Regulatory Strategy For Pre-IND Meetings With FDA: Why .

Regulatory Strategy forPre-IND Meetings with FDA:Why Meet and What to AskAuthorsRonald A. Salerno, PhDKerin Ablashi, MSDebra Barngrover, PhD, RACKelly Reich, MS, RACAcknowledgementsDavid Lin, PhDChristopher Bussineau, PhDLeslie Wolfe, PhDBenjamin Del Tito, PhDBiologics Consulting White Paper – December 2017 2017 BIOLOGICS CONSULTING GROUP, INC. All Rights Reserved.1

TABLE OF CONTENTS1.INTRODUCTION . 41.1. Background. 41.2. Purpose . 42.PRE-IND MEETING DESCRIPTION . 42.1. FDA Guidance and Observations . 42.2. PDUFA Timelines . 53.WHY MEET? BENEFITS OF PRE-IND MEETING . 63.1. Reduce Time to Market . 63.2. Accelerate Drug Development Activities. 73.3. Define Drug Development Strategy . 83.4. Getting the Most from a Pre-IND Meeting . 93.4.1. Face-to-Face Meetings, or Teleconferences . 93.4.2. Written Responses Only . 113.5. Pre-IND Meeting Minutes . 114.WHAT TO ASK? FREQUENT PRE-IND QUESTIONS. 114.1. CMC . 114.2. Nonclinical . 134.3. Clinical . 135.STRATEGIC DECISION MAKING . 135.1. Pre-IND Risk Assessment of Potential Clinical Hold for IND Initial Study . 135.2. To Comply or Not to Comply with FDA Requests/Comments . 145.3. Plan to Answer all FDA pre-IND Comments in the IND Submission . 145.4. Track Timing and Commitments to Meet FDA Expectations During Clinical Development and for theBLA/NDA Submission . 146.7.SUMMARY AND CONCLUSIONS . 15REFERENCES . 157.1. FDA Resources. 157.2. Other References. 16Biologics Consulting White Paper – December 2017 2017 BIOLOGICS CONSULTING GROUP, INC. All Rights Reserved.2

GLOSSARYAgencyThe Food and Drug Administration (FDA)CMCChemistry, Manufacturing, and ControlsDrugProductA finished dosage form, for example, tablet, capsule, or solution, that contains adrug substance, generally, but not necessarily, in association with one or moreother ingredientsDrugSubstanceAn active ingredient that is intended to furnish pharmacological activity or otherdirect effect in the diagnosis, cure, mitigation, treatment, or prevention ofdisease or to affect the structure or any function of the human body, but doesnot include intermediates use in the synthesis of such ingredient.FormalmeetingAny Type A, B or C meeting that is requested by a Sponsor (hereafterRequester(s)) following the request procedures provided in the FDA Guidancefor Industry, “Formal Meetings Between the FDA and Sponsors or Sponsors ofPDUFA Products” and includes meetings conducted in any format (i.e., face toface, teleconference, videoconference, or written response).INDInvestigational New Drug application (also synonymous with "Notice of ClaimedInvestigational Exemption for a New Drug"). (CDER Guidance Document onContent and Format of Investigational New Drug Applications (INDs) for Phase 1Studies of Drugs or 21 CFR 314.312.)PDUFAPrescription Drug User Fee ActPre-INDPre-Investigational New Drug ApplicationRPMRegulatory Project Manager (at the FDA)SponsorSponsor means a person who takes responsibility for and initiates a clinicalinvestigation. The sponsor may be an individual or pharmaceutical company,governmental agency, academic institution, private organization, or otherorganization. The sponsor does not actually conduct the investigation unless thesponsor is a sponsor-investigator. A person other than an individual that usesone or more of its own employees to conduct an investigation that it has initiatedis a sponsor, not a sponsor-investigator, and the employees are investigators.WROWritten Response OnlyBiologics Consulting White Paper – December 2017 2017 BIOLOGICS CONSULTING GROUP, INC. All Rights Reserved.3

