Industry Experience: Early Collaboration with FDA on Combination Products. Kristi Kistner, Amgen Inc. CMC Strategy Form January 26, 2015

Transcription

1 Industry Experience: Early Collaboration with FDA on Combination Products Kristi Kistner, Amgen Inc. CMC Strategy Form January 26, 2015

2 Collaboration is working together to achieve shared goals Given the U.S. FDA (Agency) is the regulator and industry is the regulated, what are key shared goals? Improving access to safe, effective, and innovative medical products Helping to speed innovations that may make medicines and devices safer and more effective Efficient development and approval processes FDA recognizes that innovative technologies may raise a spectrum of scientific and technical development issues. Combination products are increasingly incorporating cutting edge, novel technologies that hold great promise for advancing patient care. Innovative drug, biological product, device combinations have the potential to make treatments safer, more effective, or more convenient or acceptable to patients. Guidance for Industry and FDA Staff: Early Development Considerations for Innovative Combination Products (Office of Combination Products [OCP], Sept 2006)

3 Benefits for early collaboration are realized by industry and the Agency Benefits = Timely and Efficient Reviews Initial feedback and input into development planning reduces redundancy/misses Agency exposure to innovation and critical issues identified facilitate focused discussions FDA has the opportunity to develop appropriate scientific expertise for intercenter review teams Submitted applications are complete and fileable Science-based reviews occur for understood technology and applications include agreed upon data packages

4 Early collaboration is an important step in navigating combination product challenges Understanding regulatory requirements/expectations and implementing effective strategies for ensuring regulatory compliance and meeting business goals can be difficult. Ambiguity, differences, and late changes may increase challenges Center-specific guidance may focus on drug/biologic or device issues only, or may include information the other Center(s) are not required to follow Different review divisions within a Center may request data packages that vary significantly for combination products having equivalent risk profiles Limitation on direct access to non-lead Center for constituent part topics may hinder access to subject matter experts Output from HFE/UE and clinical trial protocol Agency reviews may not be specific or timely enough to provide effective input into the study design(s) Requests from the Agency for changes to labeling at the end of application review cycles may cause confusion on design validation requirements Unaligned drug and device development processes may influence robustness of Agency access Early collaboration is a solid beginning for a challenging process, but not the final solution

5 Example of a Potential Challenge for Meeting Success Unaligned Drug and Device Development Processes Pre-IND Mtg EOP1 Mtg EOP2 Mtg Pre-NDA/BLA Mtg Drug Pre-clinical Phase 1 Phase 2 Phase 3 Filing Launch/ Post- Launch Critical Device Development Design Inputs are Needed For Planning Phase 6 9 months Proposed Commercial Equivalent Device is Needed for Phase 3 Clinical Study Post-approval Feedback Mtg Device Concept Feasibility Planning Development Verification/ Validation Transfer to Life Cycle Management 1-4 years

6 Multiple access opportunities enable early interactions with Agency Centers and OCP Early interactions include opportunities for direct and indirect access to current Agency thinking. Direct Access for Single Program (examples follow) Agency Meetings CDRH: Informational, Pre-Submission (Pre-Sub), Agreement, Determination, Study Risk Determination CDER Type B (clinical & CMC): Pre-IND (prehuman research), EOP1, EOP2 & Pre-Phase 3, Pre-NDA/BLA Meeting CDER Type C: Any meeting other than a Type A or Type B regarding the development & review of a product (may grant as written response only [WRO]) Agency meetings are appropriate when there are specific questions which are not adequately addressed by existing guidance When CDER is the lead center, Pre-Sub with CDRH may be appropriate if seeking input on the device constituent part only and no expected impact on the drug constituent part of the combination product Indirect Access via Coalition and Industry Groups (examples follow) Combination Products Coalition (CPC) Submitted positions/comments, e.g., proposed rules (GMPs for combination products) and draft FDA guidance (labeling, HFE/UE, clinical trials, home use design considerations, injectors, companion diagnostics) Annual and ad hoc meetings with OCP and combination product liaisons for Centers Standards Development through AAMI/ISO/IEC Technical Committee Participation By topic, e.g., HFE/UE, biocompatibility/toxicity, software, electrical safety By type of device, e.g., needle-based injection systems, blood processing equipment, clinical decision-making software

