Nonclinical Studies Subcommittee Advisory Committee for Pharmaceutical Science CMC Issues for Screening INDs Eric B. Sheinin, Ph.D. Acting Deputy Director Office of Pharmaceutical Science Center for Drug Evaluation and Research Food and Drug Administration December 14, 1999

Guidance for Industry Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products November 1995

Guidance for Industry - Phase 1 INDs Under current regulations, any use 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 and contain the general principles underlying the IND submission and the general requirements for an IND’s content and format.

Guidance for Industry - Phase 1 INDs CMC Information Amount of information needed in each phase to assure the identity, strength, quality, purity and potency of an investigational drug will vary based on the phase, the dosage form, and the amount of information otherwise available. Emphasis is on IND sponsors providing sufficient information to allow reviewers to evaluate the safety of subjects in the proposed studies.

Guidance for Industry - Phase 1 INDs CMC Information Safety concern, or lack of sufficient data to evaluate safety, is the only basis for a clinical hold –product made with unknown or impure components –product possessing chemical structures of unknown or highly like toxicity –product that will not be chemically stable throughout the proposed study(ies) –product with an impurity profile indicative of a potential health hazard (or insufficiently defined to assess) –poorly characterized master or working cell bank

Guidance for Industry - Phase 1 INDs CMC Information Sponsors should relate the drug product proposed for use in a clinical study to the drug product used in animal studies

Guidance for Industry - Phase 1 INDs CMC Information Introduction –Are there any signals of potential human risk? If yes, discuss and propose steps to monitor these risks or discuss why signals can be dismissed –Describe any differences between proposed clinical material and that used in animal trials. How do these differences affect safety profile of the drug product?

Guidance for Industry - Phase 1 INDs CMC Information Drug Substance –Reference to the current USP-NF may be used –Brief description-physical, chemical, biological –Name and address of manufacturer –Brief description-manufacturing process detailed flow diagram suggested more information needed for biotechnology- derived drugs or those extracted from human or animal sources

Guidance for Industry - Phase 1 INDs CMC Information Drug Substance –Brief description of analytical procedures and proposed acceptance criteria copy of Certificate(s) of Analysis validation data and established specifications not ordinarily needed except for some well- characterized, therapeutic biotechnology- derived products

Guidance for Industry - Phase 1 INDs CMC Information Drug Substance –Brief description-stability study and procedures to monitor stability during proposed study(ies) preliminary tabular data suggested detailed stability data and protocol not needed

Guidance for Industry - Phase 1 INDs CMC Information Drug Product –List of all components including reasonable alternatives for inactives quality should be cited; e.g., NF, ACS –Quantitative composition including reasonable variations –Name and address of manufacturer

Guidance for Industry - Phase 1 INDs CMC Information Drug Product –Brief description-manufacturing process diagrammatic presentation/flow diagram suggested sterilization process for sterile products –Brief description-stability study and procedures to monitor stability during proposed study(ies) preliminary tabular data suggested detailed stability data and protocol not needed

Guidance for Industry - Phase 1 INDs CMC Information –Brief description of analytical procedures and proposed acceptance criteria copy of Certificate(s) of Analysis validation data and established specifications not ordinarily needed except for some well- characterized, therapeutic biotechnology- derived products data should be available

Guidance for Industry - Phase 1 INDs CMC Information Drug Product –Brief description-composition, manufacture, and control of any placebo to be used –Copy of all labels and labeling Caution: New Drug - Limited by Federal (or United States) law to investigational use –Claim for categorical exclusion from or submission of an environmental assessment

Guidance for Industry INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic Biotechnology- Derived Products Chemistry, Manufacturing, and Controls Content and Format Draft February 1999

Guidance for Industry - Phase 2 & 3 INDs CMC Information Focus on safety issues relating to phase 2 and phase 3 studies Safety information and data and safety updates should be submitted as information amendments If changes do not affect safety, information can be submitted in summary annual reports

Guidance for Industry - Phase 2 & 3 INDs CMC Information CMC modification that may effect safety include, but are not limited to –change in method of sterilization –change in container/closure system affecting product quality –change in synthesis resulting in different impurity profiles –change from synthetic to biological source for drug substance