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Conducting Successful pre-IND Meetings

to Reach FDA Concurrence for Sound

505(b)(2) Development

Kimberly Raines, Ph.D.

Lead Pharmacologist

Quality Assessment Lead (Acting)

Office of New Drug Product/Division of Biopharmaceutics III

2015 AAPS Annual Meeting and Exposition October 28, 2015

Pre-IND Meetings

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• Definition per (21 CFR 312.82)

– Prior to the submission of the initial IND, the sponsor may request a meeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on the design of animal studies needed to initiate human testing. The meeting may also provide an opportunity for discussing the scope and design of phase 1 testing, plans for studying the drug product in pediatric populations, and the best approach for presentation and formatting of data in the IND.

• The context of this presentation is on pre-INDs for 505(b)(2) submissions

– In which the is focus concentrates on the following specific scientific and/or regulatory issues:

• Clinical Study Design

• Toxicity

• Unique Metabolites

• Pharmaceutical Development (i.e. Formulation, Manufacturing Process and Controls, Microbiological Attributes)

• Dosing Limitations

• Immunogenicity

A productive pre-IND meeting may increase the likelihood of a successful drug development

strategy

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http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm053131.htm

Pre-IND Meeting Package

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• 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

The 505(b)(2) Pathway

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• Allows a sponsor to rely partially on existing clinical pharmacology safety and efficacy data via an NDA.

• Unlike approval under Section 505(j), the 505(b)(2) applicant may qualify for three to five years of market exclusivity*.

• The impact of changes in a 505(b)(2) submission are evaluated for influence on the safety and efficacy of the proposed drug product.

• A “bridge” (e.g., via comparative bioavailability data) between the proposed drug product and the listed drug upon which you propose to rely should be established to demonstrate that such reliance is scientifically justified.

*Orphan Drug Exclusivity is seven years

IND – Interactions/Ongoing Review

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Product Development Program (CMC) – Loosely Conceptualized

• Simple – POC • (Powder in

capsule) • Manual process • API considerations

Phase 1

• Form Dev • Dosage form • Process design/

optimization • Methods

Phase 2 • Registration? • Clinical/Com. Site • Methods • Final optimization

(QbD)

Phase 3

• Registration? • Com. Site • Scale • Process Validation

Commercial

Benefits of a pre-IND Meeting

• Opportunity to resolve critical drug developmental issues – Identification of “bridging data” needed to support the proposed

changes in the existing or previously approved drug product

– Prevent possible clinical hold issues from arising

• Obtain FDA input for the selection of Listed Drug, number and scope of safety/efficacy and toxicological studies and CMC programs

• Keeps the Sponsor up to date on FDA’s current thinking within the context of the regulatory environment.

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Pre-IND meeting can reduce time to market

• Identifying and avoiding unnecessary studies

• Ensuring that necessary studies are designed to provide useful information

• Gaining FDA support for a proposed strategy

• Potentially minimizing potiential 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

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Common Pitfalls at 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 form

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Factors for a Successful Pre-IND for 505(b)(2) • Design the drug development program with the end

product in mind – therapeutic indication, patient population, route of administration, clinical endpoints to be measured

• Plan the timing of a pre-IND meeting so that sufficient data are available to inform decisions

• Present data clearly and consistently, as provided in the meeting package

• Ask specific, well-phrased questions

• Prioritize questions

• Be forthcoming with potential issues of concern

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THANK YOU

Additional Slides

• Case Studies related to Biopharmaceutics issues

• References

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Case Study: BCS Biowaiver

• Drug company X proposes to submit a formal request for a waiver of in vivo Bioavailability/Bioequivalence studies in the 505(b)(2) submission for its capsule formulation based on a listed tablet formulation.

– The information provided in the waiver request will demonstrate that the drug substance is highly soluble and highly permeable and that the different dosage forms used in the clinical studies and proposed for commercial manufacture are very rapidly dissolving.

• Does the FDA agree that this strategy satisfies the requirement “to provide bridging information to show the PK of the tablets is similar to that of the capsules”

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FDA Response: The proposal to request a biowaiver for bridging the tablet and capsule formulations on the basis of the BCS designation of the listed tablet formulation as a Class 1 compound seems reasonable; the proposal to demonstrate that both dosage forms are rapidly dissolving is also acceptable. Submit the solubility, permeability, gastric stability, and dissolution data package to the IND, stating that you are requesting the FDA’s BCS Committee to assess and determine BCS Class 1 designation to the drug product.

Case Study: Process Change

• To reduce the overall mass and size of the tablet, instead of a hot melt extrusion process, Drug Company Z is developing the product using a wet ball milling process to achieve nanoparticles. Particle size distribution during subsequent steps of drug product manufacturing and over the shelf life will be evaluated by analytical methods such as, dissolution. Does the Agency agree?

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FDA Response: Your approach to use dissolution, to demonstrate that the nanoparticle size in the final drug product is maintained, appears reasonable. We recommend that you develop a discriminating dissolution method that is optimized for your proposed product prior to the NDA filing.

Case Study: Dissolution Development

• Drug Y is a highly soluble drug and despite attempts to manufacture drug product outside of the normal manufacturing process, dissolution of the product remained extremely rapid and the method was not able to discriminate formulations made within and outside of the acceptable manufacturing ranges (i.e. hardness).

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FDA Response: Submit all the dissolution testing and method validation data in the NDA to support the lack of discriminating ability of the method. The sponsor stated that the changes in hardness of the product resulted in changes in disintegration time but had no impact on dissolution. The FDA suggested that the sponsor may consider the use of a disintegration test in lieu of dissolution if the conditions stated in the decision tree (Setting Acceptance Criteria for Drug Product Dissolution) as per ICHQ6A are met. The FDA also states that even though disintegration may be adequate and dissolution may not be needed as a quality control specification, all the dissolution data must be submitted in the NDA for review.

Additional Information

• 21 CFR 312.47 (meetings)

• 312.82 (early consultation)

• Guidance for Industry- Formal Meetings Between the FDA and Sponsors or Applicants – 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)

• Guidance for Industry- E6 Good Clinical Practice: Consolidated Guidance – April 1996 (PDF - 311KB)

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