Small Business and Industry Assistance: Frequently Asked Questions on the Pre-Investigational New Drug (IND) Meeting
The pre-IND meeting can be very valuable in planning a drug development program, especially if sponsors' questions are not fully answered by guidances and other information provided by FDA. Early interactions with FDA staff can help to prevent clinical hold issues from arising. A pre-IND meeting can also provide sponsors information that will assist them in preparing to submit complete investigational new drug applications. Efficient use of FDA resources can lead to more efficient drug development. These questions and answers can be especially helpful to small businesses that may have limited experience interacting with the Agency, or are unfamiliar with pre-IND meetings.
What are the definitions of the terms used in these questions and answers?
IND — The IND (investigational new drug application) is the vehicle through which a sponsor advances to the next stage of drug development known as clinical trials (human trials). Information on the IND application process is available at the IND Applications website.
Active Pharmaceutical Ingredient — Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug becomes an active ingredient of the drug product.
Good Clinical Practice — Good Clinical Practice (GCP) is a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials. For more information to the Good Clinical Practice website.
Orphan Drug — The term orphan drug refers to a product that treats a rare disease affecting fewer than 200,000 Americans. For additional information go to the FDA Orphan Products website.
Fast Track — Fast track programs are designed to facilitate the development and expedite the review of new drugs or biologics that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. The page Fast Track may be helpful
Accelerated Approval — Accelerated approval is a program that FDA developed to make new drug products available for life-threatening diseases when they appear to provide a benefit over available therapy (which could mean there was no existing effective treatment). The page Fast Track may be helpful
505(b)(1) Application — A 505(b)(1) application is an application that contains full reports of investigations of safety and effectiveness. The investigations the applicant relied on for approval were conducted by or for the applicant or the applicant has obtained a right of reference or use for the investigations.
505(b)(2) Application —A 505(b)(2) application is an application submitted under section 505(b) for which
- Some or all of the investigations the applicant relied on for approval were not conducted by or for the applicant
- The applicant has not obtained a right of reference or use for the investigations (21 U.S.C. 355(b)(2))
Section 505(b)(2) expressly permits FDA to rely, for approval of an NDA, on data not developed by the applicant, such as published literature or the Agency's finding of safety and/or effectiveness of a previously approved drug product.
Animal Efficacy Rule — The animal efficacy rule permits FDA to rely on animal evidence when
(1) the agent's mechanism of toxicity is well understood;
(2) the endpoints in the animal trials are clearly related to benefit in humans;
(3) the drug's effect is demonstrated in a species expected to react similarly to humans; and
(4) data allow selection of an effective human dose.
Can pre-IND meetings reduce time to market? Yes, time can be reduced by the following:
- Identifying and avoiding unnecessary studies
- Ensuring that necessary studies are designed to provide useful information
- Gaining FDA support for a proposed strategy
- Potentially minimizing potential for clinical hold
- Providing opportunity for creative exchange of ideas
- Obtaining regulatory insight
- Minimizing costs
- Clearly defining endpoints and goals of the development program
- Allowing early interactions/negotiations with FDA
In the process of drug development, when can a pre-IND meeting be very important?
- When the product is intended to treat a serious or life-threatening disease
- When there is a novel indication
- When there are no current guidance documents
- When there are sponsors new to drug development
- When there are questions from the sponsor
- When there are pharmacologic or toxicologic signals of concern
- When the drug is a new molecular entity
Can pre-IND meetings be helpful in developing a strategy for drug development? Yes. The following can be helpful in developing a strategy:
- Identifying studies that will support the initiation of clinical trials
- Discussing available methods to enhance development, for example:
- Orphan Drug Designation
- Fast Track Designation
- Accelerated Approval
- Animal Efficacy Rule
- Discussing the differences between submitting a 505(b)(1) or 505(b)(2) application
What information should be included in the meeting request?
Sponsors should review the guidance Formal Meetings with Sponsors and Applicants for PDUFA Products (PDF - 30KB) for information on formal meetings with sponsors and applicants. Adequate information in the meeting request is a very important part of having a successful outcome of a pre-IND meeting and should include the following information:
- Meeting objective
- Proposed agenda, including estimated times needed for each agenda item
- Listing of specific questions categorized and grouped by discipline, for example, chemistry, manufacturing, and controls (CMC), pharmacology/toxicology, clinical pharmacology and biopharmaceutics, and clinical investigations
- List of sponsor participants
- List of requested participants from CDER
- Quantitative composition (all ingredients by percent composition) of the drug proposed for use in the study to be discussed
- Proposed indication
- Dosing regimen, including concentration, amount dosed, and frequency and duration of dosing if known
- Proposed meeting date (propose 6-8 weeks in the future)
- When the background packet will be available (at least 4 weeks before the proposed meeting date)
What is the purpose of the pre-IND meeting packet?
- Provides the historical background information on the chemical development concept
- Provides information on the active ingredient
- Provides an initial clinical and preclinical development strategy
- Provides future development strategy including product scale-up and final formulation, and animal and clinical studies proposed in support of an NDA
- Provides FDA with a clear and concise overview of the planned development program
- Allows FDA the opportunity to comment on a proposed program of development
What do you include in a pre-IND meeting packet?
- Overall program synopsis
- Whether the animal efficacy rule is being considered
- Clinical study synopsis to obtain FDA input on inclusion, exclusion, and endpoints
- Results for in vitro and early in vivo toxicology
- Rationale for safety, based on toxicological profile and safety margin using dose regimen and exposure
- Brief description of the manufacturing scheme for the active pharmaceutical ingredient (API) and formulation for clinical study
- Brief assay descriptions
- Full description of the development plan
- Copy of the meeting request with updates to reflect the most current information
Is communication important in a pre-IND meeting? Yes, be sure to:
- Ask specific, well-phrased questions
- Prioritize questions
- Stay focused on the agenda
- Don't hide concerns
- Don't present data not included in the meeting packet
- Obtain clear and concise information through clear questions and listening
Are there recurrent problems at pre-IND meetings? Yes, the following have been identified in pre-IND meetings:
- Inadequate CMC information
- Insufficient pre-clinical support
- Unacceptable clinical trial design
- Noncompliance with Good Clinical Practices (GCPs)
- Lack of information on selection of dosage
In addition to the above, what else can be helpful?
- Make the best use of allotted time
- Agree with FDA on timing and required attendees
- Identify questions to ask FDA
- Make sure that a pre-IND meeting is necessary; answers to your questions may be available in the guidances
- Make sure that issues support good use of industry and FDA time
- Present data clearly and consistently
Additional information (regulations, guidances, and websites)
- 21 CFR 312.47 (meetings)
- Formal Meetings with Sponsors and Applicants for PDUFA Products – May 2009 (PDF 78KB)
- Guidance for Industry- M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals – January 2010 (PDF - 325KB)
- CDER Small Business and Industry Assistance webpage