These comments also stated that 

sponsors may exercise medical and 

scientific judgment in deciding whether 

expedited reporting is appropriate. One 

comment stated that allowing a sponsor 

to determine severity would change the 

nature of the assessment and result in 

increased reporting of events assessed 

by those with often incomplete 

information. One comment pointed out 

that FDA’s rationale for expanding the 

role of the sponsor is not supported by 

the quote from the ICH E2A guidance in 

the preamble to the proposed rule (68 

FR 12406 at 12419) because the ICH 

E2A guidance quote refers to causality 

assessment, not assessment of 

seriousness. 

(Response) The agency agrees with 

the comments that support expanding 

this definition to include reporting of an 

adverse event as life-threatening if 

either the investigator or the sponsor 

considers it to be life-threatening. The 

agency believes that, in some cases, the 

sponsor may not agree with the 

investigator’s assessment that an 

adverse event does not qualify as lifethreatening. In such cases, because these 

events are critically important for the 

identification of significant safety 

problems, the agency believes that 

broadening the definition to allow 

sponsors to also make this assessment is 

prudent and appropriate. While the 

agency agrees with the comment that 

pointed out that the preamble to the 

proposed rule misinterpreted the quote 

from the ICH E2A guidance, we 

nonetheless believe that the revision to 

the definition is consistent with the 

overall intent of the ICH E2A guidance. 

(Comment 3) Several comments 

disagreed with the agency’s position 

articulated in the preamble to the 

proposed rule that reasons for any 

differences of opinion between the 

investigator and sponsor regarding a 

determination that an SADR is lifethreatening would be included in the 

IND safety report (68 FR 12406 at 

12419). The comments argued that this 

adds no value and is not appropriate or 

necessary in all cases. In addition, 

comments stated that obtaining the 

investigator’s view when he or she 

deems the event non-life-threatening 

would be difficult. 

(Response) The agency agrees that 

reasons for differences of opinion 

between the sponsor and investigator 

are not always important and, therefore, 

not necessary to include in the IND 

safety report in all cases. Therefore, in 

this final rule, the agency does not 

require including the reasons for 

differences of opinion in the IND safety 

report. However, it is important that any 

adverse event or suspected adverse 

reaction considered life-threatening by 

either the sponsor or the investigator be 

reported as such. 

(Comment 4) Some comments 

suggested that FDA clarify the definition 

of life-threatening to take into account 

the role of other study staff making 

safety observations. The comments 

suggested that the definition be clarified 

to state that investigators or sponsors 

must evaluate information 

communicated to them or recorded by 

their qualified staff or agents and 

transmit reportable information to the 

sponsor or FDA. One comment 

recommended that the definition be 

modified to include contractors as well 

as sponsors. 

(Response) The agency does not agree 

that the recommended revisions to the 

definition are necessary because taking 

the observations of staff into account is 

inherent in the obligations of the 

investigator. Any qualified study staff 

could make pertinent safety 

observations, and it is the investigator’s 

responsibility in supervising the 

conduct of the clinical investigation (see 

§§ 312.53 and 312.60) to report adverse 

experiences to the sponsor in 

accordance with § 312.64. Further 

information on the supervisory 

responsibilities of investigators can be 

obtained in the agency’s guidance for 

industry entitled ‘‘Investigator 

Responsibilities: Protecting the Rights, 

Safety, and Welfare of Study Subjects’’ 

(74 FR 55052, October 26, 2009).2 The 

agency does not believe that it is 

necessary to change the definition to 

include contractors because, under 

§ 312.52, a contract research 

organization that assumes any 

obligation of a sponsor must comply 

with the applicable regulation. 

4. Minimum Data Set 

Under § 312.32(a), FDA proposed the 

term ‘‘minimum data set’’ to mean that 

‘‘the report includes an identifiable 

patient, an identifiable reporter, a 

suspect drug product, and an SADR.’’ 

(Comment 5) Two comments 

requested further clarification regarding 

the meaning of ‘‘identifiable’’ with 

respect to the kind and amount of 

information needed to meet the criteria 

for an ‘‘identifiable patient’’ and 

‘‘identifiable reporter.’’ One comment 

questioned whether patient 

characteristics, such as age or gender, 

would be adequate, or if the ability to 

contact the patient is necessary. 

(Response) As discussed in comments 

13 and 14 of this document, because the 

four elements of the minimum data set 

are generally readily available in the 

clinical trial setting, the agency has 

determined that the definition and the 

requirement are unnecessary and has 

decided not to require a minimum data 

set for IND safety reports as proposed in 

§ 312.32(c). Because the agency is not 

adopting this definition in the IND 

safety reporting requirements, the 

comments requesting clarification about 


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the elements of the definition are no 

longer relevant. 

5. Serious SADR 

FDA proposed to define ‘‘serious 

SADR’’ in the same way as the thencurrent definition of ‘‘serious adverse 

drug experience’’ under § 312.32(a) as 

follows: ‘‘Serious SADR means any 

SADR that results in any of the 

following outcomes: Death, a lifethreatening SADR, inpatient 

hospitalization or prolongation of 

existing hospitalization, a persistent or 

significant disability/incapacity, or a 

congenital anomaly/birth defect. 

Important medical events that may not 

result in death, be life-threatening, or 

require hospitalization may be 

considered a serious SADR when, based 

upon appropriate medical judgment, 

they may jeopardize the patient or 

subject and may require medical or 

surgical intervention to prevent one of 

the outcomes listed in this definition. 

Examples of such medical events 

include allergic bronchospasm requiring 

intensive treatment in an emergency 

room or at home, blood dyscrasias or 

convulsions that do not result in 

hospitalization, or the development of 

drug dependency or drug abuse.’’ 

(Comment 6) One comment suggested 

that the definition of ‘‘serious SADR’’ be 

revised to expressly allow the sponsor 

to determine if an adverse event is 

serious, in the absence of a reporter’s 

assessment of seriousness. 

(Response) For reasons similar to 

those stated in Comment 2 of this 

document (definition of lifethreatening), the agency agrees that the 

definition of ‘‘serious adverse event or 

serious suspected adverse reaction’’ 

should be revised to allow the 

determination that an adverse event or 

suspected adverse reaction is ‘‘serious’’ 

if either the investigator or sponsor 

considers it serious. Therefore, the 

agency has revised this definition to add 

the phrase ‘‘in the view of either the 

investigator or sponsor.’’ 

6. Unexpected SADR 

FDA proposed that the definition of 

‘‘unexpected SADR’’ be the same as the 

then-current definition for ‘‘unexpected 

adverse drug experience’’ under 

§ 312.32(a), except that the following 

sentence was added to make clear 

which SADRs are considered 

unexpected: ‘‘SADRs that are mentioned 

in the investigator’s brochure as 

occurring with a class of drugs but not 

specifically mentioned as occurring 

with the particular drug are considered 

unexpected.’’ 

(Comment 7) One comment stated 

that in the proposed definition, the 

‘‘severity’’ standard is vague, leaving the 

determination of ‘‘expectedness’’ to the 

investigator’s judgment. 

(Response) Unless a sponsorinvestigator is responsible for the 

clinical trial, the sponsor, rather than 

the investigator, generally determines if 

a suspected adverse reaction is 

unexpected for reporting purposes. 

However, the agency acknowledges that 

judgment is needed to decide if the 

severity of a suspected adverse reaction 

is greater than described in the 

investigator brochure. The definition of 

‘‘unexpected adverse event or 

unexpected suspected adverse reaction’’ 

in the final rule includes an example of 

a suspected adverse reaction that would 

be considered unexpected by virtue of 

its greater severity than other suspected 

adverse reactions mentioned in the 

investigator brochure (i.e., hepatic 

necrosis would be considered 

unexpected where the investigator 

brochure includes elevated hepatic 

enzymes or hepatitis). 

(Comment 8) Another comment 

recommended that FDA provide 

guidance on what should be considered 

‘‘expected’’ for regulatory reporting 

purposes, in particular, what safety 

information to include in the 

investigator brochure and what subset of 

such information would be considered 

‘‘expected’’ (i.e., only those for which a 

causal relationship is suspected, 

reasonably established, or inferred 

based on evidence). Some comments 

stated that if the basis for evaluating 

expectedness is that an event is listed in 

the investigator’s brochure, sponsors 

may add long lists of adverse events, 

thereby delaying important safety 

reports from being submitted to FDA. 

One comment recommended that FDA 

require that, until the applicable 

reference safety information document 

is officially updated (e.g., reprinted and 

distributed) to include a new serious, 

suspected adverse reaction (thereby 

making it expected), all subsequent 

reports of similar serious adverse drug 

reactions be submitted expeditiously as 

an IND safety report. Another comment 

suggested adopting use of the 

Developmental Core Safety Information 

(DCSI) document, proposed by a CIOMS 

Working Group, as the reference for 

‘‘expectedness’’ instead of the 

investigator brochure because the DCSI 

document contains only those adverse 

events that, after careful analysis are 

believed by the company to be likely 

related to the drug (Refs. 2 and 3). 

(Response) The purpose of the 

investigator brochure is to provide the 

investigator with information (clinical 

and nonclinical) about the 

investigational drug that is relevant to 

study of the drug in human subjects. 

The investigator brochure should 

include the information that is 

important for the investigator, who is 

administering the drug to human 

subjects, to know and understand. The 

investigator brochure is required to 

include information about the drug 

substance and formulation, 

pharmacological and toxicological 

effects of the drug in animals (and in 

humans, if known), pharmacokinetics 

and biological disposition of the drug in 

animals (and in humans, if known), 

information relating to safety and 

effectiveness in humans obtained from 

prior clinical studies, and information 

about possible risks and side effects to 

be anticipated on the basis of prior 

experience with the drug under 

investigation or with related drugs, and 

precautions or special monitoring to be 

done as part of the investigational use 

of the drug (see § 312.23(a)(5)). 

In general, the investigator brochure 

lists those adverse events that have been 

observed with the investigational drug 

and for which a causal relationship with 

the drug is suspected or confirmed. It is 

not appropriate for sponsors to add long 

lists of adverse events that are unlikely 

to have been caused by the drug to the 

investigator brochure because such lists 

could dilute the importance of clinically 

meaningful risk information and as a 

result, may put subjects at risk. The 

sponsor needs to exercise judgment 

when deciding if the threshold has been 

reached for adding a newly observed 

adverse event to the investigator 

brochure. This decision usually 

depends on the strength of the evidence 

from individual or multiple cases and 

previous knowledge about the drug or 

drug class. In some cases, the threshold 

for including an adverse event may be 

lower if it could result in a significant 

adverse outcome for trial participants. 

The investigator brochure describes 

adverse events that may be predicted to 

occur based on the pharmacological 

properties of the drug. For reporting 

purposes, if an adverse event occurs that 

has not previously been observed with 

the drug under investigation, the event 

is considered ‘‘unexpected.’’ To make 

clear that such predicted adverse events 

are considered ‘‘unexpected,’’ the final 

rule revises the proposed definition of 

‘‘unexpected’’ to state explicitly that the 

term also refers to adverse events or 

suspected adverse reactions that are 

mentioned in the investigator brochure 

as occurring with a class of drugs or as 

anticipated from the pharmacological 

properties of the drug, but are not 

specifically mentioned as occurring 

with the particular drug under 

investigation. 


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The agency expects the sponsor to 

update the investigator brochure on an 

ongoing basis with new important safety 

information. However, the agency agrees 

with the comment that, until the 

investigator brochure and other 

applicable reference safety information 

are updated to include a new serious, 

suspected adverse reaction, subsequent 

reports of similar serious, suspected 

adverse reactions must be submitted 

expeditiously in IND safety reports. 

Finally, sponsors submit and the 

agency accepts a variety of formats for 

the investigator brochure. For this 

reason, we are not formally adopting use 

of the DCSI document in this final rule. 

However, we agree that a sponsor could 

incorporate a document such as the 

DCSI into the investigator brochure for 

use as the reference for ‘‘expectedness’’ 

for reporting purposes if the DCSI 

contains the required safety information 

about the investigational drug. 

B. Review of Safety Information— 

Proposed § 312.32(b) 

IND safety reporting regulations in 

former § 312.32(b) required that 

sponsors promptly review all 

information relevant to the safety of the 

drug obtained or otherwise received by 

the sponsor from any source, foreign or 

domestic. Examples of potential sources 

of information in the former regulation 

included information derived from any 

clinical or epidemiological 

investigations, animal investigations, 

commercial marketing experience, 

reports in the scientific literature, as 

well as unpublished scientific papers, 

and reports from foreign regulatory 

authorities that had not been previously 

reported to FDA by the sponsor. 

Proposed § 312.32(b) would have 

amended this requirement to include in 

vitro studies as another example of a 

potential source of information and to 

clarify that ‘‘reports from commercial 

marketing experience’’ is intended to 

apply only to reports from foreign 

commercial marketing experience for 

drugs that are not marketed in the 

United States. As proposed, reports 

from IND studies of drugs that are 

marketed in the United States would be 

required to be reported as described 

under § 312.32(c)(4), if applicable. 

(Comment 9) One comment stated 

that reportable information can come 

from a wider variety of media or sources 

than those listed in the proposed rule. 

The comment maintained that 

investigators or sponsors participating 

in public or private meetings or 

conferences can learn of reportable 

events from colleagues or other 

professionals. The comment 

recommended that the list of potential 

sources of reportable information 

include such alternative sources. 

(Response) The sponsor is required to 

‘‘promptly review all information 

relevant to the safety of the drug 

obtained or otherwise received by the 

sponsor from foreign or domestic 

sources, including information derived 

from any clinical or epidemiological 

investigations, animal or in vitro studies 

***’’ (emphasis added). The sources 

listed in the requirement are not all 

inclusive, but represent examples of the 

variety of sources that may yield safety 

information. Therefore, the agency 

agrees that reportable information can 

come from sources other than those 

listed in § 312.32(b) and that one such 

source could be from public or private 

meetings. However, the agency does not 

believe that it is necessary to amend the 

requirement to provide additional 

examples. 

(Comment 10) One comment agreed 

with the clarification that reporting from 

commercial marketing experience 

applies only to foreign commercial 

marketing experience for drugs that are 

not marketed in the United States. The 

comment requested that FDA further 

make it clear that expedited reporting 

under § 312.32 is not required for 

reports from foreign commercial 

marketing experience for a different 

formulation of the same active moiety as 

a drug product that is lawfully marketed 

in the United States and that those 

reports should be submitted to the most 

appropriate new drug application (NDA) 

for the active moiety. 

(Response) As described further in 

Comment 31 of this document, IND 

safety reports are required under 

§ 312.32(c)(4) for suspected adverse 

reactions observed in clinical studies 

that are being conducted under an IND 

for a drug marketed or approved in the 

United States. In general, an expedited 

report from domestic or foreign 

commercial marketing experience for a 

drug lawfully marketed in the United 

States would not be submitted to the 

IND, but instead, must be submitted in 

accordance with the relevant 

postmarketing reporting requirements 

(e.g., §§ 310.305, 314.80, and 600.80). 

Similarly, a report of a suspected 

adverse reaction from foreign marketing 

experience for a different formulation of 

the drug product (same active moiety) 

that is lawfully marketed in the United 

States must be submitted in accordance 

with the relevant postmarketing 

reporting requirements. 

(Comment 11) One comment agreed 

with the proposal to add in vitro studies 

to the list of information that should be 

reviewed by the sponsor in its ongoing 

assessment of the safety of an 

investigational drug. Some comments 

stated that it would be helpful if FDA 

could provide examples, in addition to 

carcinogenicity, mutagenicity and 

teratogenicity, of when safety data from 

in vitro studies would yield relevant, 

important information that should be 

reviewed for IND reporting purposes. 

(Response) Data from in vitro 

microsusceptibility, drug interaction, or 

genotoxicity studies are examples of 

other data from in vitro studies that may 

yield important safety information. 

(Comment 12) One comment 

expressed concern that once a sponsor 

provides FDA with the animal and in 

vitro studies, emails, and reports from 

foreign regulatory authorities and any 

other information it reviewed in 

determining whether to report safety 

information, FDA may have to make the 

information publicly available under the 

Freedom of Information Act (FOIA). The 

comment stated that, before 

implementing the requirement, FDA 

should explain why these additional 

data are needed and how they will be 

handled for FOIA purposes. The 

comment requested that the requirement 

be withdrawn. 

(Response) The agency uses the safety 

information submitted by the sponsor, 

from any source, to continually monitor 

and evaluate the safety of the drug. Data 

and information in an IND are disclosed 

consistent with applicable statutes and 

regulations. The requirements under 

§ 312.130 describe the availability for 

public disclosure of data and 

information in an IND. The minor 

clarifications made to these 

requirements do not change these 

protections against public disclosure. 

Therefore, the agency declines to 

withdraw the requirement as requested 

by the comment. 

C. IND Safety Reports (Requirement for 

Minimum Data Set)—Proposed 

§ 312.32(c) 

FDA proposed to amend § 312.32(c) to 

require that sponsors must not submit 

an individual case safety report for an 

SADR if the report does not contain a 

minimum data set, but instead must 

maintain records of any information 

received or otherwise obtained for the 

SADR along with a record of its efforts 

to obtain a minimum data set. In the 

preamble to the proposed rule, the 

agency stated that sponsors should 

include in any written IND safety 

reports subsequently filed with FDA a 

chronological history of their efforts to 

acquire the minimum data set if there is 

a delay in obtaining the information, but 

that it was not necessary to include the 

chronological history in IND safety 

reports sent to investigators (68 FR 


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12406 at 12424). In addition, FDA 

proposed in § 312.32(c)(1)(i) that a 

sponsor must submit an IND safety 

report within 15 calendar days after 

receipt by the sponsor of the minimum 

data set for the SADR. 

