Guidance for Industry

Content and Format of Investigational

New Drug Applications (INDs) for Phase

1 Studies of Drugs, Including WellCharacterized, Therapeutic,

Biotechnology-derived Products

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

November 1995
i

CLIN 2

TABLE OF CONTENTS

I. INTRODUCTION ....................................... 1

II. CURRENT REQUIREMENTS AND PRACTICES ................... 2

III. CLARIFICATIONS OF PRESENT IND REGULATIONS ............... 2

A. Cover Sheet ...................................... 3

B. Table of Contents .................................. 3

C. Introductory Statement and General Investigational Plan ........ 3

D. Investigator's Brochure .............................. 3

E. Protocols ........................................ 3

F. Chemistry, Manufacturing, and Control Information ........... 4

G. Pharmacology and Toxicology Information ................ 10

H. Previous Human Experience with the Investigational Drug ...... 14

I. 21 CFR 312.23(a)(10), (11) and (b), (c), (d), and (e) ......... 14

IV. REFERENCES ........................................ 14
 This guidance has been prepared by the Center for Drug Evaluation and 1

Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at

the Food and Drug Administration. Although this guidance does not create or

confer any rights for or on any person and does not operate to bind FDA or the

industry, it does represent the agency’s current thinking on data requirement

issues related to the initial entry of an unapproved drug into human studies in the

United States. For additional copies of this guidance, contact the Consumer

Affairs Branch (formerly the Executive Secretariat Staff), HFD-210, CDER, FDA,

5600 Fishers Lane, Rockville, MD 20857 (Phone: 301-594-1012) or the

Congressional and Consumer Affairs Branch (HFM-12), CBER, FDA, 1401

Rockville Pike (STE 200N), Rockville, MD 20852-1448 (Phone: 301-594-1800 or

800-835-4709). An electronic version of this guidance is also available via

Internet by connecting to the CDER file transfer protocol (FTP) server

(CDVS2.CDER.FDA.GOV).

GUIDANCE FOR INDUSTRY1

CONTENT AND FORMAT 

OF INVESTIGATIONAL NEW DRUG APPLICATIONS (INDs) 

FOR PHASE 1 STUDIES OF DRUGS, INCLUDING WELLCHARACTERIZED, THERAPEUTIC, BIOTECHNOLOGY-DERIVED 

PRODUCTS

I. INTRODUCTION

With FDA's recent successes in meeting the Prescription Drug User Fee Act

of 1992 (PDUFA) review action performance goals, and the resulting

significant declines in mean and median time from submission of a

marketing application to approval for marketing, attention has turned to

increasing the efficiency of other components of the drug development

process without sacrificing the long-standing safety and efficacy standards

Americans expect their drug products to meet. One part of IND regulation

of particular interest - under active discussion for more than two years and

the subject of various degrees of attention since the McMahon Committee -

is the regulation of the initial testing of drugs in humans ( i.e., Phase 1

trials). 

This guidance clarifies requirements for data and data presentation in 21

CFR 312.22 and 312.23 related to the initial entry into human studies in

the United States of an investigational drug, including well-
 As used throughout this guidance, the term "drugs" includes well- 2

characterized, therapeutic, biotechnology-derived products.

2

characterized, therapeutic, biotechnology-derived products . 

2

Present regulations allow a great deal of flexibility in the

amount and depth of various data to be submitted in an IND

depending in large part on the phase of investigation and the

specific human testing being proposed. In some cases, the

extent of that flexibility has not been appreciated. FDA

believes clarifications of many of these requirements will help

expedite entry of new drugs into clinical testing by increasing

transparency and reducing ambiguity and inconsistencies, and

by reducing the amount of information submitted, while

providing FDA with the data it needs to assess the safety of

the proposed Phase 1 study. If the guidance specified in this

document is followed, IND submissions for Phase 1 studies

should usually not be larger than two to three, three inch, 3-

ring binders ("jackets").

 

The most significant clarifications are: 1) the explicit willingness to accept 

an integrated summary report of toxicology findings based upon the

unaudited draft toxicologic reports of completed animal studies as initial

support for human studies, and 2) specific manufacturing data appropriate

for a Phase 1 investigation. For products not covered by this Guidance,

other FDA guidance documents should be consulted. In addition, the

Center responsible for the product may be contacted for guidance.

