US Drug Development: The IND Submission

The drug-development process in the US consists of several major steps. This section of the THinc website focuses on the first major step: the submission of an IND to the FDA to allow clinical testing. Following is an overview of the type of information that would support a typical first-in-human (FIH) clinical trial. Many factors impact the decisions made during the drug-development process and can affect the development time and strategies.

Before the IND Application

The original IND can be extremely complex and complicated further by nonclinical safety or CMC issues. Sponsors may elect to request a pre-IND meeting with the FDA to avoid the possibility of the FDA delaying the start of the first clinical trial (i.e., being placed on clinical hold). The following are the types of information included in a typical original IND application.

Nonclinical Information
The goal of the nonclinical safety information is to estimate a safe starting dose and the dose range for the human trials and to identify clinical parameters to be monitored for potential adverse effects. The toxicology studies that support clinical testing in humans are discussed in the FDA Guidance for Industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, January 2010. The studies that support the first clinical trial include, but may not be limited to, single-dose toxicity studies (or appropriately conducted dose-escalation or short-duration dose-ranging studies) generally in two mammalian species, repeated-dose toxicity studies in 2 species (one nonrodent) for a minimum duration of 2 weeks to support an FIH clinical trial of up to 2 weeks duration, safety pharmacology studies, local tolerance studies, and genotoxicity studies.
Chemistry, Manufacturing, and Controls (CMC)
The goal of the CMC section of an IND is to provide sufficient information to support the identification, quality, purity, and strength of the investigational drug. The CMC section should provide information that will allow evaluation of the potential safety risks to subjects in the proposed FIH clinical trial. Safety concerns or the absence of CMC information to make a safety evaluation can be the basis for a clinical hold. The content and depth of the CMC section will vary with the complexity of the investigational drug. Clinical trial materials are to be manufactured in accordance with cGMP. General guidance on the content of the CMC section to support a first clinical trial is provided in the FDA 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.
First-in-Human Starting Dose
The first-in-human clinical starting dose depends on the results obtained from the nonclinical studies. In general, the FIH starting dose depends on the no observed adverse event level (NOAEL) in the most sensitive animal species tested. The general algorithm for deriving the maximum recommended starting dose for first clinical trials of new molecular entities in adult healthy volunteers is provided in the FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, July 2005.
Clinical Information
The proposed first clinical trial protocol will be assessed to determine if it exposes subjects to unnecessary risks. Currently, no official guideline is available for writing an FIH, Phase 1 clinical protocol. General elements of a protocol are outlined in Section 6 of the FDA Guideline for Industry: E6 Good Clinical Practice: Consolidated Guideline, April 1996. A general guideline on the IND is provided in the FDA Guideline 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.
An investigator's brochure is required in the IND and is generally provided to IRBs at the time of their protocol review. The general elements of an IB are outlined in Section 7 of the FDA Guideline for Industry: E6.
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