As noted in Comment 5 of this 

document, the agency has reconsidered 

the proposed requirement under 

§ 312.32(c) that would have required 

sponsors to only submit an individual 

case safety report for an SADR if the 

report contained a minimum data set. 

Most IND safety reports are derived 

from observations from clinical trials. In 

the setting of a clinical trial, information 

is collected in a controlled environment 

where the four elements in the 

definition of minimum data set, as well 

as other information needed to evaluate 

the suspected adverse reaction (e.g., 

information that would be contained in 

a narrative report or on FDA Form 

3500A), are generally readily available. 

Accordingly, the agency has revised 

§ 312.32(c)(1) to eliminate the minimum 

data set language and to require instead 

that the sponsor submit an IND safety 

report after it determines that the 

information qualifies for reporting 

under § 312.32(c)(1)(i), (c)(1)(ii), 

(c)(1)(iii), or (c)(1)(iv). 

(Comment 13) One comment stated 

that waiting for collection of all the 

elements of the minimum data set, 

especially for determination of 

causality, could result in a significant 

delay in reporting to FDA. The comment 

requested clarification on when the 

reporting timeclock would start. 

Another comment requested 

clarification on whether the date of 

receipt of the minimum data set for the 

SADR represents day zero or day one. 

(Response) The reporting timeclock 

starts (i.e., day zero) as soon as the 

sponsor determines that the information 

qualifies for reporting under 

§ 312.32(c)(1)(i), (c)(1)(ii), (c)(1)(iii), or 

(c)(1)(iv). For a serious and unexpected 

suspected adverse reaction from a 

clinical trial, this would be the day the 

sponsor receives information from the 

clinical investigator. If any information 

necessary to evaluate and report the 

suspected adverse reaction is missing or 

unknown, the sponsor should actively 

seek such information. 

(Comment 14) Several comments 

stated that including in an IND safety 

report a chronological history of their 

efforts to acquire the minimum data set 

is inconsistent with standards for nonU.S. regulators and the ICH E2A 

guidance, adds no value, may lead to 

potential legal risk in the event of 

litigation, may impede electronic 

transmission of individual case safety 

reports, and will become an 

administrative burden. Some comments 

suggested that records of efforts to 

obtain the minimum data set should be 

maintained within the case record in the 

sponsor’s files, available upon request 

or during agency inspections. One 

comment suggested FDA require 

manufacturers to have procedures in 

place to acquire a minimum data set. 

One comment stated that the agency 

needs to define the minimum 

requirements for conducting due 

diligence to avoid variation from 

sponsor to sponsor. Another comment 

recommended reinforcing the need for 

sponsors to conduct followup activities 

and for FDA to audit industry for 

compliance. One comment requested 

clarification on the sponsor’s timeframe 

for maintaining records of its efforts to 

obtain the minimum data set. One 

comment pointed out that although FDA 

stated in the preamble that the 

chronological history included in the 

IND safety report would not need to be 

sent to investigators, this statement 

creates conflict because sponsors must 

tell investigators the same information 

that is reported to FDA. 

(Response) The agency agrees with 

comments that including a 

chronological history in an IND safety 

report of efforts to acquire information 

is not necessary and could be an 

administrative burden without added 

value. Accordingly, the proposed 

requirement for a chronological history 

has been deleted from § 312.32(c). 

Under § 312.32(d)(1), sponsors are 

required to promptly investigate all 

safety information received, so it is 

inherent in that requirement that 

sponsors promptly and diligently 

attempt to obtain the information 

necessary for evaluating a suspected 

adverse reaction. If critical information 

is missing or unknown, the sponsor 

should actively seek the information. 

The regulations do not include specific 

procedures for conducting or 

documenting due diligence activities 

because the agency recognizes that there 

is more than one approach that would 

be appropriate, depending on the 

situation. 

Similarly, because the minimum data 

set requirement is no longer included, 

the agency is not adopting the proposed 

requirement in § 312.32(c) to maintain 

records of any information received or 

otherwise obtained for the SADR when 

the sponsor does not have a reportable 

minimum data set. The agency notes 

that sponsors are required under 

§ 312.57(c) to retain records and reports 

required under part 312 (including 

safety information received by the 

sponsor) for 2 years after a marketing 

application is approved for the drug or, 

if an application is not approved for the 

drug, until 2 years after shipment and 

delivery of the drug for an 

investigational use is discontinued and 

FDA has been so notified. The agency 

may audit these records as part of its 

inspection process. 

D. Serious and Unexpected SADR— 

Proposed § 312.32(c)(1)(i) 

In proposed § 312.32(c)(1)(i), FDA 

proposed that the sponsor must notify 

FDA and all participating investigators 

in a written IND safety report of any 

SADR that, based on the opinion of the 

investigator or sponsor, is both serious 

and unexpected, as soon as possible, but 

in no case later than 15 calendar days 

after receipt by the sponsor of the 

minimum data set for the serious, 

unexpected SADR. In addition, FDA 

proposed that the sponsor must identify 

all safety reports previously filed with 

the IND concerning a similar SADR, and 

must analyze the significance of the 

SADR in light of the previous, similar 

reports. 

(Comment 15) One comment agreed 

with the proposal that the assessment of 

whether the event is serious or 

unexpected be based on the opinion of 

the ‘‘investigator or sponsor,’’ while 

other comments expressed concern. 

Several comments indicated that 

investigators should not be required to 

assess ‘‘expectedness.’’ One comment 

stated that ‘‘expectednessx’’ is a 

regulatory definition that would be 

difficult for an investigator to apply in 

a consistent manner. Another comment 

suggested replacing the proposed 

language with ‘‘any SADR that is serious 

based on the opinion of the investigator 

or sponsor and unexpected.’’ 

(Response) The agency agrees that, in 

contrast to the assessments of whether 

an adverse event or suspected adverse 

reaction is ‘‘serious’’ and ‘‘lifethreatening,’’ which require medical 

judgment by the investigator or sponsor, 

the assessment of whether an adverse 

event or suspected adverse reaction is 

‘‘unexpected’’ in this context refers to a 

regulatory definition (i.e., not listed in 

the investigator brochure) that is more 

appropriately applied by the sponsor. 

The sponsor is usually in a better 

position to assess the adverse event 

information and determine whether the 

adverse event is ‘‘unexpected’’ for 

reporting purposes because the sponsor 

has access to more information (e.g., 

from all the investigative sites in a 

multi-center study). Therefore, the 

agency has revised this proposed 

requirement by deleting the phrase 

‘‘based on the opinion of the investigator 

or sponsor,’’ which leaves this 

determination to the sponsor. 


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(Comment 16) Several comments 

asked for clarification on various 

aspects of the requirement to identify all 

safety reports previously filed with the 

IND concerning a similar SADR and to 

analyze the significance of the SADR in 

the context of the previous, similar 

reports. One comment requested 

clarification on the meaning of 

‘‘previously filed with the IND’’ and 

whether this should include an analysis 

of previous similar reports across 

multiple open INDs or only a single 

IND. The comment noted that there 

could be company-sponsored IND 

studies and investigator-sponsored IND 

studies ongoing simultaneously, with 

safety data stored in different places. 

One comment requested clarification on 

what constitutes a ‘‘similar’’ SADR and 

on the meaning of ‘‘analyze the 

significance.’’ This comment noted that 

companies should already have 

processes and procedures in place to 

periodically review and analyze safety 

data to detect ‘‘signals,’’ and asked 

whether FDA expects an ‘‘analysis’’ for 

postmarketing study reports filed to the 

IND or all reports for the product, 

including postmarketing spontaneous 

reports. The comment suggested that 

FDA remove this requirement for both 

IND and postmarketing studies, since 

for IND studies, companies should 

already be performing these analyses 

and updating their investigator 

brochures with significant new safety 

information, and for postmarketing 

studies, analyses of all adverse events 

are being performed in the periodic 

safety update report (PSUR). 

(Response) The agency expects the 

analysis of the significance of the 

suspected adverse reaction in the 

context of similar reports to include all 

INDs held by the sponsor and any other 

relevant information of which the 

sponsor is aware. To make this clear, the 

agency revised the provision in final 

§ 312.32(c)(1) to require that in each IND 

safety report, the sponsor must identify 

all IND safety reports previously 

submitted to FDA concerning a similar 

suspected adverse reaction, and must 

analyze the significance of the 

suspected adverse reaction in light of 

previous, similar reports or any other 

relevant information. 

The agency declines to withdraw the 

requirement as suggested by the 

comment because we consider this 

information to be critical for the ongoing 

evaluation of the investigational drug’s 

safety. Because this is not a new 

requirement (see former 

§ 312.32(c)(1)(ii)), the agency agrees that 

companies should have processes in 

place to periodically review and analyze 

their safety data and update their 

investigator brochures with significant 

new safety information. This analysis 

should include an evaluation of the 

suspected adverse reaction in the 

context of other related reports or 

adverse events, including those that 

may have occurred in postmarketing 

studies. 

(Comment 17) One comment asked 

whether the IND safety report should be 

sent only to investigators participating 

in company-sponsored studies or to 

studies conducted under all open INDs 

for the product. One comment requested 

that FDA clarify its expectations for 

cross-reporting to investigators 

participating in different trials under the 

same IND or different INDs with the 

same active moiety. One comment asked 

if followup IND safety reports 

containing only minor refinements are 

to be sent to FDA and all investigators 

who received the initial safety report or 

only to FDA. 

(Response) The sponsor must report 

to any participating investigators under 

all open INDs, including those held by 

the sponsor and those to which the 

sponsor provides the investigational 

drug (investigator-sponsored). To make 

this clear, the agency revised the 

provision in § 312.32(c)(1) to require 

that a sponsor notify FDA and all 

participating investigators (i.e., all 

investigators to whom the sponsor is 

providing drug under its INDs or under 

any investigator’s IND) in an IND safety 

report of potential serious risks, from 

clinical trials or any other source, as 

soon as possible, but in no case later 

than 15 calendar days after the sponsor 

determines that the information 

qualifies for reporting under 

§ 312.32(c)(1)(i), (c)(1)(ii), (c)(1)(iii), or 

(c)(1)(iv). 

Followup reports should be sent to 

investigators to inform and update them 

about an important suspected adverse 

reaction if it significantly affects the 

care of the subjects or conduct of the 

study. Minor refinements that do not 

significantly affect care of subjects or 

conduct of the study need to be sent to 

FDA but need not be sent to 

investigators. Such information may be 

communicated to investigators in a 

routine update of the investigator 

brochure. 

(Comment 18) As stated in Comment 

1 of this document, there were many 

comments opposed to FDA’s proposed 

SADR definition, some of which 

recommended against adopting the 

proposed SADR definition, and instead, 

urged FDA to clarify the types of 

evidence that suggest there is a 

reasonable possibility that a drug 

product caused the adverse event. 

(Response) Before submitting an IND 

safety report under § 312.32(c)(1)(i), the 

sponsor must determine that the event: 

(1) Is serious, (2) is unexpected, and (3) 

meets the definition of ‘‘suspected 

adverse reaction’’ in § 312.32(a) (i.e., that 

there is a ‘‘reasonable possibility’’ that 

the drug caused the event). These 

criteria have not changed from former 

§ 312.32(c)(1)(i)(A). Making this 

determination will always require 

judgment based on the best available 

information. 

Currently, sponsors often report in an 

expedited manner serious adverse 

events that may be due to the 

underlying disease or that occur 

commonly in the study population, 

even when there is little reason to 

believe that the drug caused the event. 

Such reports are generally 

uninformative and, therefore, do not 

meaningfully contribute to the 

developing safety profile of the drug. 

The agency believes that clarifying what 

evidence suggests a causal relationship 

will increase the likelihood that 

information reported to FDA will 

meaningfully contribute to the 

developing safety profile of the product 

and improve the overall quality of safety 

reporting. 

Therefore, to assist sponsors with 

determining whether an adverse event 

meets the definition of suspected 

adverse reaction, the agency revised the 

proposed requirement under 

§ 312.32(c)(1)(i) to make it clear that 

sponsors are to report to FDA and all 

participating investigators only if there 

is evidence to suggest a causal 

relationship between the drug and the 

adverse event. Final § 312.32(c)(1)(i) 

also provides the following examples: 

• A single occurrence of an event that 

is uncommon and known to be strongly 

associated with drug exposure (e.g., 

angioedema, hepatic injury, StevensJohnson Syndrome). 

• One or more occurrences of an 

event that is not commonly associated 

with drug exposure, but is otherwise 

uncommon in the population exposed 

to the drug (e.g., tendon rupture). 

• An aggregate analysis of specific 

events observed in a clinical trial (such 

as known consequences of the 

underlying disease or condition under 

investigation or other events that 

commonly occur in the study 

population independent of drug 

therapy) that indicates those events 

occur more frequently in the drug 

treatment group than in a concurrent or 

historical control group. 

E. Alternative Reporting Arrangements 

In the preamble to the proposed rule, 

FDA acknowledged that the proposed 


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definition of SADR (which defined 

‘‘reasonable possibility’’ to mean that the 

causal relationship between a product 

and a response to the product cannot be 

ruled out) may result in submission of 

numerous safety reports to the agency 

for which the reported SADR is not 

informative as a single report because it 

is very likely to have been a 

consequence of the patient’s disease. 

FDA invited comment on use of 

alternative reporting methods that 

would minimize overreporting of 

uninformative events and assure 

submission of meaningful reports of 

unexpected events. For example, one 

such alternative would be to include in 

study protocols or other documentation 

a list of known consequences of the 

disease that would not be submitted to 

FDA in an expedited manner as 

individual case safety reports (e.g., 

events that are endpoints of the study) 

(68 FR 12406 at 12418). 

(Comment 19) Some comments agreed 

with the agency’s suggestion that 

protocols could be written to exclude 

specific disease-related events from 

expedited reporting if these events are 

study endpoints. Other comments 

expressed concern that alternative 

reporting methods would not have the 

intended effect of reducing 

overreporting and could exacerbate 

problems with the proposed SADR 

definition of reasonable possibility in 

which the causal relationship ‘‘cannot 

be ruled out.’’ They argued that 

effectively eliminating clinical judgment 

in reporting coupled with an ad hoc 

exemption mechanism would lead to 

different standards across clinical 

programs, between different sponsors of 

studies, and across FDA review 

divisions. These comments further 

pointed out that negotiating and 

managing exemptions to expedited 

reporting would place a significant 

burden on FDA and companies and 

would necessitate the creation of an 

FDA structure and process to ensure 

consistency across products. While 

many of these comments recommended 

against finalizing the proposed 

definition, others suggested alternatives 

(e.g., waiver provisions) to alleviate 

overreporting caused by the proposed 

definition. One comment recommended 

that approaches to minimize 

overreporting only be considered for 

late stage development (i.e., Phase 3 and 

4 studies). One comment recommended 

that FDA mandate expanded reporting 

for clinical trials only for those 

companies that have had documented 

poor performance in the past or for 

clinical trials once a study or design has 

been identified as posing a potential or 

unforeseen risk to participants. 

(Response) As previously described in 

the response to Comment 1 of this 

document, the agency is not adopting 

the proposed SADR definition and, 

instead, is adopting a definition of 

‘‘suspected adverse reaction’’ that relies 

on clinical judgment to determine if 

there is a reasonable possibility that the 

drug caused the event. While FDA 

believes this definition addresses many 

of the concerns about overreporting, the 

agency agrees with the comments that 

stated that protocols could be written to 

exclude from expedited reporting 

specific disease-related events that are 

study endpoints. The agency does not 

believe that it is appropriate to report 

study endpoints as IND safety reports 

for trials that are designed to evaluate 

the effect of the drug on disease-related 

mortality or morbidity. Therefore, the 

agency added the requirement at 

§ 312.32(c)(5) that study endpoints (e.g., 

mortality or major morbidity) must be 

reported to FDA by the sponsor as 

described in the protocol and ordinarily 

would not be reported under 

§ 312.32(c). However, if a serious and 

unexpected adverse event occurs for 

which there is evidence suggesting a 

causal relationship between the drug 

and the event (e.g., death from 

anaphylaxis), the event must be 

reported under § 312.32(c)(1)(i) as a 

serious and unexpected suspected 

adverse reaction even if it is a 

component of the study endpoint (e.g., 

all-cause mortality). FDA does not 

believe that this requirement will pose 

an additional burden on sponsors or the 

agency because sponsors of large 

outcome trials are accustomed to 

describing in the protocol how mortality 

or major morbidity endpoints will be 

measured and analyzed, and FDA 

review divisions are accustomed to 

reviewing such protocols. 

The agency does not agree that the 

safety reporting requirements should be 

revised, as suggested by the comment, to 

address specific study or design risks or 

company compliance. The agency is 

authorized to require additional 

reporting or inspection, or to take 

action, on a case-by-case basis if, for 

example, such problems expose human 

subjects to unreasonable and significant 

risk of illness or injury, or if the sponsor 

does not comply with the requirements 

under § 312.32 (see e.g., § 312.42 

clinical holds and requests for 

modifications, § 312.44 termination). 

(Comment 20) Several comments 

supported the use of alternative 

reporting arrangements for serious 

adverse events that are not the study 

endpoints (e.g., known consequences of 

the underlying disease or condition). 

These comments recommended that 

these events not be reported to FDA in 

an expedited manner as individual case 

safety reports, but be identified in the 

study protocol with clear instructions 

for handling, be monitored by the 

sponsor, and be reported to the agency 

if, in aggregate, it appears that the 

product may be causing an increase in 

these adverse events. One comment 

endorsed this type of arrangement 

because it offers the potential for 

improvements in protocol design by 

providing expanded opportunity for 

sponsors to discuss the ‘‘ground rules’’ 

for SADR reporting for specific studies 

with the agency during the protocol 

design phase. Two comments 

recommended that FDA make clear to 

investigators, sponsors, manufacturers, 

and IRBs that such arrangements are 

acceptable. One comment stated that 

allowing this type of alternative 

reporting arrangement will provide a 

loophole for industry to underreport 

adverse events. 