Because of the manufacturing and toxicologic differences between wellcharacterized, therapeutic, biotechnology-derived products and other

biologic products, this Guidance only applies to drugs and wellcharacterized, therapeutic, biotechnology-derived products. For products

not covered by this Guidance, the Center responsible for the product should

be contacted for guidance.

This guidance applies equally to both commercial and individual investigator

sponsored INDs. 

II. CURRENT REQUIREMENTS AND PRACTICES

Under current regulations, any use in the United States of a drug product

not previously authorized for marketing in the United States first requires
3

submission of an IND to the FDA. Current regulations at 21 CFR 312.22

and 312.23 contain the general principles underlying the IND submission

and the general requirements for an IND's content and format. 

III. CLARIFICATIONS OF PRESENT IND REGULATIONS

An IND submission for Phase 1 studies is required by regulation to contain

the sections enumerated below. Clarifications are described when

appropriate beneath each section heading.

A. Cover Sheet (FDA Form-1571) [21 CFR 312.23(a)(1)]:

No clarifications.

B. Table of Contents [21 CFR 312.23(a)(2)]:

No clarifications.

C. Introductory Statement and General Investigational Plan [21 CFR

312.23(a)(3)]:

Regulations repeatedly describe this section as brief. Ordinarily, two

to three pages should suffice. The information requested here is

intended to place the developmental plan for the drug into

perspective and to help FDA anticipate sponsor needs. Often a

sponsor in the first human studies is simply attempting to determine

early pharmacokinetic and perhaps early pharmacodynamic properties

of the drug. Detailed developmental plans are contingent on the

outcomes of such studies. In that case, sponsors should simply state

this in this section and not attempt to develop and write detailed

developmental plans that will, in all likelihood, change considerably

should the product proceed to further development. 

D. Investigator's Brochure [21 CFR 312.23(a)(5)]:

Under the auspices of the International Conference on Harmonization

(ICH), a document that provides general guidance on the

Investigator's Brochure has been developed and will soon be

published in the Federal Register (Good Clinical Practice: Guideline for

the Investigator's Brochure). Sponsors are referred to this document

for further information on recommended elements of an Investigator's
4

Brochure.

E. Protocols [21 CFR 312.23(a)(6)]:

The regulation requires submission of a copy of the protocol for the

conduct of each proposed clinical trial. Sponsors are reminded that 

the regulations were changed in 1987 specifically to allow Phase 1

study protocols to be less detailed and more flexible than protocols

for Phase 2 or 3 studies. This change recognized that these

protocols are part of an early learning process and should be

adaptable as information is obtained, and that the principal concern

at this stage of development is that the study be conducted safely. 

The regulations state that Phase 1 protocols should be directed

primarily at providing an outline of the investigation: an estimate of

the number of subjects to be included; a description of safety

exclusions; and a description of the dosing plan, including duration,

dose, or method to be used in determining dose. In addition, such

protocols should specify in detail only those elements of the study

that are critical to subject safety, such as: 1) necessary monitoring

of vital signs and blood chemistries and 2) toxicity-based stopping or

dose adjustment rules. In addition, the regulations state that

modifications of the experimental design of Phase 1 studies that do

not affect critical safety assessments are required to be reported to

FDA only in the IND annual report. 

F. Chemistry, Manufacturing, and Control Information [21 CFR

312.23(a)(7)]:

The regulations at 312.23(a)(7)(i) emphasize the graded nature of

manufacturing and controls information. Although in each phase of

the investigation sufficient information should be submitted to assure

the proper identification, quality, purity, and strength of the

investigational drug, the amount of information needed to make that

assurance will vary with the phase of the investigation, the proposed

duration of the investigation, the dosage form, and the amount of

information otherwise available. For example, although stability data

are required in all phases of the IND to demonstrate that the new

drug substance and drug product are within acceptable chemical and

physical limits for the planned duration of the proposed clinical

investigation, if very short-term tests are proposed, the supporting

stability data can be correspondingly very limited. 
5

It is recognized that modifications to the method of preparation of the

new drug substance and dosage form, and even changes in the

dosage form itself, are likely as the investigation progresses. The

emphasis in an initial Phase 1 CMC submission should, therefore,

generally be placed on providing information that will allow evaluation

of the safety of subjects in the proposed study. The identification of

a safety concern or insufficient data to make an evaluation of safety

is the only basis for a clinical hold based on the CMC section.

