Guidance for Industry
Content and Format of Investigational New Drug Applications (INDs) for Pha 1 Studies of Drugs, Including
Well-Characterized, Therapeutic, Biotechnology-derived Products
Center for Drug Evaluation and Rearch (CDER) Center for Biologics Evaluation and Rearch (CBER)
November 1995
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)
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This guidance has been prepared by the Center for Drug Evaluation and 1Rearch (CDER) and the Center for Biologics Evaluation and Rearch (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 reprent 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)rver (CDVS2.CDER.FDA.GOV).
As ud throughout this guidance, the term "drugs" includes well-characterized,2therapeutic, biotechnology-derived products.
GUIDANCE FOR INDUSTRY 1
CONTENT AND FORMAT
OF INVESTIGATIONAL NEW DRUG APPLICATIONS (INDs) FOR PHASE 1 STUDIES OF DRUGS, INCLUDING WELL-
CHARACTERIZED, THERAPEUTIC, BIOTECHNOLOGY-DERIVED
PRODUCTS
I.INTRODUCTION
With FDA's recent success in meeting the Prescription Drug Ur 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., Pha 1 trials).
This guidance clarifies requirements for data and data prentation 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-characterized, therapeutic,biotechnology-derived products . Prent regulations allow a great deal of 2
flexibility in the amount and depth of various data to be submitted in an IND
depending in large part on the pha of investigation and the specific human
testing being propod. In some cas, the extent of that flexibility has not been appreciated. FDA believes clarifications of many of the 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 asss the safety of the propod Pha 1 study. If the guidance specified in this
document is followed, IND submissions for Pha 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 bad upon the unaudited draft toxicologic reports of completed animal studies as initial support for human
studies, and 2) specific manufacturing data appropriate for a Pha 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.
Becau of the manufacturing and toxicologic differences between well-
characterized, therapeutic, biotechnology-derived products and other biologic
products, this Guidance only applies to drugs and well-characterized,
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 u in the United States of a drug product not
previously authorized for marketing in the United States first requires
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 Pha 1 studies is required by regulation to contain the
ctions enumerated below. Clarifications are described when appropriate
beneath each ction heading.
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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 ction 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 ca, sponsors should simply state this in this ction 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 Brochure.
E.Protocols [21 CFR 312.23(a)(6)]:
The regulation requires submission of a copy of the protocol for the
conduct of each propod clinical trial. Sponsors are reminded that the
regulations were changed in 1987 specifically to allow Pha 1 study
protocols to be less detailed and more flexible than protocols for Pha 2 or 3 studies. This change recognized that the 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 Pha 1
protocols should be directed primarily at providing an outline of the
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