(Response) Under former 

§ 312.32(c)(3), sponsors were permitted 

to propose alternative reporting formats 

or frequencies for submitting IND safety 

reports; this requirement has not 

changed in this final rule. The agency 

agrees with the comments 

recommending that at the time of 

protocol development the sponsor 

identify the serious adverse events (i.e., 

known consequences of the disease or 

those otherwise common in the study 

population) that it plans not to report 

individually in an expedited manner 

but that it will monitor during the 

course of the trial. FDA encourages use 

of this process. Should an aggregate 

analysis indicate that those events occur 

more frequently in the drug treatment 

group, the sponsor must then report that 

information in an IND safety report 

under § 312.32(c)(1)(i). However, the 

agency recognizes that it is not possible, 

nor desirable, to list in the protocol 

every adverse event that may be 

anticipated to occur in the study 

population; the protocol should 

therefore limit such a list to those events 

that are common, even in the absence of 

drug exposure. For example, in a longterm osteoporosis trial in an elderly 

population, it would be reasonable to 

list myocardial infarction, but 

unreasonable to list acute narrow angle 

glaucoma—an event that can occur in 

this elderly population, but is relatively 

rare. In addition, the agency believes 

that there may be other situations for 

which alternative reporting 

arrangements are appropriate based on 

the clinical circumstances. For example, 


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the agency may require a sponsor to 

continue to report expeditiously a 

medically significant suspected adverse 

reaction that is listed in the investigator 

brochure as observed with the drug (i.e., 

expected) so that its rate can be 

carefully monitored. The agency may 

also require an alternative reporting 

format or frequency for clinical trials 

once a study or design has been 

identified as posing a potential or 

unforeseen risk to participants. In other 

instances, a sponsor may request that a 

certain adverse event be submitted in a 

different format or at a different 

frequency than required. Section 

312.32(c)(3) permits such arrangements. 

The agency does not agree that allowing 

alternative reporting formats or 

frequencies creates loopholes for 

sponsors to underreport, but believes 

that such arrangements will lead to 

greater vigilance since particular 

adverse events of interest have been 

identified in advance. The agency is 

clarifying the language in former 

§ 312.32(c)(3) that stated ‘‘FDA may 

request a sponsor to submit IND safety 

reports in a format or at a frequency 

different than that required under this 

paragraph’’ by replacing the word 

‘‘request’’ with ‘‘require’’ to better reflect 

the existing process. 

F. Unblinding 

In the preamble to the proposed rule, 

FDA noted that reports from blinded 

clinical studies should have the blind 

broken to identify the drug product, but 

that alternative arrangements could be 

made with FDA for exceptions to 

breaking the blind for a clinical study in 

which mortality or serious morbidities 

are the clinical endpoint of the study. 

FDA invited comment on whether the 

blind should also be broken for other 

serious SADRs that are not the clinical 

endpoint of the study, but occur at a rate 

high enough that the overall study blind 

would be threatened if each such case 

were individually unblinded (68 FR 

12406 at 12420). 

(Comment 21) Several comments 

expressed concern that breaking the 

blind to identify the suspect drug could 

potentially bias both the sponsor and 

investigator, and suggested alternatives 

to unblinding so that sponsors and 

investigators could remain blinded. In 

addition, several comments responded 

to FDA’s request for comment on 

whether the blind should be broken for 

serious SADRs that are not the clinical 

endpoint of the study. One comment 

stated that for other serious SADRs (e.g., 

expected), if a safety signal is observed, 

sponsors are obligated to unblind 

studies for individual subject cases, but 

other comments stated that medical 

management of the subject who 

experiences the serious SADR does not 

always require unblinding. One 

comment stated that the sponsor and 

FDA should define in advance the 

nature of such serious SADRs that 

would not be subject to routine 

expedited reporting and unblinding. 

One comment stated that for studies in 

which alternative arrangements have 

been made to maintain the blind, FDA 

should receive interim analyses, 

disaggregated by group, which might 

suggest increased overall dangers to 

those getting the drug. 

(Response) The agency believes that 

the concerns expressed about breaking 

the blind have been addressed by 

clarifying the reporting requirements for 

serious and unexpected suspected 

adverse reactions (§ 312.32(c)(1)(i)) and 

for study endpoints (§ 312.32(c)(5)), and 

the provision permitting alternative 

reporting arrangements (§ 312.32(c)(3)). 

In particular, because there should 

generally be no need to report study 

endpoints in an IND safety report, 

unblinding due to such endpoints 

should typically not occur. In other 

cases, however, where the serious, 

unexpected, suspected adverse reaction 

must be reported expeditiously, the 

agency expects the blind to be broken. 

Knowledge of the treatment received 

may be essential for the medical 

management of the subject and may 

provide critical safety information about 

the drug that could have implications 

for the ongoing conduct of the trial (e.g., 

monitoring, informed consent). The 

agency does not believe that unblinding 

single or small numbers of informative 

cases will compromise the integrity of 

the study. However, if patient safety can 

be assured without breaking the blind, 

the agency encourages the sponsor to 

discuss alternative reporting 

arrangements with the appropriate FDA 

review division. Any anticipated 

alternative arrangements to maintain the 

blind would need to be described in the 

protocol, including identification of the 

serious adverse events that will not be 

reported on an individual basis and the 

plan for monitoring and reporting 

results to FDA. 

(Comment 22) Several comments 

made recommendations on the need for, 

and role of independent data safety 

monitoring boards (DSMBs), called Data 

Monitoring Committees (DMCs) in 

FDA’s guidance for industry entitled 

‘‘Guidance for Clinical Trial Sponsors: 

Establishment and Operation of Clinical 

Trial Data Monitoring Committees’’ (71 

FR 15421, March 28, 2006) (DMC 

guidance). One comment stated that an 

obligation to have an independent 

DSMB would prevent routine 

unblinding. Other comments 

recommended the use of DSMBs that 

have processes for vetting and reporting 

adverse reactions to the agency, 

including monitoring for increases in 

disease-related complications. One 

comment recommended that the agency 

concurrently amend the IRB regulations 

and guidelines to incorporate a mandate 

of more frequent review of overall safety 

data, including a requirement for an 

independent safety monitoring 

committee, under predefined 

circumstances. Another comment urged 

the agency to require a DSMB for all 

Phase 3 studies and to also require that 

sponsors provide DSMB reports to IRBs. 

One comment said that clarity on the 

role of the DSMB for Phase 3 and 4 

studies when reviewing SADRs could 

help reduce redundancy of SADR 

reporting evaluations by IRBs, and allow 

IRBs to more efficiently focus their 

attention on local SADRs. 

(Response) The agency agrees that 

DMCs can be useful for monitoring 

adverse events and preventing routine 

unblinding in certain trials. A DMC is 

not required and is not necessary for 

most studies, particularly those 

evaluating symptomatic treatments. 

DMCs are generally associated with a 

large, randomized multisite trial that is 

designed to evaluate treatments 

intended to improve survival or reduce 

the risk of major morbidity. In that case, 

the independent DMC would be 

expected to monitor serious events that 

are study endpoints and also may assess 

the rate of other known consequences of 

the underlying disease or other events 

that are common in the study 

population. FDA’s DMC guidance also 

notes another potential use for a DMC. 

Some sponsors have used a DMC to 

monitor the overall event rates as the 

safety database accumulates in ongoing 

studies (DMC guidance at p. 23). A DMC 

could periodically analyze and evaluate 

the aggregated, unblinded events in the 

entire IND safety database to determine 

if the drug is the suspected cause. 

During these analyses, investigators and 

study participants would remain 

blinded. FDA’s DMC guidance also 

provides more information on 

determining the need for and the role of 

a DMC. In addition, the agency’s 

guidance for industry entitled 

‘‘Guidance for Clinical Investigators, 

Sponsors, and IRBs: Adverse Event 

Reporting—Improving Human Subject 

Protection’’ provides recommendations 

on efficient approaches to meeting the 

requirements for reporting 

unanticipated problems to IRBs (74 FR 

2599, January 15, 2009). 


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G. Information Sufficient to Consider 

Product Administration Changes— 

Proposed § 312.32(c)(1)(ii) 

In addition to requiring sponsors to 

provide written IND safety reports to 

FDA and investigators for any serious 

and unexpected adverse experience, 

former § 312.32(c)(1)(i) required a 

written IND safety report for ‘‘[a]ny 

finding from tests in laboratory animals 

that suggests a significant risk for 

human subjects including reports of 

mutagenicity, teratogenicity, or 

carcinogenicity.’’ FDA proposed to 

revise this requirement to require 

sponsors to submit a written IND safety 

report if the sponsor receives 

information sufficient to consider 

product administration changes. The 

proposed rule described information 

sufficient to consider product 

administration changes as ‘‘information 

that, based on appropriate medical 

judgment, might materially influence 

the benefit-risk assessment of an 

investigational drug or that would be 

sufficient to consider changes in either 

product administration or in the overall 

conduct of a clinical investigation’’ (68 

FR 12406 at 12476). Examples of the 

types of information that might give rise 

to such a report were described as ‘‘any 

significant unanticipated safety finding 

or data in the aggregate from an in vitro, 

animal, epidemiological, or clinical 

study, whether or not conducted under 

an IND, that suggests a significant 

human risk, such as reports of 

mutagenicity, teratogenicity, or 

carcinogenicity or reports of a lack of 

efficacy with a drug product used in 

treating a life-threatening or serious 

disease’’ (68 FR 12406 at 12476). 

(Comment 23) Several comments 

maintained that the threshold for 

submission of this category of IND 

safety report—information sufficient to 

consider product administration 

changes—needs clarification. Some 

comments stated the ‘‘information 

sufficient to consider product 

administration changes’’ is too vague a 

criterion on which to base a reporting 

requirement and that ‘‘product 

administration’’ may have different 

interpretations in the context of safety. 

Some comments pointed out that there 

is ongoing ‘‘consideration’’ of the 

implications, for product 

administration, of information that 

emerges during the conduct of a trial 

and often, upon consideration, it will be 

concluded that no changes are needed. 

Some comments recommended that 

there be an IND safety report only in the 

event of a product administration 

change or other change in the conduct 

of the investigation. One comment 

recommended that FDA consider the 

implications (e.g., potential confusion) 

of informing investigators about 

information sufficient to consider 

product administration changes before a 

decision has been made about whether 

to make a change. That comment 

recommended that only FDA receive the 

information sufficient to consider 

product administration changes and that 

the investigator be notified only in the 

event of an actual product 

administration change. Some comments 

pointed out that the proposed language 

does not differentiate among the range 

of possible product administration 

changes and thus would seem to require 

an expedited report for minor changes 

that do not warrant expedited reporting. 

The comments suggested that there be 

expedited reporting only in the event of 

significant product administration 

changes. One comment stated that 

information sufficient to consider 

product administration changes is a 

reasonable category for an IND safety 

report. The comment asked that FDA 

clarify that significant risk to humans is 

intended to include instances of 

significant impairment or dysfunction. 

(Response) The agency concurs that, 

as proposed, the requirement may be 

confusing. In response to comments, the 

agency has revised the proposed 

requirement for reporting data or 

findings from clinical or 

epidemiological studies to address the 

concerns about vagueness of terms and 

criteria that could lead to differences in 

interpretation. The revised requirement 

eliminates the association with ‘‘product 

administration changes’’ and makes 

clear the types of findings that would 

trigger the requirement to report under 

this provision. In addition, the revised 

requirement also makes clear that the 

findings from clinical studies that are 

subject to this requirement are other 

than those reported under 

§ 312.32(c)(1)(i) (e.g., findings from a 

drug interaction study). The agency has 

revised § 312.32(c)(1)(ii) to require the 

sponsor to report any findings from 

epidemiological studies, pooled analysis 

of multiple studies, or clinical studies 

(other than those reported under 

§ 312.32(c)(1)(i)),whether or not 

conducted under an IND and whether or 

not conducted by the sponsor, that 

suggest a significant risk in humans 

exposed to the drug. The provision goes 

on to state that, ordinarily, such a 

finding would result in a safety-related 

change in the protocol, informed 

consent, investigator brochure 

(excluding routine updates of these 

documents), or other aspects of the 

overall conduct of the clinical 

investigation. 

These changes to the proposed 

requirement also address the comments 

concerned about potentially 

prematurely notifying all investigators 

prior to conclusively determining 

whether a finding might change the 

product administration or conduct of 

the investigation because the sponsor 

would report to FDA and notify all 

participating investigators, as required 

by § 312.32(c)(1), after that 

determination has been made by the 

sponsor. 

In addition, FDA agrees with the 

comment that ‘‘significant risk in 

humans’’ would include instances of 

significant impairment or dysfunction. 

(Comment 24) One comment asked 

that FDA clarify what is meant by 

‘‘might materially influence the benefitrisk assessment’’ (68 FR 12406 at 12476). 

The comment pointed out that a literal 

interpretation would require an IND 

safety report for a finding that is 

favorable to the benefit-risk assessment 

as well as a finding that is unfavorable 

to the benefit-risk assessment, but 

would have no effect on the clinical use 

of the drug. Another comment 

maintained that the term benefit-risk 

has no clear meaning in the premarket 

context because efficacy has not been 

proven, i.e., there is no established 

benefit for the product being studied. 

(Response) The agency agrees that the 

proposed requirement may be 

confusing. Therefore, the agency has not 

included the phrase ‘‘might materially 

influence the benefit-risk assessment’’ in 

§ 312.32(c)(1)(ii). 

(Comment 25) Some comments 

questioned FDA’s intent and otherwise 

expressed concern about requiring IND 

safety reports of lack of efficacy for a 

drug intended to treat a life-threatening 

or serious disease. One comment 

pointed out that ‘‘lack of efficacy’’ is 

rarely used in the clinical trial setting to 

refer to cases of disease progression or 

nonresponders. The comment 

maintained that because of the difficulty 

in judging lack of efficacy, such reports 

should be limited to cases in which the 

investigator has specifically determined 

that there was lack of efficacy. One 

comment maintained that the term is 

incongruous in the clinical trial setting 

because efficacy of the drug has not 

been demonstrated. One comment 

pointed out that the term ‘‘lack of 

efficacy’’ is not used consistently 

throughout the proposed rule (i.e., 

premarket compared to postmarket 

setting). 

(Response) The agency agrees with 

the comment stating that the term ‘‘lack 

of efficacy’’ is incongruous in the 


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clinical trial setting because the 

effectiveness of the drug has generally 

not been established. Therefore, the 

final rule does not include this 

proposed provision. 

(Comment 26) One comment stated 

that in vitro and animal findings should 

not be lumped together with clinical 

findings for purposes of the information 

sufficient to consider product 

administration changes IND safety 

reports because in vitro and animal 

findings typically are assessed 

differently than clinical findings. The 

comment also argued that there is 

significant variation in the 

interpretation of the current reporting 

requirements for nonclinical findings 

and recommended establishing distinct, 

well-defined criteria for reporting of 

nonclinical findings. The comment 

recommended a separate safety report 

for animal and in vitro findings with the 

following criteria: (1) A drug-related 

finding, (2) an unanticipated finding, 

and (3) a finding that suggests a serious 

risk to humans. The comment further 

maintained that the company’s core 

safety information about the drug 

should be the basis for determining 

whether the finding is unanticipated 

and the term ‘‘serious’’ should be 

defined, in this context, as suggesting a 

significant human risk, including, but 

not limited to, reports of 

carcinogenicity, mutagenicity, or 

teratogenicity. 

(Response) The agency agrees that the 

way in which in vitro and animal 

findings are assessed differs from 

clinical findings. To make this 

distinction clear, the agency has revised 

the proposed requirement to separate 

reports of findings from nonclinical and 

clinical studies. Under 

§ 312.32(c)(1)(iii), the sponsor must 

report any findings from any animal or 

in vitro testing, whether or not 

conducted by the sponsor, that suggest 

a significant risk in humans exposed to 

the drug, such as reports of 

mutagenicity, teratogenicity, 

carcinogenicity, or reports of significant 

organ toxicity at or near the expected 

human exposure. The provision states 

that, ordinarily, any such findings 

would result in a safety-related change 

in the protocol, informed consent, 

investigator brochure (excluding routine 

updates of these documents), or other 

aspects of the overall conduct of the 

clinical investigation. 

The revised requirement also 

eliminates the terms ‘‘unanticipated’’ 

and ‘‘serious.’’ The agency agrees with 

the comment that an unanticipated, 

drug-related finding that suggests a 

significant risk to humans would meet 

the requirement for reporting. 

(Comment 27) Two comments asked 

FDA to clarify the scope of what is 

meant by ‘‘an animal finding suggestive 

of significant human safety risk.’’ One 

comment asked whether there are any 

animal findings other than 

carcinogenicity, mutagenicity, or 

teratogenicity that would be considered 

a significant human safety risk and 

whether a finding needs to originate 

from a reproducible validated controlled 

model. One comment stated that the 

final rule should state explicitly that 

only those findings of carcinogenicity, 

mutagenicity, or teratogenicity that the 

sponsor considers suggestive of 

significant risk to humans should be 

reported. The comment pointed out that 

some carcinogenicity, mutagenicity, and 

teratogenicity findings are known to be 

species-specific or for other reasons 

known not to suggest significant 

potential human risk and thus should 

not be subject to expedited reporting. 

Another comment suggested a 

distinction be made between a 

nonclinical finding that requires 

‘‘changes in either product 

administration or in the overall conduct 

of a clinical investigation’’ as opposed to 

a nonclinical finding that requires 

information only (e.g., action is limited 

to a nonurgent update of the investigator 

brochure and informed consent). 