Reasons for concern may include, for example: 1) a product made

with unknown or impure components; 2) a product possessing

chemical structures of known or highly likely toxicity; 3) a product

that cannot remain chemically stable throughout the testing program

proposed; or 4) a product with an impurity profile indicative of a

potential health hazard or an impurity profile insufficiently defined to

assess a potential health hazard; or 5) a poorly characterized master

or working cell bank.

In addition, for pre-clinical studies to be useful in assuring the safety

of human studies, sponsors should be able to relate the drug product

being proposed for use in a clinical study to the drug product used in

the animal toxicology studies that support the safety of the proposed

human study.

The information discussed in the following numbered paragraphs

should usually suffice for a meaningful review of the manufacturing

procedures for drug products used in Phase 1 clinical studies. 

Additional information should ordinarily be submitted for review of

the larger-scale manufacturing procedures used to produce drug

products for Phase 2 or Phase 3 clinical trials or as part of the

manufacturing section of a marketing application. Any questions

sponsors have about potential large scale IND clinical trials or

potential marketing application manufacturing requirements or

specifications should be directed to the appropriate division in the

CDER Office of New Drug Chemistry, or the appropriate CBER

division with responsibility for the product, for clarification and

discussion. As clinical development of a drug product proceeds,

sponsors should discuss the manufacturing data that will be needed

to support the safe use of their products in Phase 2 and 3 trials with

the appropriate division in the CDER Office of New Drug Chemistry,

or the appropriate CBER division with responsibility for the product. 
6

1. Chemistry and Manufacturing Introduction:

At the beginning of this section, the sponsor should state

whether it believes: 1) the chemistry of either the drug

substance or the drug product, or 2) the manufacturing of

either the drug substance or the drug product, presents any

signals of potential human risk. If so, these signals of potential

risks should be discussed, and the steps proposed to monitor

for such risk(s) should be described, or the reason(s) why the 

signal(s) should be dismissed should be discussed. 

In addition, sponsors should describe any chemistry and

manufacturing differences between the drug product proposed

for clinical use and the drug product used in the animal

toxicology trials that formed the basis for the sponsor's

conclusion that it was safe to proceed with the proposed

clinical study. How these differences might affect the safety

profile of the drug product should be discussed. If there are no

differences in the products, that should be stated.

2. Drug Substance [312.23 (a)(7)(iv)(a)]:

Sponsors are reminded that, under present regulations,

references to the current edition of the USP-NF may be used to

satisfy some of the requirements, when applicable. 

Information on the drug substance should be submitted in a

summary report containing the following items.

a. A description of the drug substance, including its

physical, chemical, or biological characteristics:

A brief description of the drug substance and some

evidence to support its proposed chemical structure

should be submitted. It is understood that the amount

of structure information will be limited in the early stage

of drug development.

b. The name and address of its manufacturer:

The full street address of the manufacturer of the clinical
7

trial drug substance should be submitted.

c. The general method of preparation of the drug

substance:

 

A brief description of the manufacturing process,

including a list of the reagents, solvents, and catalysts

used, should be submitted. A detailed flow diagram is

suggested as the usual, most effective, presentation of

this information. More information may be needed to

assess the safety of biotechnology-derived drugs or

drugs extracted from human or animal sources.

d. The acceptable limits and analytical methods used to

assure the identity, strength, quality, and purity of the

drug substance:

A brief description of the test methods used should be

submitted. Proposed acceptable limits supported by

simple analytical data, (e.g., IR spectrum to prove the

identity, and HPLC chromatograms to support the purity

level and impurities profile) of the clinical trials material

should be provided. Submission of a copy of the

certificate of analysis is also suggested. The specific

methods will depend on the source and type of drug

substance (e.g., animal source, plant extract,

radiopharmaceutic, other biotechnology-derived

products). Validation data and established specifications

ordinarily need not be submitted at the initial stage of

drug development. However, for some wellcharacterized, therapeutic biotechnology-derived

products, preliminary specifications and additional

validation data may be needed in certain circumstances

to ensure safety in Phase 1. 

e. Information to support the stability of the drug

substance during the toxicologic studies and the

proposed clinical study(ies):

A brief description of the stability study and the test

methods used to monitor the stability of the drug
8

substance should be submitted. Preliminary tabular data

based on representative material may be submitted. 