1. INTRODUCTION1.1. BackgroundBiologics Consulting is a full-service regulatory and product development consulting firm for biologics,pharmaceuticals and medical devices. Founded in 1993, Biologics Consulting works with companies large andsmall seeking to bring innovative, safe and effective products to market within the U.S. Biologics Consulting’s teamis comprised of subject-matter experts with decades of industry and/or FDA experience. In this paper, the authorsaim to utilize their years of experience preparing meeting requests and meeting packages, participating in pre-INDmeetings, and reviewing and responding to pre-IND meeting comments from the FDA to provide generalrecommendations for organizations looking to make the most out of their pre-IND meeting with FDA.1.2. PurposePre-Investigational New Drug Application (pre-IND, PIND) meetings are defined in 21 CFR 312.82 EarlyConsultation. According to this regulation, “Prior to the submission of the initial IND, the sponsor may request ameeting with FDA-reviewing officials. The primary purpose of this meeting is to review and reach agreement on thedesign of animal studies needed to initiate human testing. The meeting may also provide an opportunity fordiscussing the scope and design of phase 1 testing, plans for studying the biologic or drug product in pediatricpopulations, and the best approach for presentation and formatting of data in the IND.” These meetings can serveas a valuable tool, allowing the Sponsor an opportunity to discuss challenges specific to development of their newbiologic or drug product and design of their proposed nonclinical studies directly with the FDA early in the drugdevelopment process. The meeting also provides an opportunity for the Sponsor to discuss their CMC developmentplan to address the CMC requirements for phase 1 clinical studies.This paper provides an overview of the current FDA guidance and recommendations for pre-IND meetings. It alsodiscusses the benefits of having a pre-IND meeting with the FDA.Finally, the paper provides examples of frequently asked questions (FAQ) and responses by the FDA along withgeneral information which may be included as part of the FDA’s pre-IND meeting comments.2. PRE-IND MEETING DESCRIPTION2.1. FDA Guidance and ObservationsAccording to the FDA’s “Guidance for Industry: Formal Meetings Between the FDA and Sponsors (March 2015,Revision 2)”, pre-IND meetings are classified as Type B meetings and are subject to the timelines provided inSection 2.2. The Sponsor may request a teleconference, face-to-face meeting, or Written Response Only (WRO)and if the FDA meeting schedule permits, FDA may grant teleconferences or face-to-face meetings requested bythe Sponsor.In the current regulatory environment, pre-IND meetings are often granted as a WRO in which the Agency willprovide written responses to the questions in the meeting package and reviewers’ comments about the informationcontained within the meeting package in lieu of a meeting. Granting of a WRO will be noted in the response letterfrom the FDA provided to the Sponsor within 21 days of the FDA’s receipt of the meeting request. In the last fewyears certain Offices within the FDA, such as the Office of Vaccines Research and Review (OVRR), may denyphase 3 pre-IND meeting requests, and require the Sponsor to submit a Master File (MF) instead to allow sufficienttime for the review of this mature program. The need for a MF will be noted in the response letter from the FDA.Due to the limited opportunity to interact directly with the FDA, Sponsors should ensure that their meeting requestand meeting package provide information relevant to their specific product, highlighting any challenges oranticipated regulatory hurdles in a direct, succinct manner. The pre-IND meeting package should containsummaries relevant to the product and proposed clinical trial, along with sufficient supplemental material to provideBiologics Consulting White Paper – December 2017 2017 BIOLOGICS CONSULTING GROUP, INC. All Rights Reserved.4

the reviewer with an understanding of the issues raised in the meeting questions. Sponsors should avoid includingextraneous materials in the meeting package that are unrelated to the meeting question topics. If the volume ofinformation provided in the meeting package is too great, the reviewing division may reschedule the meeting toallow the reviewers sufficient time to go through the information, so brevity is advised. Furthermore, in response tosome recent pre-IND meeting requests, FDA has instructed the Sponsor to limit the number of questions toapproximately 10 key inquiries with no subquestions. While this may pose a challenge, it encourages the Sponsorsto focus on key issues, allowing the FDA reviewers to provide comments on those issues at high risk for a clinicalhold.In addition to the 2015 “Formal Meetings” Guidance, certain divisions within the FDA, e.g. the Division of Anti-ViralProducts' (DAVP), provide information on their websites which serves as excellent resources for the format andsuggested content of pre-IND meeting requests and meeting packages. Even if a Sponsor has prepared pre-INDsubmissions in the past, it is prudent to consult these FDA division-specific resources prior to submitting a meetingrequest and meeting package to ensure that the most recent recommendations from the reviewing division havebeen incorporated.2.2. PDUFA TimelinesAs noted above, the “Formal Meetings” guidance defines pre-IND meetings as Type B meetings. Timelines forthese meetings are governed by the current version of the Prescription Drug User Fee Act (PDUFA). Thesetimelines are provided in the “Formal Meetings” guidance and are also summarized below. These are generaltimelines; the Sponsor should check the specific review division website for any division-specific timelines. Alsonote that these timelines are specific to Type B meetings. Receipt of the Sponsor’s meeting request by the Agency initiates the submission “clock”. This may differslightly from the date on which the meeting request was sent by the Sponsor. Within 21 days of receipt of the meeting request, the FDA review division should respond to the Sponsorproviding notification that the meeting has either been granted or that the meeting has been denied. If themeeting has been granted, this communication will provide the meeting date and meeting type. If thereviewing division only plans to provide written comments (WRO) in lieu of a face-to-face meeting orteleconference, this will be specified in the response letter along with the date on which comments will beprovided to the Sponsor. Meeting dates are set by the reviewing division. Meetings should be scheduled to occur within 60 days ofthe Agency’s receipt of the meeting request. If the Sponsor requests a date for the meeting that is morethan 60 days from the date the Agency receives the request, the meeting should be scheduled to occur notmore than 14 days after the requested date. When written responses will be provided in lieu of a meeting,these should be transmitted by the reviewing division within 60 days of the Agency’s receipt of the meetingrequest. The meeting package (a.k.a. background package, information package, briefing package, briefingdocument, etc.) must be received by the Agency at least 4 weeks prior to the formal meeting or WROdeadline, otherwise the Agency may postpone or cancel the meeting. Due to this firm submission deadline,it is advised that the Sponsor have a working draft of the meeting package before the meeting request issubmitted. In most cases, the Agency will provide initial written comments 24 – 48 hours prior to the meeting. If theSponsor feels these comments have sufficiently addressed all of the pre-IND questions, they may contactthe Agency and cancel the meeting. The Agency targets to issue official minutes to all FDA attendees (with copies to appropriate files) and tothe Sponsor within 30 calendar days of the formal meeting. If a WRO is provided, that serves as the finalpiece of communication related to the meeting. PDUFA VI (effective for fiscal years 2018 – 2022) pre-IND meeting timelines are shown in Table 1 derivedfrom the PDUFA VI commitment letter.Biologics Consulting White Paper – December 2017 2017 BIOLOGICS CONSULTING GROUP, INC. All Rights Reserved.5