(Response) The requirement has been 

revised to make it clear that, ordinarily, 

a finding would be considered 

suggestive of a significant risk in 

humans if it results in a safety-related 

change in the protocol, informed 

consent, investigator brochure, or other 

aspects of the overall conduct of the 

clinical investigation. Nonurgent, 

routine updates to the investigator 

brochure and informed consent would 

not meet the criteria for reporting under 

this provision and should not be 

reported in an expedited IND safety 

report. 

The sponsor must determine whether 

a finding suggests a significant risk in 

humans in order for the finding to be 

reportable. Animal findings such as 

carcinogenicity, mutagenicity or 

teratogenicity are meant to be examples 

of the types of findings that could 

suggest a significant human risk, but 

there are others that could meet the 

criteria for reporting. For clarity, the 

agency added another example in 

§ 312.32(c)(1)(iii) (i.e., reports of 

significant organ toxicity at or near the 

expected human exposure). Findings 

from animal studies do not necessarily 

need to be replicated to meet the criteria 

for expedited reporting to FDA. For 

example, the agency would not expect 

a long-term carcinogenicity study to be 

replicated if findings from the original 

study suggested a significant risk to 

humans. The validity of the model 

would be a factor taken into account in 

evaluating the strength of the evidence 

of significant risk. 

(Comment 28) Many comments 

expressed concern about in vitro testing 

alone as a basis for an IND safety report. 

One comment pointed out that certain 

types of in vitro findings that are known 

to be associated with an increased risk 

of carcinogenicity or mutagenicity are 

always reported, but other findings are 

not obviously worthy of reporting. Some 

comments argued that expanding the 

scope of expedited reporting to include 

in vitro testing is not warranted or 

useful. Some comments maintained that 

in vitro testing is often exploratory and 

not validated and thus lends itself to 

unanticipated findings, but the clinical 

implications of in vitro testing are often 

not understood until later when the data 

can be assessed in light of animal or 

clinical findings. Given this delay in the 

interpretability of in vitro findings, the 

comments asked FDA to clarify when an 

in vitro finding becomes reportable for 

purposes of an IND safety report. Some 

comments argued that the increased 

reporting burden for in vitro findings 

would result in large numbers of 

uninformative reports that would 

burden FDA and dilute the impact of 

truly informative safety reports. Some 

comments also maintained that 

expanded reporting requirements may 

deter sponsors from conducting the 

kinds of in vitro testing that could 

reduce the number of animal studies 

needed. 

(Response) In response to comments 

and as stated in Comments 26 and 27, 

the agency has revised the proposed 

requirement § 312.32(c)(1)(iii) to make it 

clear that an in vitro or animal finding 

is reportable for the purposes of an IND 

safety report if it suggests a significant 

risk in humans exposed to the drug. The 

sponsor would not report an in vitro 

finding in an expedited report unless it 

determined that the finding suggests a 

significant risk in humans. 

(Comment 29) Some comments asked 

FDA to clarify the timeframe for 

reporting under this requirement, 

including when in vitro and animal 

studies become reportable sources of 

safety information by explaining how 

‘‘the determination by the sponsor that 

the information qualifies for reporting 

under this paragraph’’ applies to 

nonclinical findings. One comment 

suggested that the reporting clock for in 

vitro and animal findings start on the 

date the final study report is completed. 

One comment asked that FDA clarify 

that the day that the 15-day period 

begins is day zero and not day one. 


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(Response) The agency believes that 

the revisions to this requirement have 

sufficiently detailed how information 

qualifies for reporting by providing 

examples of the outcome of such a 

finding (i.e., the finding would 

ordinarily result in a safety-related 

change in the protocol, informed 

consent, investigator brochure, or in 

other aspects of the overall conduct of 

the clinical investigation). The 15–day 

reporting clock begins (i.e., day zero) on 

the day that the sponsor determines that 

a finding suggests a significant risk in 

humans. In general, it is not necessary 

for a final study report to be completed 

before a sponsor is able to make this 

determination. 

H. Submission of Written Reports— 

Proposed § 312.32(c)(1)(iii) 

Under proposed § 312.32(c)(1)(iii), 

FDA proposed that each written report 

may be submitted on an FDA Form 

3500A or in a narrative format. Foreign 

SADRs may be submitted on an FDA 

Form 3500A or on a CIOMS I form. FDA 

also proposed that reports of overall 

findings or data in the aggregate from 

published and unpublished in vitro, 

animal, epidemiological, or clinical 

studies must be submitted in a narrative 

format. In addition, FDA proposed to 

require that each written notice bear 

prominent identification of its contents 

and be transmitted to the FDA review 

division that has responsibility for the 

review of the IND. FDA also proposed 

to require that if the agency determines 

that additional data are needed, FDA 

may require further data to be 

submitted. 

The agency has also revised the 

requirement (final § 312.32(c)(1)(v)) to 

allow for electronic submission of these 

reports because the agency anticipates 

that these reports will be submitted by 

means other than paper in the future. In 

addition, the agency has revised the 

requirement to make clear that the 

period of time for submitting additional 

data requested by the agency is 15 

calendar days, the same as required 

under § 312.32(d) for submitting 

followup information. The time for 

submission of this additional 

information was not specified in the 

proposed rule. 

(Comment 30) Two comments asked if 

the agency would accept the CIOMS I 

form for reporting domestic SADRs. One 

comment strongly recommended that 

the CIOMS I form be acceptable for 

reporting domestic SADRs because it 

would decrease workload burden, 

enhance timeliness compliance with 

reporting timeframes, and integrate 

globally accepted formats. 

(Response) FDA will continue, as 

proposed, the current practice of 

permitting submission of IND safety 

reports on FDA Form 3500A or in a 

narrative format for reports of domestic 

suspected adverse reactions and on FDA 

Form 3500A, in a narrative format or on 

a CIOMS I form for reports of foreign 

suspected adverse reactions. FDA 

declines to permit submission of 

domestic suspected adverse reactions on 

the CIOMS I form because the CIOMS I 

form has fewer data elements than FDA 

Form 3500A (see 60 FR 11284 at 11287, 

March 1, 1995; 62 FR 52237 at 52246, 

October 7, 1997) and FDA believes the 

additional data elements are useful for 

evaluating the report. FDA is continuing 

to accept the CIOMS I form for foreign 

reports because we believe that 

harmonization facilitates compliance 

with the reporting requirements, thereby 

expediting FDA’s receipt of foreign 

suspected adverse reaction reports. In 

the future, the agency anticipates that 

electronic reporting of suspected 

adverse reactions will replace the use of 

paper forms. 

I. Telephone and Facsimile 

Transmission Safety Reports—Proposed 

§ 312.32(c)(2) 

FDA proposed to require that the 

sponsor notify FDA by telephone or by 

facsimile transmission of any 

unexpected fatal or life-threatening 

SADR based on the opinion of the 

investigator or sponsor as soon as 

possible but in no case later than 7 

calendar days after receipt by the 

sponsor of the minimum data set. 

Because the agency anticipates that 

these reports will be submitted by 

means other than telephone or facsimile 

in the future (e.g., electronically), the 

agency has revised the requirement to 

eliminate the specificity that these 

reports be submitted only by telephone 

or facsimile. The agency also changed 

the paragraph heading to ‘‘Unexpected 

fatal or life-threatening suspected 

adverse reaction reports.’’ For 

consistency with the agency’s decision 

that assessment of whether the event is 

serious and unexpected should be based 

on the opinion of the sponsor (not the 

investigator), the agency eliminated the 

phrase ‘‘based on the opinion of the 

investigator or sponsor’’ (see comment 

15 of this document and 

§ 312.32(c)(1)(i)). For consistency with 

the agency’s decision to eliminate the 

definition of ‘‘minimum data set,’’ the 

agency replaced the phrase ‘‘after receipt 

by the sponsor of the minimum data set’’ 

in the proposed codified with ‘‘after the 

sponsor’s initial receipt of the 

information’’ (see section III.C of this 

document). 

J. Investigations of Marketed Drugs— 

Proposed § 312.32(c)(4) 

FDA proposed that ‘‘a sponsor of a 

clinical study under an IND for a drug 

marketed in the United States is only 

required to submit IND safety reports to 

FDA (review division that has 

responsibility for the IND) for SADRs 

from the clinical study itself, whether 

from domestic or foreign study sites of 

the IND.’’ As proposed, the sponsor 

would also be required to submit to 

FDA safety information from these 

clinical studies as prescribed by the 

postmarketing safety reporting 

requirements under §§ 310.305, 314.80, 

and 600.80. 

(Comment 31) One comment 

supported the clarification of this 

requirement. Other comments requested 

further clarification. One comment 

asked what should be submitted to the 

IND from foreign studies not conducted 

under an IND (e.g., Phase 1–3 studies, 

Phase 4 postmarketing studies), both 

before and after a U.S. NDA is approved. 

One comment recommended that FDA 

finalize a provision to require that 

serious, unexpected SADRs that occur 

in studies not being conducted under an 

IND be submitted as expedited reports 

to an IND, if one exists. This comment 

also requested that FDA clarify whether 

serious, unexpected SADRs observed in 

IND-exempt studies of marketed drugs 

are required to be submitted to both an 

IND if one exists and the NDA. The 

comment recommended submitting 

these cases only to the NDA. One 

comment stated that although the 

requirement references the 

postmarketing safety reporting 

requirements, the postmarketing 

requirements do not mention foreign 

studies. This comment requested that 

FDA clarify the postmarketing 

requirements. Another comment stated 

that for products marketed and being 

studied globally, it is confusing to 

decide on the appropriate route of 

reporting given the different licensed 

status of products in different countries 

and different indications being 

investigated. This comment 

recommended that FDA provide a 

centralized reporting location so that 

FDA could route and file the report to 

the appropriate application. 

(Response) The only reports that must 

be submitted to an IND for a drug 

marketed or approved in the United 

States are those arising from a study 

conducted under the IND (at domestic 

or foreign sites). All other reports (e.g., 

marketing experience, studies not under 

an IND), must be reported in accordance 

with the relevant postmarketing safety 

reporting requirements. In response to 


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the comments, the agency clarified 

§ 312.32(c)(4) to state that a sponsor of 

a clinical study of a drug marketed or 

approved in the United States that is 

conducted under an IND is required to 

submit IND safety reports for suspected 

adverse reactions that are observed in 

the clinical study at domestic or foreign 

study sites. The sponsor must also 

submit safety information from the 

clinical study as prescribed by the 

postmarketing safety reporting 

requirements (e.g., §§ 310.305, 314.80, 

and 600.80). 

Table 2 of this document summarizes 

the reporting requirements for the 

various scenarios identified in the 

comments about submitting safety 

reports from a clinical study. 

TABLE 2.—SAFETY REPORTING REQUIREMENTS FROM CLINICAL STUDIES1

Drug marketed or approved2 in 

the United States? Under U.S. IND? Trial site Must report to IND? Must report per postmarketing requirements? 

Yes Yes U.S. or Foreign Yes Yes 

Yes No U.S. or Foreign No Yes 

No Yes U.S.or Foreign Yes 

No No Foreign 

1Areas in the table are left blank when an IND or marketing application would not exist. 

2 If a drug is approved in the United States, but is not currently being marketed in the United States, the postmarketing requirements would still 

apply. 

The agency does not agree with the 

comment that stated that the 

postmarketing requirements do not 

mention foreign studies. The 

postmarketing reporting requirements 

do apply to postmarketing studies 

conducted at foreign sites if the drug is 

marketed in the United States. For 

example, §§ 314.80(b) and 600.80(b) 

require applicants to review all adverse 

drug experience information from any 

source, ‘‘foreign or domestic,’’ and 

§§ 314.80(e) and 600.80(b) require 

expedited reporting from a 

postmarketing study, whether or not 

conducted under an IND, if there is a 

reasonable possibility that the drug 

caused the adverse experience. 

In addition, the agency revised the 

proposed language listing the 

postmarketing safety reporting 

requirements by including the 

parenthetical ‘‘(e.g., §§ 310.305, 314.80, 

and 600.80),’’ thereby clarifying that the 

listed postmarketing regulations are 

examples and other postmarketing 

safety reporting requirements may apply 

(e.g., reports related to certain over-thecounter (OTC) products under the 

Dietary Supplement and 

Nonprescription Drug Consumer 

Protection Act (Public Law 109–462); 

records regarding blood or blood 

products under § 606.170). 

With respect to submitting reports to 

FDA to one central location, currently, 

postmarketing safety reports are entered 

into the Adverse Event Reporting 

System (AERS) database, whereas IND 

safety reports are sent directly to the 

review division that has responsibility 

for the review of the IND. Current 

capabilities do not permit direct 

electronic submission through a Webbased system. However, FDA is 

committed to adapting its business 

practices to evolving technology, 

including using the significant 

advancements in Web-based, electronic 

systems. We anticipate that, in future 

rulemakings, Web-based filing of most 

submissions will eventually be required. 

We anticipate that when such a change 

to an electronic submission system is 

implemented, future guidance will 

address any technical questions related 

to such submissions. Until such time 

that FDA develops a system to route and 

manage IND safety reports within the 

AERS database, or another database, the 

sponsor must submit them in the 

manner described in the regulations and 

to the appropriate FDA location 

identified in the regulations. 

K. Followup—Proposed § 312.32(d) 

Section 312.32(d) provides the 

requirements for investigating and 

submitting followup information to an 

IND safety report, making minor 

revisions in § 312.32(d)(2) to clarify how 

relevant followup information 

submitted under this paragraph must be 

identified (i.e., ‘‘Followup IND Safety 

Report’’). The agency proposed revising 

the terminology in § 312.32(d)(3) to be 

consistent with the proposed use of the 

term SADR. The terminology in 

§ 312.32(d)(3) is consistent with terms 

used in the final rule. Former 

§ 312.32(d)(4) required that results of a 

sponsor’s investigation of other safety 

information must be submitted, as 

appropriate, in an information 

amendment or annual report. The 

agency has eliminated this requirement 

because it is redundant—§§ 312.31 and 

312.33 contain the submission 

requirements for information 

amendments and annual reports. 

L. Disclaimer—Proposed § 312.32(e) 

The agency proposed revising the 

terminology in § 312.32(e) to be 

consistent with the proposed use of the 

term SADR. The terminology in 

§ 312.32(e) is consistent with terms used 

in the final rule. 

M. Annual Reports 

Although the agency did not propose 

any changes to the IND annual reporting 

requirements, FDA stated in the 

preamble to the proposed rule that it 

would not require reports of an increase 

in the rate of occurrence of expected, 

serious SADRs to be submitted to the 

agency in an expedited manner. The 

agency stated that instead, sponsors 

should report this information to FDA 

in their IND annual reports under 

§ 312.33(b)(1) (68 FR at 12406 at 12425). 

(Comment 32) One comment 

disagreed with FDA’s proposal to 

deviate from the ICH E2A guidance, 

which recommends rapid 

communication to regulatory authorities 

for an increase in the rate of occurrence 

of an ‘‘expected,’’ serious ADR that is 

judged to be clinically important (60 FR 

11284 at 11286), because expedited 

reporting of this information may alert 

FDA to situations of more widespread 

and serious risks than were previously 

known or of use in populations that had 

not been previously identified as at risk. 

One comment agreed with the agency’s 

departure from the ICH E2A guidance 

recommendation for expedited reporting 

of increased frequency of serious, 

expected SADRs. However, it 

questioned the utility of including this 

information in the IND annual report, as 

proposed by FDA. The comment stated 

that including this information may be 

difficult, given the timing of various 


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59952 Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 

clinical trials relative to the IND annual 

reporting cycle. The comment suggested 

that rather than requiring increased 

frequency analysis of serious SADRs in 

IND annual reports, sponsors should 

routinely review incidence rates of all 

serious and nonserious adverse events 

within their clinical program, and report 

any significant changes in the IND 

annual report, when detected. Another 

comment recommended that the agency 

provide guidance on what would be 

deemed a ‘‘clinically important’’ 

increased rate of reports. The comment 

asked that FDA explain what the value 

added of such reporting is, given the 

agency’s statements that such reports 

have limited reliability and have proven 

to be of little value in identifying 

increased incidences of serious, labeled 

events in the postmarketing setting (see 

62 FR 34166, June 25, 1997). 

(Response) To be consistent with the 

recommendations in the ICH E2A 

guidance and in response to comments 

about reporting serious )‘‘expected’’ 

SADRs, the agency is adding a 

requirement under § 312.32(c)(1)(iv) that 

the sponsor expeditiously report any 

clinically important increase in the rate 

of a serious suspected adverse reaction 

over that listed in the protocol or 

investigator brochure. The agency 

acknowledges that baseline incidence 

rates from clinical trial data as a basis 

for comparison may not be available in 

all cases, and as explained in the 

preamble to the proposed rule (68 FR 

12406 at 12425), for this reason, FDA 

did not explicitly propose to require 

these reports in the proposed rule. 

However, the agency believes that when 

rates are available, a clinically 

important increase provides important 

safety information and warrants 

expedited, rather than annual, reporting. 

Deciding if an increase in the rate of a 

serious suspected adverse reaction over 

that listed in the protocol or investigator 

brochure is ) ‘‘clinically important’’ is a 

matter of judgment based on a variety of 

factors including the study population, 

the nature and seriousness of the 

reaction, and the magnitude of the 

observed increase in rate. 

The agency also agrees with the 

comment that sponsors should routinely 

review incidence rates of all serious and 

nonserious adverse events within their 

clinical program and expects that this is 

current practice within the industry. If 

a clinically important increase in a 

serious suspected adverse reaction is 

identified when compared to the rate 

described in the protocol or investigator 

brochure, the sponsor must report it to 

FDA expeditiously. Changes in 

incidence rates for the most frequent 

nonserious adverse events would be 

reported in the IND annual report. 