Neither detailed stability data nor the stability protocol

should be submitted.

3. Drug Product [21 CFR 312.23 (a)(7)(iv)(b)]:

Sponsors are reminded that, under present regulations,

references to the current edition of the USP-NF may be used to

satisfy some of these requirements, when applicable.

Information on the drug product should be submitted in a

summary report containing the following items:

a. A list of all components, which may include reasonable

alternatives for inactive compounds, used in the

manufacture of the investigational drug product,

including both those components intended to appear in

the drug product and those which may not appear, but

which are used in the manufacturing process:

A list of usually no more than one or two pages of

written information should be submitted. The quality

(e.g., NF, ACS) of the inactive ingredients should be

cited. For novel excipients, additional manufacturing

information may be necessary.

b. Where applicable, the quantitative composition of the

investigational new drug product, including any

reasonable variations that may be expected during the

investigational stage:

A brief summary of the composition of the

investigational new drug product should be submitted. 

In most cases, information on component ranges is not

necessary. 

c. The name and address of the drug product

manufacturer: 

The full street address(es) of the manufacturer(s) of the

clinical trial drug product should be submitted.
9

d. A brief, general description of the method of

manufacturing and packaging procedures as appropriate

for the product:

A diagrammatic presentation and a brief written

description of the manufacturing process should be

submitted, including sterilization process for sterile

products. Flow diagrams are suggested as the usual,

most effective, presentations of this information.

e. The acceptable limits and analytical methods used to

assure the identity, strength, quality, and purity of the

drug product:

A brief description of the proposed acceptable limits and

the test methods used should be submitted. Tests that

should be submitted will vary according to the dosage

form. For example, for sterile products, sterility and

non-pyrogenicity tests should be submitted. Submission

of a copy of the certificate of analysis of the clinical

batch is also suggested. Validation data and established

specifications need not be submitted at the initial stage

of drug development. For well-characterized,

therapeutic, biotechnology-derived products, adeaute

assessment of bioactivity and preliminary specifications

should be available.

f. Information to support the stability of the drug

substance during the toxicologic studies and the

proposed clinical study(ies):

A brief description of the stability study and the test

methods used to monitor the stability of the drug

product packaged in the proposed container/closure

system and storage conditions should be submitted. 

Preliminary tabular data based on representative material

may be submitted. Neither detailed stability data nor the

stability protocol should be submitted. 
10

4. A brief general description of the composition, manufacture,

and control of any placebo to be used in the proposed clinical

trial(s) [21 CFR 312.23(a)(7)(iv)(c)]:

Diagrammatic, tabular, and brief written information should be

submitted. 

5. A copy of all labels and labeling to be provided to each

investigator [21 CFR 312.23(a)(7)(iv)(d)]:

A mock-up or printed representation of the proposed labeling

that will be provided to investigator(s) in the proposed clinical

trial should be submitted. Investigational labels must carry a

"caution" statement as required by 21 CFR 312.6(a). That

statement reads: "Caution: New Drug - Limited by Federal (or

United States) law to investigational use." 

6. A claim for categorical exclusion from or submission of an

environmental assessment [21 CFR 312.23(a)(7)(iv)(e)]:

FDA believes the great majority of products should qualify for a

categorical exclusion. Sponsors who believe their

investigational product meets the exclusion categories under

21 CFR 25.24 should submit a statement certifying that their

product meets the exclusion requirements and requesting a

categorical exclusion on that basis. (For INDs submitted to

CDER, see Guidance for Industry for the Submission of

Environmental Assessments for Human Drug Applications and

Supplements, November, 1995.)

G. Pharmacology and Toxicology Information [21 CFR 312.23(a)(8)]:

[The following pharmacology and toxicology guidance is applicable to

all phases of IND development of products covered by this guidance.]