In response to the comment that 

requested clarification on the utility of 

these reports in the premarket setting 

when they have proven to be of little 

value in the postmarketing setting, the 

agency believes that there are 

differences between the premarket 

setting (where these reports would 

usually be based on incidence rates 

from clinical trials) and the 

postmarketing setting (where estimation 

of incidence rates from spontaneous 

reports is more difficult because, for 

example, the size of the exposed 

population is unknown). The agency 

believes that these reports contribute 

information important for 

understanding and updating the safety 

profile of the investigational drug 

product. 

(Comment 33) Another comment 

noted that although FDA’s proposed 

rule did not address the U.S. IND 

annual reporting requirements, it 

recommended that they be modified to 

be consistent with the ICH and EU 

annual reports in light of the 

finalization of the EU Clinical Trial 

Directive 2001/20/EC and the 

publication of their final detailed 

guidance. 

(Response) The agency has been 

participating in the development of the 

ICH draft guidance, entitled ‘‘E2F 

Developmental Safety Update Report’’ 

(DSUR draft guidance), that describes 

the format, content, and timing for 

periodic reporting for an investigational 

drug. As stated in the notice announcing 

the availability of the DSUR draft 

guidance, the DSUR would serve as an 

internationally harmonized, annual 

clinical trial safety report that could be 

submitted in the United States in place 

of an annual report for an IND (73 FR 

45462, August 5, 2008). After the DSUR 

draft guidance is finalized, the agency 

will evaluate the need to revise our IND 

annual reporting requirements to take 

into account international standards and 

recommendations. 

(Comment 34) One comment 

requested clarification of IND annual 

reporting after an NDA has been 

approved and clinical studies continue 

under the IND, particularly in light of 

adoption of the PSUR, which includes 

clinical study data. The comment asked 

if safety sections in the IND annual 

report would be required after the NDA 

has been approved and the PSUR format 

is then being followed. The comment 

also requested clarification on whether 

the data cutoff date would be the IND 

effective date, the NDA approval date, 

or the international birth date. 

(Response) Clinical development of a 

drug frequently continues even after it 

has been approved for marketing (e.g., 

for new indications, new dosage 

strengths, different populations). 

Therefore, the IND annual report 

continues to be important for evaluating 

and monitoring the safety of the drug. In 

addition, the DSUR draft guidance 

discusses the relationship between the 

DSUR and PSUR when clinical studies 

continue after a drug is approved for 

marketing, and when to initiate a DSUR 

for a marketed product. The guidance 

recommends that once a drug has 

received marketing approval in any 

country or region, and clinical trials 

continue or are initiated, both a PSUR 

and a DSUR should be prepared in 

accordance with directions from local 

authorities (DSUR draft guidance at p. 

7). After the DSUR draft guidance is 

finalized, the agency will consider 

whether to revise our IND annual 

reporting requirements to take into 

account its current thinking on the 

issue, including adopting an 

international birthdate. Until that time, 

the data cutoff date for the IND annual 

report is the IND effective date because 

the annual report must be submitted to 

FDA within 60 days of the anniversary 

of the date that the IND went into effect 

(see § 312.33). 

N. Investigator Reports—Proposed 

§ 312.64(b) 

FDA proposed to require that an 

investigator report to the sponsor any 

serious SADR immediately and any 

other SADR promptly unless the 

protocol or investigator’s brochure 

specifies a different timetable for 

reporting the SADR. 

(Comment 35) One comment 

suggested that FDA require investigators 

to report all protocol-defined treatmentemergent adverse events (TEAEs) 

expeditiously regardless of their causal 

attribution, but record their causality 

assessment when reporting such events. 

The comment defined a TEAE as an 

event that emerges during treatment 

having been absent pretreatment, or 

worsens relative to the pretreatment 

state. The comment stated that if the 

agency’s SADR definition is 

implemented as proposed, it is 

conceivable that investigators will not 

report certain TEAEs if they feel a 

causal relationship can be ruled out. 

Because there are no standard 

guidelines for ruling out a possible 

causal relationship, there could be 

inconsistent causality assessments and 

adverse event reporting across study 

sites. Another comment stated that 

applying the SADR definition to 

investigator reporting could result in 


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underreporting of serious adverse 

events. The comment maintained that 

the investigator should report all serious 

adverse events to the sponsor, without 

making a causality assessment. The 

comment further stated that the 

proposed approach would not be in 

harmony with ICH standards and 

European regulatory requirements, 

which require that all serious adverse 

events be immediately reported to the 

sponsor. One comment stated that 

investigators provide an important and 

informed medical review of causality, 

especially in the presence of complex 

disease states where many adverse 

events occur as a result of the 

underlying disease process. The 

comment suggested that FDA provide 

clear guidance on reportable causality. 

(Response) As noted in Comment 1 of 

this document, the agency has decided 

not to adopt the proposed SADR 

definition. FDA believes that there is 

more uncertainty when assessment of 

causality is based on an individual 

event rather than on aggregate data. The 

agency also believes that the sponsor is 

better positioned than the individual 

investigator to assess the overall safety 

of the investigational drug because the 

sponsor has access to serious adverse 

event reports from multiple study sites 

and is able to aggregate and analyze 

these reports. Therefore, the agency has 

determined that the sponsors should 

immediately receive reports from 

investigators of any serious adverse 

events, without regard to causality. 

However, the agency agrees that, 

because the investigator is 

knowledgeable about the human subject 

(e.g., medical history, concomitant 

medications), administers the 

investigational drug, and monitors the 

subject’s response to the drug, the 

investigator’s view on the causal 

relationship between an adverse event 

and the investigational drug is 

important, especially in the presence of 

complex disease states where many 

adverse events occur as a result of the 

underlying disease process. Because the 

insight from the investigator is 

important for the sponsor to consider in 

assessing the safety of the drug and 

determining whether to report 

expeditiously to FDA, the agency has 

revised the requirement to require that 

the investigator include an assessment 

of causality in the report to the sponsor. 

Revised § 312.64(b) requires 

investigators to immediately report to 

the sponsor any serious adverse event, 

whether or not considered drug related, 

including those listed in the protocol or 

investigator brochure and the report 

must include an assessment of whether 

there is a reasonable possibility that the 

drug caused the event. Study endpoints 

that are serious adverse events (e.g., allcause mortality) must be reported in 

accordance with the protocol unless 

there is evidence suggesting a causal 

relationship between the drug and the 

event (e.g., death from anaphylaxis). In 

that case, the investigator must 

immediately report the event to the 

sponsor. 

(Comment 36) Several comments 

requested clarification of the terms 

‘‘immediately’’ and ‘‘promptly’’ in the 

proposed requirement. The comments 

disagreed with the requirement to report 

other SADRs (i.e., nonserious) promptly 

to the sponsor, as the term ‘‘promptly’’ 

implies ‘‘quickly.’’ The comments stated 

that nonserious SADRs are traditionally 

recorded on case report forms during 

the study, then verified and collected by 

the sponsor during scheduled 

monitoring visits. One comment 

recommended that the requirement be 

revised to require investigators to 

record, rather than report, other SADRs 

promptly. 

(Response) The agency expects that, 

for serious adverse events, the 

investigator would notify the sponsor 

immediately. The agency recognizes 

that it may take a day to collect 

adequate information to confirm the 

occurrence of the adverse event but 

expects that as soon as the investigator 

has confirmed that the event occurred, 

the investigator will report it to the 

sponsor without delay. 

The agency agrees with the comments 

that the term ‘‘promptly’’ does not 

appropriately describe the best process 

for documenting and notifying the 

sponsor about nonserious adverse 

events. Therefore, the agency has 

revised § 312.64(b) to state that the 

investigator must record nonserious 

adverse events and report them to the 

sponsor according to the timetable for 

reporting specified in the protocol. The 

sponsor would need to determine the 

appropriate interval for collecting and 

analyzing nonserious adverse event 

information based on the drug under 

investigation and other study 

considerations, and delineate the 

timetable in the protocol. 

O. Bioavailability and Bioequivalence 

Requirements—Proposed § 320.31(d) 

FDA proposed to require that persons 

conducting human bioavailability or 

bioequivalence studies that are not 

subject to an IND submit expedited 

safety reports to FDA in accordance 

with § 312.32. In the preamble to the 

proposed rule (68 FR 12406 at 12415), 

the agency stated that, in general, 

bioavailability and bioequivalence 

studies that are not being conducted 

under an IND are safe. However, the 

agency is occasionally made aware of 

safety-related information associated 

with these types of studies, which could 

reflect either a problem with the drug 

product being evaluated or with the 

study design being used. Timely review 

of this safety information is critical to 

ensuring the safety of study subjects. 

FDA proposed to require that these 

safety reports be transmitted to all 

participating investigators and to the 

appropriate FDA division in CDER (i.e., 

safety reports for the reference listed 

drug would be sent to the new drug 

review division that has responsibility 

for that drug, safety reports for the 

investigational drug product would be 

sent to the Director, Division of 

Bioequivalence, Office of Generic Drugs) 

and each report bear prominent 

identification of its contents. For 

reporting purposes under § 320.31(d)(3), 

an unexpected SADR would be any 

SADR the specificity or severity of 

which is not consistent with the U.S. 

labeling for the reference listed drug. 

In general, the occurrence of a serious 

adverse event is very unusual in a 

bioavailability or bioequivalence study 

because the number of subjects enrolled 

in the study is small, the subjects are 

usually healthy volunteers, and drug 

exposure is typically brief. For these 

reasons, the occurrence of any serious 

adverse event is of interest. The agency 

reviewed the numbers and types of 

serious adverse events that we have 

received from these trials (i.e., in study 

reports submitted in abbreviated new 

drug applications (ANDAs)), and 

determined that they are typically listed 

in the labeling of the reference listed 

drug and, therefore, would not be 

subject to reporting under 

§ 312.32(c)(1)(i) as serious and 

unexpected suspected adverse reactions 

because they would not meet the 

regulatory definition of ‘‘unexpected.’’ In 

addition, because serious adverse events 

are so unusual in these studies, FDA 

believes that the causality assessment is 

unnecessary under these circumstances 

and that it is important to review all 

serious ‘‘adverse events.’’ Thus, the 

proposed requirement to report serious 

and unexpected SADRs would not have 

served its intended purpose of alerting 

the agency to serious adverse events 

occurring in these trials, so the agency 

has revised the requirement. The agency 

continues to believe that receiving 

reports from these trials is important for 

human subject protection and, therefore, 

has revised § 320.31(d)(3) to require that 

any serious adverse event must be 

reported, instead of any serious and 

unexpected SADR. The person 


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conducting the study, including any 

contract research organization, must 

notify FDA and all participating 

investigators of any serious adverse 

event, as defined in § 312.32(a), from the 

study as soon as possible but in no case 

later than 15 calendar days after 

becoming aware of its occurrence. Each 

report must be submitted on FDA Form 

3500A or in an electronic format that 

FDA can process, review, and archive. 

FDA will periodically issue guidance on 

how to provide the electronic 

submission (e.g., method of 

transmission, media, file formats, 

preparation, and organization of files). 

As proposed, each report must bear 

prominent identification of its contents, 

i.e., ‘‘bioavailability/bioequivalence 

safety report.’’ The person conducting 

the study, including any contract 

research organization, must also notify 

FDA of any fatal or life-threatening 

adverse event from the study as soon as 

possible but in no case later than 7 

calendar days after becoming aware of 

its occurrence. Each notification under 

§ 320.31(d)(3) must be submitted to the 

Director, Office of Generic Drugs in 

CDER. Relevant followup information to 

a bioavailability/bioequivalence safety 

report must be submitted as soon as the 

information is available and must be 

identified as such, i.e., ‘‘Followup 

bioavailability/bioequivalence safety 

report.’’ Upon request from FDA, the 

person conducting the study, including 

any contract research organization, must 

submit to FDA any additional data or 

information that the agency deems 

necessary, as soon as possible, but in no 

case later than 15 days after receiving 

the request. 

(Comment 37) Some comments 

requested clarification about the 

requirement to submit expedited safety 

reports for qualifying SADRs that arise 

in human bioavailability and 

bioequivalence studies that do not 

require an IND. The comments 

requested that the agency clarify 

whether this includes studies conducted 

outside of the United States and how 

these reports should be submitted in the 

absence of an IND. 

(Response) Under § 320.31(d)(3), 

sponsors of human bioequivalence or 

bioavailability studies that are exempt 

from the IND requirements under part 

312, but are conducted in the United 

States, must report any serious adverse 

events from the study to FDA (to the 

Office of Generic Drugs in CDER) and to 

all participating investigators. These 

requirements do not apply to human 

bioavailability and bioequivalence 

studies that are exempt from the IND 

requirements under part 312 and are 

conducted outside of the United States. 

However, as part of the information 

required to establish that the proposed 

drug product can be expected to have 

the same therapeutic effect as the 

reference listed product, adverse event 

reports that occurred in foreign clinical 

studies must be included in the ANDA 

submission (see § 314.94(a)(7)). 

P. Reports to Investigators and IRBs 

In proposed § 312.32(c)(1)(i) and 

(c)(1)(ii), FDA proposed to require that 

sponsors notify FDA and all 

participating investigators in a written 

IND safety report of any serious and 

unexpected SADR or information 

sufficient to consider product 

administration changes. Although both 

of these requirements have been revised 

(see response to Comments 15 to 17 and 

23 to 29 of this document), the 

requirement that FDA and all 

participating investigators receive IND 

safety reports for potential serious risks 

that emerge during the conduct of a 

clinical investigation has not changed in 

this final rule (see final § 312.32(c)(1)). 

In addition, under current § 312.66, 

the investigator must, among other 

things, assure that he or she will 

promptly report to the IRB all changes 

in the research activity and all 

unanticipated problems involving risk 

to human subjects or others, and that he 

or she will not make any changes in the 

research without IRB approval, except 

where necessary to eliminate apparent 

immediate hazards to human subjects. 

The agency did not propose any changes 

to this requirement. 

(Comment 38) Some comments 

pointed out that the proposed rule did 

not change the frequency or format for 

providing clinical investigators with 

information on serious, unexpected 

adverse events associated with the use 

of a drug. One comment agreed that it 

is imperative that investigators 

responsible for the conduct of studies be 

informed by the sponsor of findings that 

could adversely affect the safety of 

study participants. However, the 

comment noted that this process can be 

confusing and overwhelming, 

particularly for investigators of IND 

studies conducted outside the United 

States. Several comments proposed 

alternative reporting approaches that 

would provide investigators with 

reports that are more useful and 

efficient and less confusing. One 

comment recommended that the 

requirements for notifying all 

participating investigators be changed to 

allow a periodic summary and analysis 

of qualifying SADRs rather than 

individual reports that are difficult to 

track, aggregate, analyze, and interpret 

at the investigational site. Several 

comments encouraged FDA to further 

harmonize with CIOMS VI and the EU 

Clinical Trial Directive approach for 

investigator notification because: (1) 

Periodic (quarterly) aggregate line 

listings of suspected unexpected serious 

adverse reactions (SUSARs) 

accompanied by a summary of the 

evolving safety profile would provide 

useful information to investigators and 

IRBs, especially for Phase l–3 studies; 

(2) presenting all serious, unexpected, 

associated events in line listings 

regardless of medication administered 

(e.g., active drug, comparator, or 

placebo) would maintain the blind to 

the investigator; and (3) significant 

safety issues would be communicated as 

soon as possible to the investigators. 

These comments stated that 

investigators would recognize that these 

expedited communications represent 

significant safety information that is to 

be immediately reviewed and provided 

to their IRBs. The comments noted that 

expedited reporting to FDA and 

processes for updating the investigator 

brochure would remain unchanged. 

In addition, one comment requested 

that FDA not require investigator 

notification letters for investigations of 

marketed products, even if conducted 

under an IND, unless the investigation 

is for a patient population or indication 

that is different from that approved. The 

comment stated that any significant new 

safety information will be evaluated by 

the sponsors as part of their signal 

detection process and, if necessary, will 

be incorporated in the product label. 

The comment recommended that FDA 

allow periodic line-listings to be sent to 

investigators in lieu of individual 

reports. 

(Response) The agency is aware that 

for large, multi-center trials, 

investigators have expressed concern 

about receiving large numbers of 

individual adverse event reports that 

may not be useful. The agency believes 

that these final requirements will 

significantly diminish the numbers of 

individual reports that, in isolation, do 

not provide useful information to the 

investigator. For example, the 

requirement under § 312.32(c)(1)(i), 

described in the response to Comment 

18 of the document, makes it clear that 

specific events (such as known 

consequences of the underlying disease 

or condition under investigation or 

other events that commonly occur in the 

study population independent of drug 

therapy) are to be reported to FDA and 

all participating investigators only if 

there is evidence, based on an aggregate 

analysis, to suggest a causal relationship 

between the drug product and the 

adverse event. The rule also makes it 


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clear that study endpoints would 

ordinarily not be reported as serious, 

unexpected suspected adverse reactions 

(response to Comment 19 of this 

document). These clarifications are 

expected to reduce the number of 

reports that do not contribute in a 

meaningful way to the developing 

profile of the drug. 

FDA does not agree with the comment 

that suggested that investigators not be 

notified of serious, unexpected 

suspected adverse reactions from 

investigations of marketed products 

unless the investigation is for a patient 

population or indication different from 

that approved. Regardless of the patient 

population or indication, information 

about a serious, unexpected suspected 

adverse reaction may influence the 

investigator’s management of a clinical 

trial participant and, is therefore, 

critical information for the investigator 

to receive. 

(Comment 39) Some comments stated 

that although the IRB’s charge is to have 

written procedures for reporting ‘‘any 

unanticipated problems involving risks 

to human subjects or others,’’ the 

proposed rule is silent about sending 

any information to IRBs. These 

comments recommended that the 

agency provide guidance to sponsors, 

manufacturers, investigators, and IRBs 

that clearly delineates the 

responsibilities of reporting SADRs to 

the IRB. One comment requested that 

FDA require that the IRB receive from 

the sponsor the same expedited reports 

that the sponsor sends to FDA and all 

participating investigators (under 

proposed § 312.32(c)(1)). Other 

comments pointed out that IRBs are 

currently overwhelmed with IND safety 

reports and recommended that sponsors 

provide IRBs with routine timely 

aggregated reports of listings of adverse 

events instead of individual reports. 

Another comment suggested that 

investigators be permitted to provide 

these line-listings to their IRBs in lieu of 

individual reports. One comment urged 

FDA to adopt the CIOMS VI 

recommendations for IRB notification. 

(Response) The agency concurs with 

the overall sentiments expressed by the 

comments and has provided 

recommendations for reporting adverse 

event information to IRBs in our 

‘‘Guidance for Clinical Investigators, 

Sponsors, and IRBs: Adverse Event 

Reporting—Improving Human Subject 

Protection.’’ We also expect that the 

more useful individual reports 

submitted by sponsors to FDA and 

investigators will translate into more 

useful information being provided by 

investigators to their IRBs. In addition, 

the agency may consider revisions to 

investigator reporting requirements to 

IRBs in a separate rulemaking initiative. 

Q. Miscellaneous Comments 

FDA stated in the preamble to the 

proposed rule that the term ‘‘sponsors’’ 

would be used to describe persons 

subject to the premarketing safety 

reporting regulations (68 FR 12406 at 

12412). 

(Comment 40) Two comments asked 

FDA to clarify how the safety reporting 

requirements apply to investigatorinitiated studies, since such studies are 

not mentioned in the agency’s definition 

of ‘‘sponsors.’’ 

(Response) The agency considers 

investigator-initiated studies to be 

synonymous with studies conducted by 

a sponsor-investigator. A sponsorinvestigator, 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 safety reporting 

requirements under § 312.32 would 

apply to an investigator-initiated study. 

(Comment 41) One comment 

suggested that FDA request that the 

National Institutes of Health (NIH) and 

other Federal agencies that have agreed 

to the Federal Policy for the Protection 

of Human Subjects (Common Rule) also 

adopt the proposed regulations. The 

comment stated that all participants in 

the research enterprise must be fully 

committed to the protection of research 

participants, and fostering better and 

more complete safety reporting will 

support that commitment. 

(Response) This final rule would 

apply to FDA-regulated research 

conducted by NIH and other Federal 

agencies. The agency agrees that 

improved safety reporting should 

enhance the protection of human 

subjects participating in clinical trials. 

(Comment 42) FDA proposed that the 

final rule would become effective 180 

days after its date of publication in the 

Federal Register, except for any final 

rule regarding the proposal to require 

that postmarketing SADRs in the 

individual case safety reports be coded 

using the Medical Dictionary for 

Regulatory Activities (MedDRA), which 

would become effective 1 year after its 

date of publication in the Federal 

Register. 

Many comments expressed concern 

that the proposed timeline for 

implementing the new requirements is 

too aggressive, given its impact on 

systems and processes (e.g., to develop, 

test, and validate a new system). Some 

comments did not believe 180 days was 

sufficient implementation time unless 

the final rule was significantly 

modified. One comment requested that 

FDA allow for a transition period for 

ongoing clinical trials if FDA continues 

with its interpretation of ‘‘related,’’ as 

used in the proposed SADR definition. 

One comment agreed with the adoption 

of MedDRA for premarketing safety 

reporting for clinical trials, but did not 

believe that the 1-year proposed 

timeline was realistic. Comments 

requested other implementation 

schedules, ranging from 12 to 18 months 

for all the requirements. 

(Response) The agency does not agree 

that an effective date of 180 days after 

the date of publication in the Federal 

Register is too aggressive. The agency 

believes that the revisions to the 

requirements in this final rule will 

streamline adverse event reporting and 

are crucial to ensuring that timely and 

accurate safety information about 

clinical trials is received, analyzed, and 

disseminated. Therefore, as proposed, 

the agency has retained the effective 

date for the final rule to be 180 days 

after the date of publication in the 

Federal Register. The concerns raised 

by the comments about the agency’s 

interpretation of ‘‘related’’ are no longer 

an issue because the agency did not 

adopt the SADR definition. In addition, 

the agency did not propose, and is not 

requiring in this final rule, the use of 

MedDRA for IND safety reporting. 

R. Initial Analysis of Impacts and 

Paperwork Burden Estimates 

For the initial analysis of impacts, 

FDA estimated the costs of adding the 

new premarketing safety reporting 

requirements (68 FR 12406 at 12456 and 

12457, table 14) (see section VI of this 

document for discussion). For the initial 

paperwork burden estimates, FDA 

estimated the total annual reporting 

burden associated with the 

premarketing safety reporting 

requirements, accounting for not only 

the additional burdens associated with 

the proposed new requirements, but 

also for burdens already approved by 

the Office of Management and Budget 

(OMB) for requirements under thencurrent §§ 312.32 and 312.64 (68 FR 

12406 at 12470, table 21) (see section 

VII of this document for further 

discussion). 

For narrative reports based on 

information sufficient to consider a 

change in product administration 

(discussed in section III.G of this 

document), for the initial analysis of 


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impacts, FDA estimated that sponsors 

would spend an additional 4 hours per 

report for up to 600 IND safety reports. 

For the paperwork burden, however, for 

the same 600 IND safety reports, FDA 

estimated that sponsors would spend a 

total of 8 hours per report. The 4-hour 

per report estimate in the initial analysis 

of impacts accounted only for the 

incremental burden of the proposed 

reports from in vitro studies, 

epidemiological studies, and clinical 

studies and did not account for required 

reports of ‘‘any finding from tests in 

laboratory animals that suggests a 

significant risk in human subjects’’ 

under then-current § 312.32(c)(1)(i)(B). 

However, the 8-hour per report 

paperwork burden estimate accounted 

not only for the burden of complying 

with the new proposed requirements, 

but also the then-current requirement to 

submit reports from animal tests. 

(Comment 43) Comments from 

industry stated that FDA 

underestimated the number of IND 

safety reports and that the proposed 

SADR definition could increase the 

volume of IND safety reports from 2-fold 

to 10-fold. Furthermore, comments 

claimed that any additional reports 

would be uninformative. An increase in 

the number of uninformative safety 

reports would create an additional 

burden on investigators and IRBs 

without a corresponding benefit. 

Comments noted that FDA’s analysis 

failed to account for the potential 

impact of these additional reports on 

IRBs and investigators. Moreover, in 

some cases, additional uninformative 

reports could force sponsors to 

unnecessarily break the blind of a 

clinical trial, potentially reducing the 

power of double-blind clinical trials to 

detect safety issues and imposing 

additional burdens to industry. 

(Response) As discussed in response 

to Comment 1 of this document, the 

agency has decided not to adopt the 

proposed SADR definition, and instead 

adopted definitions for the terms 

‘‘adverse event’’ and ‘‘suspected adverse 

reaction.’’ In addition, FDA clarified the 

circumstances under which IND safety 

reports need to be submitted. With these 

changes, we expect fewer reports. 

Therefore, the comments stating that 

FDA underestimated the number of IND 

safety reports have been addressed. 

(Comment 44) Some industry 

comments stated that FDA 

underestimated the number of hours 

required to prepare a narrative report 

based on information sufficient to 

consider changes in product 

administration or risk profile. These 

comments stated that preparing a 

narrative report requires more than 8 

hours. 

(Response) Although comments stated 

that preparing a narrative report 

requires more than 8 hours, none of 

these comments provided estimates for 

a specific number of hours. Without 

other information, we are unable to 

respond directly to these comments. 

Nevertheless, we recognize that there 

may be some situations and types of 

findings that would require sponsors to 

spend more time preparing a narrative 

report. Therefore, to capture the 

uncertainty of this estimate, FDA has 

decided to use a range of hours (from 4 

to 12 hours) to estimate the incremental 

burden of this requirement instead of 

the 4-hour estimate used in our initial 

analysis of impacts (section VI of this 

document) or the total 8-hour estimate 

used in the initial paperwork burden 

analysis (section VII of this document). 

IV. Legal Authority 

The premarket approval provisions of 

the act authorize FDA to require that 

drug labeling provide the practitioner 

with adequate information to permit 

safe and effective use of the drug 

product. Section 505 of the Federal 

Food, Drug, and Cosmetic Act (the act) 

(21 U.S.C. 355) requires us to weigh 

evidence of effectiveness and safety to 

determine whether the evidence 

supports drug approval, whether data 

are adequate to permit a clinical 

investigation to proceed under the IND 

regulations, and/or whether a product is 

appropriately labeled. Section 

351(a)(2)(C)(i)(1)) of the Public Health 

Service Act (the PHS Act) (42 U.S.C. 

262(a)(2)(C)(i)(I)) authorizes the agency 

to approve a biologics license 

application (BLA) only if the applicant 

demonstrates that the product is safe, 

pure, and potent. Section 351(a)(2)(A) of 

the PHS Act authorizes the agency to 

establish, by regulation, requirements 

for the approval, suspension, and 

revocation of biologics licenses. Section 

701(a) of the act (21 U.S.C. 371(a)) 

authorizes FDA to issue regulations for 

the efficient enforcement of the act. 

These statutory provisions authorize us 

to issue regulations requiring sponsors 

to submit safety information to the 

agency to support an IND, NDA, ANDA, 

or BLA. 

V. Environmental Impact 

The agency has determined under 21 

CFR 25.30(h) that this action is of a type 

that does not individually or 

cumulatively have a significant effect on 

the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

VI. Analysis of Impacts 

FDA has examined the impacts of the 

final rule under Executive Order 12866 

and the Regulatory Flexibility Act (5 

U.S.C. 601–612), and the Unfunded 

Mandates Reform Act of 1995 (Public 

Law 104–4). Executive Order 12866 

directs agencies to assess all costs and 

benefits of available regulatory 

alternatives and, when regulation is 

necessary, to select regulatory 

approaches that maximize net benefits 

(including potential economic, 

environmental, public health and safety, 

and other advantages; distributive 

impacts; and equity). The agency 

believes that this final rule is not a 

significant regulatory action under the 

Executive order. 

The Regulatory Flexibility Act 

requires agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because the new reporting 

requirements are likely to impose a 

minimal burden on small entities (less 

than 0.2 percent of the average value of 

shipments of entities with less than 10 

employees), the agency believes that the 

final rule will probably not have a 

significant economic impact on a 

substantial number of small entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $135 

million, using the most current (2009) 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this final rule to result in any 1-year 

expenditure that would meet or exceed 

this amount. 

In accordance with Executive Order 

12866, FDA has previously analyzed the 

potential economic effects of the 

proposed rule. Although FDA 

determined that the proposed rule was 

an economically significant rule as 

described in the Executive order, the 

final rule covers a smaller subset of the 

proposed regulatory actions and is only 

related to premarket safety reporting 

and safety reporting for certain 

bioavailability and bioequivalence 

studies. Consequently, the annual 

estimated costs of this final rule are 

projected to equal less than $0.7 

million. We are unable to quantify the 

benefits of the final rule, but expect that 


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Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 59957 

3The proposed premarketing reporting 

requirement revised the existing requirements and 

expanded the types of findings that sponsors should 

report as expedited narrative IND safety reports. As 

discussed in sections III.R and VII of this document, 

the estimated average incremental burden of the 

regulatory action in the initial analysis of impacts 

(i.e., 4 hours) accounted for then-current 

compliance (i.e., reports based on findings from 

animal tests) under then-current 

§ 312.32(c)(1)(i)(B)). 

the potential benefits of harmonized and 

improved safety reporting will justify 

the minimal costs of this rule. 

A. Need for the Regulation 

Ambiguous regulatory requirements 

may cause sponsors to unnecessarily 

submit certain IND safety reports to 

FDA and investigators. As described in 

section I of this document, lack of 

clarity about definitions and regulatory 

reporting requirements may create 

uncertainty about when to submit an 

IND safety report and may lead to overor underreporting to FDA and 

investigators. Uncertainty about safety 

reporting requirements can result in 

reports being submitted for adverse 

events when there is little evidence of 

a causal relationship between the drug 

and the adverse event. Such reports can 

produce so-called ‘‘noise’’ in the system 

and hinder the development of the 

premarket safety profile of an 

investigational drug. Conversely, 

exempting certain bioavailability and 

bioequivalence studies from safety 

reporting requirements may lead to 

underreporting of some serious adverse 

events. 

The rule will finalize definitions and 

IND safety reporting standards that are 

as consistent as possible with ICH 

documents, require expedited reporting 

of study findings suggesting a 

significant risk to humans, and establish 

reporting requirements for certain 

bioavailability and bioequivalence 

studies. Moreover, the final rule clarifies 

when certain safety information, such as 

study endpoints, should be reported, 

potentially reducing the number of 

uninformative reports sent to FDA, 

participating investigators, and IRBs. 

B. Costs of the Regulation (to Prepare 

and Submit Safety Reports) 

1. Number of Reports 

For the initial analysis of impacts, we 

estimated that sponsors would submit 

up to 200 reports per year to comply 

with the new requirement for safety 

reporting of bioavailability and 

bioequivalence studies under proposed 

§ 320.31(d). No comments were received 

on this estimate. Consequently, in the 

final analysis of impacts, we retain our 

original estimate of 200 reports per year. 

In the initial analysis of impacts, we 

estimated that sponsors would submit 

up to 600 written IND safety reports 

annually based on information 

sufficient to consider a change in 

product administration (proposed 

§ 312.32(c)(1)(ii))3. Consistent with ICH 

recommendations for IND safety 

reporting, the proposed rule would have 

clarified that sponsors should submit 

written IND safety reports when they 

receive information suggesting 

significant human risk sufficient to 

consider changes in the conduct of a 

clinical trial or product administration. 

Information suggesting a significant 

human risk could come from animal 

studies, in vitro studies, 

epidemiological studies, or clinical 

studies. We received no comments on 

this estimate. 

In contrast to the ICH 

recommendation that sponsors rapidly 

report an increase in the rate of 

occurrence of an expected, serious 

SADR, the preamble of the proposed 

rule noted that sponsors should submit 

this type of information in IND annual 

reports under § 312.33(b)(1) (68 FR at 

12406 at 12425). Because no changes to 

the IND annual reports were proposed, 

FDA did not estimate the incremental 

impact of these reports. For the final 

rule, however, increases in the 

occurrence rates of serious suspected 

adverse reactions over that listed in the 

protocol or investigator brochure must 

be reported as expedited IND safety 

reports. We have insufficient 

information to determine the potential 

impact of reporting increases in 

occurrence rates of serious suspected 

adverse reactions over that listed in the 

protocol or investigator brochure as 

expedited reports as opposed to 

including this information in annual 

reports. As part of good clinical 

practice, sponsors routinely review and 

analyze the incidence rates of serious 

and nonserious adverse events of their 

investigational drugs. Therefore, we 

expect that the incremental burden of 

this requirement will be minimal and 

estimate that sponsors will submit up to 

10 additional reports per year. 

Furthermore, the final rule clarifies 

the definition of a suspected adverse 

reaction for reporting purposes 

(§ 312.32(a)) and adds a requirement 

that sponsors only submit reports of 

study endpoints in unusual 

circumstances not described in the 

protocol (§ 312.32(c)(5)). We anticipate 

that by clarifying what is a suspected 

adverse reaction for reporting purposes 

and the circumstances under which 

study endpoints should be submitted as 

expedited reports, the number of 

uninformative expedited reports will be 

reduced, thus reducing the burden on 

sponsors, investigators, IRBs, and FDA. 

However, we have no information to 

estimate the magnitude of this reduced 

burden. 

Last, the final rule clarifies safety 

reporting requirements for investigators 

to report to sponsors (§ 312.64(b)). 

Instead of requiring that investigators 

promptly report any adverse event 

reasonably caused or probably caused 

by the drug, the final rule requires that 

investigators immediately report any 

serious adverse event to the sponsor and 

include an assessment of whether there 

is a reasonable possibility that the drug 

caused the event. Because it is common 

practice for sponsors to outline similar 

reporting responsibilities in their 

clinical trial protocols, we assume that 

this final requirement will impose no 

additional burden. 

2. Costs to Prepare and Submit Safety 

Reports 

As shown in table 3 of this document, 

we estimate that it takes an average of 

14 hours to prepare a safety report for 

a bioavailability and bioequivalence 

study. Based on 2007 hourly median 

wages for the pharmaceutical 

manufacturing industry, each of these 

reports will cost sponsors about $950. 

As discussed in Comment 44 of this 

document, the additional time needed 

to prepare a report of findings 

suggesting a significant risk in humans 

may vary. We estimate that sponsors 

could spend from 4 to 12 hours 

additional time to prepare a narrative 

IND safety report. The average 

incremental cost of a narrative IND 

safety report ranges from $250 to $750 

(table 3 of this document). 


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TABLE 3.—ESTIMATED INCREMENTAL BURDEN AND UNIT COSTS FOR IND SAFETY REPORTS

Type of Report 

Burden (hours) and Type of Expertise Required 

Total Burden 

(hours) Total Cost ($)4

Clerical1

Epidemiology 

and Clinical 

Medicine2

Regulatory 

Affairs3

Bioavailability and Bioequivalence Safety Reports 2 1 11 14 950 

IND Safety Reports—lower estimate5 1 1 2 4 250 

IND Safety Reports—upper estimate5 3 3 6 12 750 

Numbers are rounded. 