1. Pharmacology and Drug Distribution [21 CFR 312.23(a)(8)(i)]:

This section should contain, if known: 1) a description of the

pharmacologic effects and mechanism(s) of actions of the drug
11

in animals, and 2) information on the absorption, distribution,

metabolism, and excretions of the drug. The regulations do

not further describe the presentation of these data, in contrast

to the more detailed description of how to submit toxicologic

data. A summary report, without individual animal records or

individual study results, usually suffices. In most

circumstances, five pages or less should suffice for this

summary. If this information is not known, it should simply be

so stated. 

To the extent that such studies may be important to address

safety issues, or to assist in evaluation of toxicology data, they

may be necessary; however, lack of this potential effectiveness

information should not generally be a reason for a Phase 1 IND

to be placed on clinical hold. 

2. Toxicology: Integrated Summary [21 CFR 312.23(a)(8)(ii)(a)]

Present regulations require an integrated summary of the

toxicologic effects of the drug in animals and in vitro. The

particular studies needed depend on the nature of the drug and

the phase of human investigation. When species specificity,

immunogenicity, or other considerations appear to make many

or all toxicological models irrelevant, sponsors are encouraged

to contact the agency to discuss toxicological testing.

The regulations are not specific as to the nature of the report

of toxicology data needed in an IND submission and the nature

of the study reports upon which the report submitted to the

IND is based. The regulations are silent on whether the

submitted material should be based on: 1) "final fully qualityassured" individual study reports, or 2) earlier, unaudited draft

toxicologic reports of the completed study(ies). Most

sponsors have concluded that a submission based on final fully

quality-assured individual study reports is required, and a

substantial delay in submission of an IND for several months is

often encountered to complete such final fully quality-assured

individual reports from the time the unaudited draft toxicologic

reports of the completed studies are prepared.

Moreover, although the regulation does not specifically require
12

individual toxicology study reports to be submitted, referring

only to an integrated summary of the toxicologic findings, the

requirement at 21 CFR 312.23(a)(8)(ii)(b) for a full tabulation

of data from each study suitable for detailed review has led

most sponsors to provide detailed reports of each study. 

Although the GLP and quality assurance processes and

principles are critical for the maintenance of a toxicology study

system that is valid and credible, it is unusual, as far as FDA is

aware, for findings in the unaudited draft toxicologic report of

the completed studies to change during the production of the

"final," quality-assured individual study reports in ways

important to determining whether use in humans is safe.

Therefore, if final, fully quality-assured individual study reports

are not available at the time of IND submission, an integrated

summary report of toxicologic findings based on the unaudited

draft toxicologic reports of the completed animal studies may

be submitted. This integrated summary report should

represent the sponsor's evaluation of the animal studies that

formed the basis for the sponsor's decision that the proposed

human studies are safe. It is expected that the unaudited draft

reports that formed the basis of this decision might undergo

minor modifications during final review and quality assurance

auditing. Full toxicology department individual study reports

should be available to FDA, upon request, and individual study

reports should be available to FDA, upon request, as final, fully

quality-assured documents within 120 days of the start of the

human study for which the animal study formed part of the

safety conclusion basis. These final reports should contain in

the introduction any changes from those reported in the

integrated summary. If there are no changes, that should be

so stated clearly at the beginning of the final, fully qualityassured report.

If the integrated summary is based upon unaudited draft

reports, sponsors should submit an update to their integrated

summary by 120 days after the start of the human study(ies)

identifying any differences found in the preparation of the final

fully quality-assured study reports and the information

submitted in the initial integrated summary. If there were no
13

differences found, that should be stated in the integrated

summary update.

.

In addition, any new finding discovered during the preparation

of the final, fully quality-assured individual study reports that

could affect subject safety must be reported to FDA under 21

CFR 312.32. 

Usually, 10 to 15 pages of text with additional tables (as

needed) should suffice for the integrated summary. It should

represent the sponsor's perspective on the completed animal

studies at the time the sponsor decided human trials were

appropriate. Use of visual data displays ( e.g., box plots, stem

and leaf displays, histograms or distributions of lab results over

time) will facilitate description of the findings of these trials.