Source: U.S. Department of Labor, Bureau of Labor Statistics, May 2007 (Ref. 4). 

1Based on median hourly wages for Office and Administrative Support Occupations (43–0000) and 40 percent benefits ($24.43 = $17.44 x 

1.4). 2Based on median hourly wages for Medical and Health Services Managers (11–9111) and 40 percent benefits ($75.03 = $53.59 x 1.4). 2Based on median hourly wages for Medical and Health Services Managers (11–9111) and 40 percent benefits ($75.03 = $53.59 x 1.4). 3Based on median hourly wages for Management Occupations (11–0000) and 40 percent benefits ($74.96 = $53.54 x 1.4). 

4 Unit costs are rounded. 

5 Includes reports based on findings suggesting a significant risk in humans from epidemiological studies, pooled analysis of multiple studies, 

other clinical studies, or in vitro testing. Reports from animal testing are not included (see footnote 3 of this document). 

Table 4 of this document summarizes 

the estimated total costs of the final 

rule. Annually, sponsors will submit up 

to 200 safety reports for bioavailability 

and bioequivalence studies and up to 

610 IND safety reports. We estimate that 

the total costs of the final rule will equal 

less than $0.7 million annually. 

TABLE 4.—ESTIMATED TOTAL COSTS OF THE FINAL RULE

Type of Report Unit Costs ($) Annual No. of Reports Total Annual Costs ($) 

Bioavailability and Bioequivalence Safety Reports1 950 200 190,000 

IND Safety Reports2 250 to 750 610 150,000 to 460,000 

Total Costs 340,000 to 650,000 

Numbers are rounded; total costs are rounded to the nearest ten thousand dollar increment. 

1We received no comments that provided sufficient information to revise our initial estimate. Because these events occur sporadically and the 

number of reports will vary from year to year, these numbers represent reasonable estimates of the annual average number of reports. 2The annual number of IND safety reports includes the proposed 600 reports of information suggesting a significant human risk (from epidemiological studies, pooled analysis of multiple studies, other clinical studies, or in vitro testing, but not from animal testing (see footnote 3 of this 

document)) and an additional 10 reports of increases in the occurrence rates of serious suspected adverse reactions over that listed in the protocol or investigator brochure. 

C. Benefits of the Regulation 

Benefits for the initial analysis of 

impacts were based on potential 

improvements in public health from 

better postmarket safety reporting and 

surveillance. The definitions and other 

requirements of the final rule provide a 

standardized framework against which 

adverse events and adverse reactions 

can be evaluated, reducing ambiguity 

and uncertainty about when and how to 

submit IND safety reports. 

The final rule adds a requirement to 

submit safety reports for certain 

bioavailability and bioequivalence 

studies that have been exempt from 

safety reporting. These studies have 

been exempted from safety reporting 

requirements because serious adverse 

events in these types of studies are rare. 

As described elsewhere in this 

document, most serious adverse events 

would be listed in the labeling of the 

reference listed drug and thus would 

not meet the threshold for expedited 

IND safety reporting. However, 

reporting such unusual events would 

alert FDA to serious adverse events 

occurring in these trials. For this reason, 

it is prudent that FDA review such 

safety information. However, we lack 

sufficient information to estimate the 

magnitude of these potential benefits. 

The revised IND safety reporting 

requirements will clarify when a 

sponsor should send a narrative IND 

safety report to FDA and participating 

investigators. Regardless of who 

conducts a study or whether a study is 

conducted under an IND, any finding 

that suggests a significant risk to 

humans must be reported as an 

expedited report. A risk is considered 

significant if it will ordinarily result in 

a safety-related change in the protocol, 

informed consent, investigator brochure, 

or conduct of the clinical investigation. 

Findings of a significant risk to humans 

can come from many sources, including 

epidemiological studies, pooled analysis 

of multiple studies, clinical studies, 

animal testing, or in vitro testing. 

Expedited reports of important safety 

information will enable FDA to more 

quickly review and monitor the safety 

profile of investigational drugs. 

However, because we lack estimates of 

the impact of expedited reporting on 

drug safety, we are not able to estimate 

the potential benefits of this reporting 

requirement. 

The final rule includes a new 

requirement to report clinically 

important increases in the occurrence 

rates of serious suspected adverse 

reactions over that listed in the protocol 

or investigator brochure as expedited 

IND safety reports. Because these 

reports are usually based on incidence 

rates from clinical trials (i.e., known 

exposure rates), such reports can alert 

FDA to previously undetected human 

safety risks. Although these reports can 

occur sporadically, such reports can 

provide important information that 


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Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 59959 

could affect drug safety profiles. 

However, we lack sufficient information 

to estimate the magnitude of these 

potential benefits. 

Uncertainty about reporting 

requirements can lead sponsors to 

overreport or underreport safety events. 

Overreporting can introduce so-called 

‘‘noise’’ that can delay the detection of 

possible safety problems. 

Underreporting potential safety 

problems can also delay identification 

of an important new risk. We expect 

that the final rule will remove some of 

the uncertainty that may lead sponsors 

to over- and underreport adverse events. 

In addition, we expect that FDA will 

receive expedited reports of safety 

information that suggest a significant 

risk in humans. Such reports can 

promote timely review of important 

drug safety information. Although we 

are unable to make a quantitative 

estimate of the benefits of the final rule, 

we believe that the potential benefits 

realized through more informative, 

accurate, and timely safety reports will 

justify the minimal costs of the final 

rule. 

D. Final Regulatory Flexibility Analysis 

This final rule will harmonize certain 

FDA safety reporting requirements with 

international initiatives and improve the 

quality of safety reporting for IND 

products and certain marketed products. 

According to the Table of Small 

Business Size Standards, the U.S. Small 

Business Administration (SBA) 

considers pharmaceutical preparation 

manufacturing entities (NAICS 325412) 

with 750 or fewer employees and 

biological product manufacturing 

entities (NAICS 325414) with 500 or 

fewer employees to be small. Statistics 

on the classification of firms by 

employment size from the U.S. Bureau 

of the Census show that in 2005, at least 

85 percent of pharmaceutical 

manufacturing and biological product 

manufacturing entities had fewer than 

500 employees and would have been 

considered small by SBA. 

Entities have sufficient expertise to 

comply with the new safety reporting 

requirements. As shown in table 5 of 

this document, the unit costs of a safety 

report total less than 0.2 percent of the 

average value of shipments for the 

smallest entities. As further explained 

previously, the agency does not believe 

that this final rule will have a 

significant economic impact on a 

substantial number of small entities, but 

the impact is uncertain. Although some 

final requirements extend to 

investigators, we anticipate no 

additional burden on investigators who 

would meet the SBA definition of small 

entity. 

TABLE 5.—UNIT COSTS OF SAFETY REPORTS AS A PERCENTAGE OF THE AVERAGE VALUE OF SHIPMENTS FOR VERY

SMALL ESTABLISHMENTS

Pharmaceutical Preparation Manufacturing (NAICS 325412)1Biological Product Manufacturing 

(NAICS 325414)2

No. of employees <5 <10 <5 <10 

Total value of shipments ($1,000) 187,933 561,636 32,011 115,307 

No. of establishments 228 339 67 109 

Average value of shipments ($) 824,268 1,656,743 477,776 1,057,862 

Unit costs of an IND safety report as a percentage of the average value of shipments3 0.0% to 0.1% 0.0% to 0.0% 0.1% to 0.2% 0.0% to 0.1% 

Unit costs of a bioavailability or bioequivalence report as a 

percentage of the average value of shipments4 0.1% 0.1% 0.2% 0.1% 

Numbers are rounded. 

1Source: U.S. Department of Commerce, Bureau of the Census, 2002 (Ref. 5). 

2Source: U.S. Department of Commerce, Bureau of the Census, 2002 (Ref. 6). 

3Based on a unit cost ranging from $250 to $750. 

4Based on a unit cost = $950. 

VII. Paperwork Reduction Act of 1995 

This final rule contains information 

collection requirements that are subject 

to review by OMB under the Paperwork 

Reduction Act of 1995 (44 U.S.C. 3501– 

3520) (the PRA). The title, description, 

and respondent description of the 

information collection provisions are 

shown in the following paragraphs with 

an estimate of the annual reporting 

burden. Our estimate includes the time 

for reviewing instructions, searching 

existing data sources, gathering and 

maintaining the data needed, and 

completing and reviewing each 

collection of information, not accounted 

for under then-current § 312.32 or 

§ 312.64, already approved by OMB 

(OMB control number 0910–0014). 

Title: Investigational New Drug Safety 

Reporting Requirements for Human 

Drug and Biological Products and Safety 

Reporting Requirements for 

Bioavailability and Bioequivalence 

Studies in Humans 

Description: The final rule clarifies 

the agency’s expectations for timely 

review, evaluation, and submission of 

relevant and useful safety information 

and implements internationally 

harmonized definitions and reporting 

standards for IND safety reports. The 

final rule also subjects bioavailability 

and bioequivalence studies to safety 

reporting requirements. The final rule is 

intended to improve the utility of IND 

safety reports, expedite FDA’s review of 

critical safety information, better protect 

human subjects enrolled in clinical 

trials, and harmonize safety reporting 

requirements internationally. 

The Final Rule and Estimates of 

Reporting Burden 

The rule finalizes revisions to the IND 

safety reporting requirements found in 

part 312 and the safety reporting 

requirements for bioavailability and 

bioequivalence studies found in part 

320. For the initial PRA analysis for the 

proposed rule, FDA estimated for the 

annual reporting burdens for collections 

of information for the entire proposal 

(i.e., pre- and postmarketing safety 

reporting requirements). For this PRA 

analysis, FDA has estimated only for the 

annual reporting burdens for collections 

of information included in this final 

rule (i.e., requirements found in 


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59960 Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 

§§ 312.32, 312.64, and 320.31). In 

addition, in the initial PRA analysis for 

the proposed rule, FDA estimated for 

the total reporting burden associated 

with the proposed reporting 

requirements in §§ 312.32, 312.64, and 

320.31 (as opposed to only the increased 

burdens associated with the proposed 

rule). Because OMB has approved 

paperwork burdens for many of the 

reporting requirements found in 

§§ 312.32 and 312.64, for purposes of 

this final rule and this PRA analysis, 

FDA is providing estimates for only the 

additional burdens not already 

approved by OMB for §§ 312.32, 312.64, 

and 320.31 (OMB control number 0910– 

0014). The following provisions of the 

final rule contain collections of 

information and the following burden 

estimates are based on those discussed 

in the Analysis of Impacts (section VI.B 

of this document). 

Section 312.32(c)(1)(i) specifies the 

requirements for reporting to FDA in an 

IND safety report potential serious risks 

from clinical trials within 15 calendar 

days for reports of serious and 

unexpected suspected adverse reactions 

and provides examples of what 

evidence supports a suggestion that 

there is a causal relationship between 

the drug and the adverse event. For 

purposes of this final rule, there is no 

new information collection because the 

reporting burden is unchanged from 

former § 312.32 and the information 

collection is already approved by OMB 

(OMB control number 0910–0014). 

Section 312.32(c)(1)(ii) requires 

reporting to FDA in an IND safety report 

potential serious risks from clinical 

trials within 15 calendar days for 

findings from epidemiological studies, 

pooled analyses of multiple studies, or 

other clinical studies that suggest a 

significant risk in humans exposed to 

the drug. This reporting requirement 

was not included in former § 312.32. 

Section 312.32(c)(1)(iii) specifies the 

requirements for reporting to FDA in an 

IND safety report potential serious risks 

from clinical trials within 15 calendar 

days for findings from animal or in vitro 

testing that suggest a significant risk to 

humans. While reports from in vitro 

testing that suggest a significant risk to 

humans were not required to be 

reported under former § 312.32, reports 

from any finding from tests in laboratory 

animals were required to be reported 

(former § 312.32(c)(1)(i)(B)). For 

purposes of this final rule, for the 

provisions that are unchanged from 

former § 312.32, the information 

collection is already approved by OMB 

(OMB control number 0910–0014). For 

the additional reporting requirements 

(i.e., the proposed narrative reports 

excluding animal testing) in the initial 

PRA analysis, FDA estimated that 

sponsors would spend a total of 8 hours 

per report to prepare and submit these 

narrative reports. In response to 

comments, FDA has revised the estimate 

from an incremental 4 hours to a range 

from 4 hours to 12 hours per report. 

Given this range, the upper estimate of 

additional paperwork burden associated 

with this requirement for each applicant 

could be an additional 12 hours to 

prepare each narrative report. Therefore, 

for an additional 600 reports, FDA 

estimates the total annual reporting 

burden of this final rule could be as 

high as 7,200 hours. 

Section 312.32(c)(1)(iv) requires 

reporting to FDA in an IND safety report 

within 15 calendar days any clinically 

important increase in the rate of 

occurrence of serious suspected adverse 

reactions over that listed in the protocol 

or investigator brochure 

(§ 312.32(c)(1)(iv)). These reports were 

not required to be submitted within 15 

days under former § 312.32. FDA 

estimates that the minimal incremental 

burden for this requirement to be 

approximately 10 reports per year. 

Using the same upper estimate for the 

burden as discussed previously (i.e., 12 

hours to prepare each report), FDA 

estimates the additional burden 

associated with this requirement could 

be as high as 120 hours. We request 

industry to comment on whether the 

requirement will impose an increased 

burden and if so, provide an estimate of 

the reporting burden. 

Section 312.32(c)(2) requires reporting 

within 7 days any unexpected fatal or 

life-threatening suspected adverse 

reaction. For purposes of this final rule, 

there is no new information collection 

because the reporting burden is 

unchanged from former § 312.32 and the 

information collection is already 

approved by OMB (OMB control 

number 0910–0014). 

Section 312.32(c)(4) requires a 

sponsor of a clinical study of a drug 

marketed or approved in the United 

States that is conducted under an IND 

to submit safety reports for suspected 

adverse reactions that are observed in 

the clinical study. For purposes of this 

final rule, there is no new information 

collection because the reporting burden 

is unchanged from former § 312.32 and 

the information collection is already 

approved by OMB (OMB control 

number 0910–0014). 

Section 312.32(c)(5) clarifies the 

circumstances under which study 

endpoints should be submitted to FDA. 

FDA believes that these clarifications to 

former § 312.32 are likely to result in a 

reduction in the number of expedited 

reports that currently are accounted for 

by OMB. However, FDA has insufficient 

information to provide an estimate and 

was unable to ascertain from industry 

an estimate for such a reduction. 

Therefore, FDA requests that industry 

comment on the impact of this 

provision on reporting burdens. Any 

reduction in reports will be reflected the 

next time the information collection for 

§ 312.32 (OMB control number 0910– 

0014) is extended. 

Section 312.32(d)(1)-(3) requires 

followup reporting requirements. For 

purposes of this final rule, there is no 

new information collection because the 

reporting burden is unchanged from 

former § 312.32 and the information 

collection is already approved by OMB 

(OMB control number 0910–0014). 

Section 312.64(b) requires 

investigators to report immediately to 

the sponsor any serious adverse event 

and include an assessment of whether 

there is a reasonable possibility that the 

drug caused the event. FDA revised 

former § 312.64(b) for clarity and to 

reflect current practices for investigator 

reporting to sponsors. For purposes of 

this final rule, there is no new 

information collection because we 

believe that the reporting burden is 

unchanged from former § 312.64 and the 

information collection is already 

approved by OMB (OMB control 

number 0910–0014). 

Finally, § 320.31(d)(3) subjects 

bioavailability and bioequivalence 

studies to safety reporting requirements. 

This reporting requirement was not 

included in former § 320.31. Therefore, 

all of these reports would be new. For 

purposes of the initial PRA analysis and 

this PRA analysis, FDA estimated up to 

200 new safety reports required under 

§ 320.31(d) from bioavailability and 

bioequivalence studies. For these 200 

reports, FDA estimates that it could take 

applicants an additional 14 hours to 

prepare and submit each report. The 

burden for bioavailability and 

bioequivalence safety reporting 

requirements would total 2,800 hours 

per year as a result of this final rule. 

Description of Respondents: Business 

or other for-profit organizations. 

Table 6 of this document presents the 

estimated annualized reporting burden 

of the final rule, providing estimates for 

those safety reports not already 

approved under OMB control number 

0910–0014. 


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TABLE 6.—ESTIMATED ANNUAL REPORTING BURDEN OF THE FINAL RULE1

21 CFR Section No. of 

Respondents 

No. of Responses 

per Respondent 

Total Annual 

Responses 

Hours per 

Response Total Hours 

320.31(d) Bioavailability and 

Bioequivalence Safety Reports 10 20 200 14 2,800 

312.32(c)(1)(ii) and (c)(1)(iii) 

IND Safety Reports2 100 6 600 12 7,200 

312.32(c)(1)(iv) IND Safety Reports3 10 1 10 12 120 

1There are no capital costs or operating and maintenance costs associated with this collection. The estimates are for the additional burdens 

beyond those already approved for then-current §§ 312.32 and 312.64. 2 Includes reports based on findings suggesting a significant risk in humans from epidemiological studies, pooled analysis of multiple studies, 

other clinical studies, or in vitro testing. Reports from animal testing are not included (see footnote 3 of this document). 3 Includes reports of clinically important increases in the rate of occurrence of serious suspected adverse reactions over that listed in the protocol or investigator brochure. 

The information collection provisions 

of this final rule have been submitted to 

OMB for review. Prior to the effective 

date of this final rule, FDA will publish 

a notice in the Federal Register 

announcing OMB’s decision to approve, 

modify, or disapprove the information 

collection provisions in this final rule. 

An agency may not conduct or sponsor, 

and a person is not required to respond 

to, a collection of information unless it 

displays a currently valid OMB control 

number. 

VIII. Executive Order 13132: 

Federalism 

FDA has analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. FDA has 

determined that the rule does not 

contain policies that have substantial 

direct effects on the States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. Accordingly, the 

agency has concluded that the final rule 

does not contain policies that have 

federalism implications as defined in 

the Executive order and, consequently, 

a federalism summary impact statement 

is not required. 

IX. References 

The following references have been 

placed on display in the Division of 

Dockets Management (HFA–305), Food 

and Drug Administration, 5630 Fishers 

Lane, rm. 1061, Rockville, MD 20852, 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday. (FDA has verified the 

Web site addresses, but FDA is not 

responsible for any subsequent changes 

to the Web sites after this document 

publishes in the Federal Register.) 

1. Enterprise Directorate-General, European 

Commission, ‘‘Detailed Guidance on the 

Collection, Verification and Presentation of 

Adverse Reaction Reports Arising From 

Clinical Trials on Medicinal Products for 

Human Use,’’ revision 2, Brussels, ENTR/CT 

3, April 2006 (http://ec.europa.eu/enterprise/ 

index_en.htm). 

2. Council for International Organizations 

of Medical Sciences, ‘‘Guidelines for 

Preparing Core Clinical-Safety Information 

on Drugs. Second Edition, Including New 

Proposals for Investigator’s Brochures,’’ 

Report of CIOMS Working Groups III and V, 

Geneva, 1999. 

3. Council for International Organizations 

of Medical Sciences, ‘‘Management of Safety 

Information From Clinical Trials,’’ Report of 

CIOMS Working Group VI, Geneva, 2005. 

4. U.S. Department of Labor, Bureau of 

Labor Statistics, National Industry-Specific 

Occupational Employment and Wage 

Estimates. NAICS 325400 - Pharmaceutical 

and Medicine Manufacturing, May 2007, 

extracted September 3, 2008, http:// 

www.bls.gov/oes/current/naics4_325400.htm. 

5. U.S. Department of Commerce, Bureau 

of the Census, Economic Census, 

Manufacturing Industry Series, 

Pharmaceutical Preparation Manufacturing, 

Table 4, EC02–311–325412 (RV), 2002. 

6. U.S. Department of Commerce, Bureau 

of the Census, Economic Census, 

Manufacturing Industry Series, Biological 

Product Manufacturing, Table 4, EC02–311– 

325414 (RV), 2002. 

List of Subjects 

21 CFR Part 312 

Drugs, Exports, Imports, 

Investigations, Labeling, Medical 

research, Reporting and recordkeeping 

requirements, Safety. 

21 CFR Part 320 

Drugs, Reporting and recordkeeping 

requirements. 

■ Therefore, under the Federal Food, 

Drug, and Cosmetic Act, the Public 

Health Service Act, and under authority 

delegated to the Commissioner of Food 

and Drugs, 21 CFR parts 312 and 320 are 

amended as follows: 

PART 312— INVESTIGATIONAL NEW 

DRUG APPLICATION 

■ 1. The authority citation for 21 CFR 

part 312 continues to read as follows: 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 360bbb, 371; 42 U.S.C. 262. 

■ 2. Section 312.32 is revised to read as 

follows: 

§ 312.32 IND safety reporting. 

(a) Definitions. The following 

definitions of terms apply to this 

section: 

Adverse event means any untoward 

medical occurrence associated with the 

use of a drug in humans, whether or not 

considered drug related. 

Life-threatening adverse event or lifethreatening suspected adverse reaction. 

An adverse event or suspected adverse 

reaction is considered ‘‘life-threatening’’ 

if, in the view of either the investigator 

or sponsor, its occurrence places the 

patient or subject at immediate risk of 

death. It does not include an adverse 

event or suspected adverse reaction that, 

had it occurred in a more severe form, 

might have caused death. 

Serious adverse event or serious 

suspected adverse reaction. An adverse 

event or suspected adverse reaction is 

considered ‘‘serious’’ if, in the view of 

either the investigator or sponsor, it 

results in any of the following 

outcomes: Death, a life-threatening 

adverse event, inpatient hospitalization 

or prolongation of existing 

hospitalization, a persistent or 

significant incapacity or substantial 

disruption of the ability to conduct 

normal life functions, or a congenital 

anomaly/birth defect. Important medical 

events that may not result in death, be 

life-threatening, or require 

hospitalization may be considered 

serious when, based upon appropriate 

medical judgment, they may jeopardize 

the patient or subject and may require 


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59962 Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 

medical or surgical intervention to 

prevent one of the outcomes listed in 

this definition. Examples of such 

medical events include allergic 

bronchospasm requiring intensive 

treatment in an emergency room or at 

home, blood dyscrasias or convulsions 

that do not result in inpatient 

hospitalization, or the development of 

drug dependency or drug abuse. 

Suspected adverse reaction means 

any adverse event for which there is a 

reasonable possibility that the drug 

caused the adverse event. For the 

purposes of IND safety reporting, 

‘‘reasonable possibility’’ means there is 

evidence to suggest a causal relationship 

between the drug and the adverse event. 

Suspected adverse reaction implies a 

lesser degree of certainty about causality 

than adverse reaction, which means any 

adverse event caused by a drug. 

Unexpected adverse event or 

unexpected suspected adverse reaction. 

An adverse event or suspected adverse 

reaction is considered ‘‘unexpected’’ if it 

is not listed in the investigator brochure 

or is not listed at the specificity or 

severity that has been observed; or, if an 

investigator brochure is not required or 

available, is not consistent with the risk 

information described in the general 

investigational plan or elsewhere in the 

current application, as amended. For 

example, under this definition, hepatic 

necrosis would be unexpected (by virtue 

of greater severity) if the investigator 

brochure referred only to elevated 

hepatic enzymes or hepatitis. Similarly, 

cerebral thromboembolism and cerebral 

vasculitis would be unexpected (by 

virtue of greater specificity) if the 

investigator brochure listed only 

cerebral vascular accidents. 

‘‘Unexpected,’’ as used in this definition, 

also refers to adverse events or 

suspected adverse reactions that are 

mentioned in the investigator brochure 

as occurring with a class of drugs or as 

anticipated from the pharmacological 

properties of the drug, but are not 

specifically mentioned as occurring 

with the particular drug under 

investigation. 

(b) Review of safety information. The 

sponsor must promptly review all 

information relevant to the safety of the 

drug obtained or otherwise received by 

the sponsor from foreign or domestic 

sources, including information derived 

from any clinical or epidemiological 

investigations, animal or in vitro 

studies, reports in the scientific 

literature, and unpublished scientific 

papers, as well as reports from foreign 

regulatory authorities and reports of 

foreign commercial marketing 

experience for drugs that are not 

marketed in the United States. 

(c)(1) IND safety reports. The sponsor 

must notify FDA and all participating 

investigators (i.e., all investigators to 

whom the sponsor is providing drug 

under its INDs or under any 

investigator’s IND) in an IND safety 

report of potential serious risks, from 

clinical trials or any other source, as 

soon as possible, but in no case later 

than 15 calendar days after the sponsor 

determines that the information 

qualifies for reporting under paragraph 

(c)(1)(i), (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv) 

of this section. In each IND safety 

report, the sponsor must identify all IND 

safety reports previously submitted to 

FDA concerning a similar suspected 

adverse reaction, and must analyze the 

significance of the suspected adverse 

reaction in light of previous, similar 

reports or any other relevant 

information. 

(i) Serious and unexpected suspected 

adverse reaction. The sponsor must 

report any suspected adverse reaction 

that is both serious and unexpected. The 

sponsor must report an adverse event as 

a suspected adverse reaction only if 

there is evidence to suggest a causal 

relationship between the drug and the 

adverse event, such as: 

(A) A single occurrence of an event 

that is uncommon and known to be 

strongly associated with drug exposure 

(e.g., angioedema, hepatic injury, 

Stevens-Johnson Syndrome); 

(B) One or more occurrences of an 

event that is not commonly associated 

with drug exposure, but is otherwise 

uncommon in the population exposed 

to the drug (e.g., tendon rupture); 

(C) An aggregate analysis of specific 

events observed in a clinical trial (such 

as known consequences of the 

underlying disease or condition under 

investigation or other events that 

commonly occur in the study 

population independent of drug 

therapy) that indicates those events 

occur more frequently in the drug 

treatment group than in a concurrent or 

historical control group. 

(ii) Findings from other studies. The 

sponsor must report any findings from 

epidemiological studies, pooled analysis 

of multiple studies, or clinical studies 

(other than those reported under 

paragraph (c)(1)(i) of this section), 

whether or not conducted under an IND, 

and whether or not conducted by the 

sponsor, that suggest a significant risk in 

humans exposed to the drug. Ordinarily, 

such a finding would result in a safetyrelated change in the protocol, informed 

consent, investigator brochure 

(excluding routine updates of these 

documents), or other aspects of the 

overall conduct of the clinical 

investigation. 

(iii) Findings from animal or in vitro 

testing. The sponsor must report any 

findings from animal or in vitro testing, 

whether or not conducted by the 

sponsor, that suggest a significant risk in 

humans exposed to the drug, such as 

reports of mutagenicity, teratogenicity, 

or carcinogenicity, or reports of 

significant organ toxicity at or near the 

expected human exposure. Ordinarily, 

any such findings would result in a 

safety-related change in the protocol, 

informed consent, investigator brochure 

(excluding routine updates of these 

documents), or other aspects of the 

overall conduct of the clinical 

investigation. 

(iv) Increased rate of occurrence of 

serious suspected adverse reactions. 

The sponsor must report any clinically 

important increase in the rate of a 

serious suspected adverse reaction over 

that listed in the protocol or investigator 

brochure. 

(v) Submission of IND safety reports. 

The sponsor must submit each IND 

safety report in a narrative format or on 

FDA Form 3500A or in an electronic 

format that FDA can process, review, 

and archive. FDA will periodically issue 

guidance on how to provide the 

electronic submission (e.g., method of 

transmission, media, file formats, 

preparation and organization of files). 

The sponsor may submit foreign 

suspected adverse reactions on a 

Council for International Organizations 

of Medical Sciences (CIOMS) I Form 

instead of a FDA Form 3500A. Reports 

of overall findings or pooled analyses 

from published and unpublished in 

vitro, animal, epidemiological, or 

clinical studies must be submitted in a 

narrative format. Each notification to 

FDA must bear prominent identification 

of its contents, i.e., ‘‘IND Safety Report,’’ 

and must be transmitted to the review 

division in the Center for Drug 

Evaluation and Research or in the 

Center for Biologics Evaluation and 

Research that has responsibility for 

review of the IND. Upon request from 

FDA, the sponsor must submit to FDA 

any additional data or information that 

the agency deems necessary, as soon as 

possible, but in no case later than 15 

calendar days after receiving the 

request. 

(2) Unexpected fatal or lifethreatening suspected adverse reaction 

reports. The sponsor must also notify 

FDA of any unexpected fatal or lifethreatening suspected adverse reaction 

as soon as possible but in no case later 

than 7 calendar days after the sponsor’s 

initial receipt of the information. 

(3) Reporting format or frequency. 

FDA may require a sponsor to submit 

IND safety reports in a format or at a 


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Federal Register / Vol. 75, No. 188 / Wednesday, September 29, 2010 / Rules and Regulations 59963 

frequency different than that required 

under this paragraph. The sponsor may 

also propose and adopt a different 

reporting format or frequency if the 

change is agreed to in advance by the 

director of the FDA review division that 

has responsibility for review of the IND. 

(4) Investigations of marketed drugs. 

A sponsor of a clinical study of a drug 

marketed or approved in the United 

States that is conducted under an IND 

is required to submit IND safety reports 

for suspected adverse reactions that are 

observed in the clinical study, at 

domestic or foreign study sites. The 

sponsor must also submit safety 

information from the clinical study as 

prescribed by the postmarketing safety 

reporting requirements (e.g., §§ 310.305, 

314.80, and 600.80 of this chapter). 

(5) Reporting study endpoints. Study 

endpoints (e.g., mortality or major 

morbidity) must be reported to FDA by 

the sponsor as described in the protocol 

and ordinarily would not be reported 

under paragraph (c) of this section. 

However, if a serious and unexpected 

adverse event occurs for which there is 

evidence suggesting a causal 

relationship between the drug and the 

event (e.g., death from anaphylaxis), the 

event must be reported under 

§ 312.32(c)(1)(i) as a serious and 

unexpected suspected adverse reaction 

even if it is a component of the study 

endpoint (e.g., all-cause mortality). 

(d) Followup. (1) The sponsor must 

promptly investigate all safety 

information it receives. 

(2) Relevant followup information to 

an IND safety report must be submitted 

as soon as the information is available 

and must be identified as such, i.e., 

‘‘Followup IND Safety Report.’’ 

(3) If the results of a sponsor’s 

investigation show that an adverse event 

not initially determined to be reportable 

under paragraph (c) of this section is so 

reportable, the sponsor must report such 

suspected adverse reaction in an IND 

safety report as soon as possible, but in 

no case later than 15 calendar days after 

the determination is made. 

(e) Disclaimer. A safety report or other 

information submitted by a sponsor 

under this part (and any release by FDA 

of that report or information) does not 

necessarily reflect a conclusion by the 

sponsor or FDA that the report or 

information constitutes an admission 

that the drug caused or contributed to 

an adverse event. A sponsor need not 

admit, and may deny, that the report or 

information submitted by the sponsor 

constitutes an admission that the drug 

caused or contributed to an adverse 

event. 

■ 3. Section 312.64 is amended by 

revising paragraph (b) to read as follows: 

§ 312.64 Investigator reports. 

* * * * * 

(b) Safety reports. An investigator 

must immediately report to the sponsor 

any serious adverse event, whether or 

not considered drug related, including 

those listed in the protocol or 

investigator brochure and must include 

an assessment of whether there is a 

reasonable possibility that the drug 

caused the event. Study endpoints that 

are serious adverse events (e.g., allcause mortality) must be reported in 

accordance with the protocol unless 

there is evidence suggesting a causal 

relationship between the drug and the 

event (e.g., death from anaphylaxis). In 

that case, the investigator must 

immediately report the event to the 

sponsor. The investigator must record 

nonserious adverse events and report 

them to the sponsor according to the 

timetable for reporting specified in the 

protocol. 

* * * * * 

PART 320—BIOAVAILABILITY AND 

BIOEQUIVALENCE REQUIREMENTS 

■ 4. The authority citation for 21 CFR 

part 320 continues to read as follows: 

Authority: 21 U.S.C. 321, 351, 352, 355, 

371. 

■ 5. Section 320.31 is amended in 

paragraphs (d)(1) and (d)(2) by removing 

the word ‘‘shall’’ and by adding in its 

place the word ‘‘must,’’ and by removing 

‘‘and’’ at the end of paragraph (d)(1) and 

replacing ‘‘this chapter.’’ at the end of 

paragraph (d)(2) with ‘‘this chapter; 

and’’, and by adding paragraph (d)(3) to 

read as follows: 

§ 320.31 Applicability of requirements 

regarding an ‘‘Investigational New Drug 

Application.’’ 

* * * * * 

(d) * * * 

(3) The person conducting the study, 

including any contract research 

organization, must notify FDA and all 

participating investigators of any serious 

adverse event, as defined in § 312.32(a), 

observed during the conduct of the 

study as soon as possible but in no case 

later than 15 calendar days after 

becoming aware of its occurrence. Each 

report must be submitted on FDA Form 

3500A or in an electronic format that 

FDA can process, review, and archive. 

FDA will periodically issue guidance on 

how to provide the electronic 

submission (e.g., method of 

transmission, media, file formats, 

preparation and organization of files). 

Each report must bear prominent 

identification of its contents, i.e., 

‘‘bioavailability/bioequivalence safety 

report.’’ The person conducting the 

study, including any contract research 

organization, must also notify FDA of 

any fatal or life-threatening adverse 

event from the study as soon as possible 

but in no case later than 7 calendar days 

after becoming aware of its occurrence. 

Each notification under this paragraph 

must be submitted to the Director, 

Office of Generic Drugs in the Center for 

Drug Evaluation and Research at FDA. 

Relevant followup information to a 

bioavailability/bioequivalence safety 

report must be submitted as soon as the 

information is available and must be 

identified as such, i.e., ‘‘Followup 

bioavailability/bioequivalence safety 

report.’’ Upon request from FDA, the 

person conducting the study, including 

any contract research organization, must 

submit to FDA any additional data or 

information that the agency deems 

necessary, as soon as possible, but in no 

case later than 15 calendar days after 

receiving the request. 

Dated: September 23, 2010. 

Leslie Kux, 

Acting Assistant Commissioner for Policy. 

[FR Doc. 2010–24296 Filed 9–28–10; 8:45 am] 

BILLING CODE 4160–01–S 

DEPARTMENT OF HOMELAND 

SECURITY 

Coast Guard 

33 CFR Part 165 

[Docket No. USCG–2010–0620] 

RIN 1625–AA00 

Safety Zone: Monte Foundation 

Firework Display, Monterey, CA 

AGENCY: Coast Guard, DHS. 

ACTION: Temporary final rule. 

SUMMARY: The Coast Guard is 

establishing a temporary safety zone in 

the navigable waters of Monterey Bay 

off the fishing pier of Seacliff State 

Beach, Santa Cruz, CA in support of the 

Monte Foundation Firework Display. 

This safety zone is established to ensure 

the safety of participants and spectators 

from the dangers associated with the 

pyrotechnics. Unauthorized persons and 

vessels are prohibited from entering 

into, transiting through, or remaining in 

the safety zone without permission from 

the Captain of the Port or her designated 

representative. 

DATES: This rule is effective from 7 a.m. 

through 9:30 p.m. on October 8, 2010. 

ADDRESSES: Documents indicated in this 

preamble as being available in the 

docket are part of docket USCG–2010– 

0620 and are available online by going 


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