The summary document should be accurate

contemporaneously with the IND submission ( i.e., it should be

updated so that if new information or findings from the

completed animal studies have become known since the

sponsor's decision that the proposed human study is safe,

such new information should also be included in the submitted

summary).

The integrated summary of the toxicologic findings of the

completed animal studies to support the safety of the proposed

human investigation should ordinarily contain the following

information:

a. A brief description of the design of the trials and any

deviations from the design in the conduct of the trials. 

In addition, the dates of the performance of the trials

should be included. Reference to the study protocol and

protocol amendments may suffice for some of this

information.

b. A systematic presentation of the findings from the

animal toxicology and toxicokinetic studies. Those

findings that an informed and experienced expert would

reasonably consider as possible signals of human risk

should be highlighted. The format of this part of the
14

summary may be approached from a "systems review"

perspective: (e.g., CNS, cardiovascular, pulmonary,

gastrointestinal, renal, hepatic, genitourinary,

hematopoietic and immunologic, and dermal). If a

product's effects on a particular body system have not

been assessed, that should be so noted. If any welldocumented toxicological "signal" is not considered

evidence of human risk, the reason should be given. In

addition, the sponsor should note whether these findings

are discussed in the investigator's brochure.

c. Identification and qualifications of the individual(s) who

evaluated the animal safety data and concluded that it is

reasonably safe to begin the proposed human study. 

This person(s) should sign the summary attesting that

the summary accurately reflects the animal toxicology

data from the completed studies.

d. A statement of where the animal studies were

conducted and where the records of the studies are

available for inspection, should an inspection occur. 

e. As required under 21 CFR 312.23(a)(8)(iii), a declaration

that each study subject to good laboratory practices

(GLP) regulations was performed in full compliance with

GLPs or, if the study was not conducted in compliance

with those regulations, a brief statement of the reason

for the noncompliance and the sponsor's view on how 

such non-compliance might affect the interpretations of

the findings.

NOTE: The information described in paragraphs "c", "d", and

"e" may be supplied as part of the integrated summary or as

part of the full data tabulations described below.

3. Toxicology - Full Data Tabulation [21 CFR 312.23(a)(8)(ii)(b)]:

The sponsor should submit, for each animal toxicology study

that is intended to support the safety of the proposed clinical

investigation, a full tabulation of data suitable for detailed

review. This should consist of line listings of the individual
15

data points, including laboratory data points, for each animal in

these trials along with summary tabulations of these data

points. To allow interpretation of the line listings,

accompanying the line listings should be either: 1) a brief

(usually a few pages) description (i.e., a technical report or

abstract including a methods description section) of the study

or 2) a copy of the study protocol and amendments. 

4. Toxicology - GLP Certification [21 CFR 312.23(a)(8)(iii)]:

See section III.G.2.e. above.

5. Monitoring of Effects of these Clarifications:

At the end of the first two to three years of this new

procedure, FDA will assemble and examine the instances in

which the early and later animal study individual reports

differed to determine if such differences made a material

difference in the safe conduct of human trials. Depending on

the outcomes, the acceptability of this approach to reporting

toxicology studies to INDs may be re-examined. 

H. Previous Human Experience with the Investigational Drug [21 CFR

312.23(a)(9)]:

Present regulations require this information only if there has been

previous human experience with the investigational drug. If there has

been no previous human experience, the submission should so state. 

When there has been previous human experience, such experience 

may be presented in an integrated summary report. Individual study

reports should not be routinely submitted.

I. 21 CFR 312.23(a)(10), (11) and (b), (c), (d), and (e):

No clarifications.

IV. REFERENCES

A. Food and Drug Administration, Center for Drug Evaluation and

Research, "IND Process and Review Procedures" (MAPP xxxx.x),
16

Manual of Policies and Procedures, November, 1995.

B. International Conference on Harmonization: Good Clinical Practice:

Guideline for the Investigator's Brochure.

Submitted by:

____________________________________

Murray Lumpkin, M.D.

Deputy Director for Review Management

Center for Drug Evaluation and Research

Approved by:

____________________________________

Janet Woodcock, M.D.

Director, Center for Drug Evaluation and Research

____________________________________

Kathryn Zoon, Ph.D.

Director, Center for Biologics Evaluation and Research