7 FDA guidance documents communicate Agency expectations for early collaboration Constituent part involves novel technology or first of a kind indication/use, for example: Not within established regulatory pathway, i.e., applicant/sponsor desires input on a proposed regulatory strategy Applicant/sponsor desires FDA guidance on specific issues related to nonclinical and/or clinical study protocols prior to initiating the studies (e.g., no recognized consensus standard or multiple standards from which to choose, or complex/novel statistical approaches) Applicant/sponsor desires input on the extent that existing data may be leveraged Insufficient combination product guidance for a specific topic, which is being addressed on a program by program basis Examples: CGMP topics, HFE/UE data requirements, clinical study data requirements, labeling topics (package component and Instructions for Use) Key topics include analytical and clinical data requirements

8 Clarity in meeting requests is critical to the Agency granting the request Requests should include adequate information for the Agency to assess the potential utility of and necessary participants for the meeting. Statement of purpose and objectives Background of the issues underlying the agenda Summary of studies or data intended for discussion General nature of critical questions to be asked Where meeting fits in overall development plans List of proposed questions Precise and grouped by discipline Explanation of the context and purpose of each question List of attendees Sponsor/applicant, consultants and/or development partners FDA staff, by name or discipline Method for feedback (in-person, teleconference) and duration

9 Comprehensive briefing information facilitates best answers from the Agency The meeting package should be clear and concise, providing summary information relevant to the product and any supplementary information needed to develop responses to raised issues. List of final questions and updated list of sponsor/applicant attendees Background section (brief history of development program, status of product development for the target indication, previous Agency discussions/submissions) Product description, to include: physical and biological characteristics; materials of construction; combination product interfaces (constituent part and user); pictures/drawings/samples (where feasible and appropriate); manufacturing and packaging configuration Preliminary risk analysis (potential risks to health with mitigation plan and expected risk/benefit assessment, if available) Data to support discussion organized by discipline and question, and may include complete protocols for clinical studies or HFE/UE studies

10 Examples of Meeting Questions (End Of Phase 2 through Pre-Submission) Explanation of Context/Purpose Design verification plans for drug delivery systems include requirements from identified standards/guidance that are applicable to the technology and intended use. Testing will be conducted in accordance with these plans to assure safe and effective drug administration. Regarding the biocompatibility of the materials used, the drug delivery system will be evaluated in accordance with relevant consensus standards and applicable USP compendial testing requirements. Regarding software verification and validation, FDA guidance and IEC are being followed and a Level of Concern is indicated in the briefing document. Usability validation plans for the combination product are included in the briefing document. The testing outlined in these plans is proposed for execution in support of the BLA filing package. Stability data to support the commercial shelf life will be collected in accordance with ICH guidelines (Q1A, Q5C). Formal stability studies will be conducted on drug substance and drug product in the primary container closures and as combination products. Question Does the Agency agree the design verification requirements and identified applicable standards and guidance in the briefing document are adequate to support licensure of the drug delivery systems for HCP administration and self-administration (home use)? Does the Agency agree that the plan to evaluate the device in accordance with ISO requirements and the primary container in accordance with compendial testing requirements is sufficient? Does the Agency agree with this classification assignment? Does the Agency agree: (1) with the scope, tone, and triggers for the scripted questions in the usability plans? (2) the plans provide the breadth of information FDA will want to review in the final report? Does the Agency agree that the proposed stability strategy for drug substance and the drug combination products are appropriate to support commercial registration?

11 Examples of Meeting Questions (EOP through Pre-Submission) continued Explanation of Context/Purpose The bioavailability of the drug product is not expected to be affected by route of administration. To confirm this expectation, a BE study is planned and described in the briefing document. The specifications for drug substance, drug product, and the combination product are based on product and process knowledge gained through characterization studies, process development experience, and lot release and stability data for batches used in preclinical, phase 1, and phase 2 clinical studies. Information pertaining to the drug delivery device will be incorporated throughout each respective 3.2.P section. This information will include details of the delivery device as it relates to the design, manufacturing, risk management, verification/validation, post-approval complaint and adverse event reporting for the combination product. Question Does the Agency agree with the design of the proposed BE study, in particular with the sample size, study endpoints, comparability criterion, and the anatomical injection site to be representative of all indicated sites? Does the Agency agree the proposed specification strategy as detailed in the briefing document is adequate with respect to identification of all proposed release test methods and method types: (1) for initiation of phase 3 clinical studies? (2) for collection of data to establish specifications for commercial registration? Does the Agency agree the proposed: Module 3 structure and format of data will facilitate a joint review by both CDER and CDRH? Device Reviewer s Guide structure and format of data will facilitate a joint review by both CDER and CDRH? Additional questions may include topics such as clinical bridging study Plans or type(s) of clinical and/or marketing applications

12 What has been Amgen s experience during the last four years? Amgen has requested over 30 Agency meetings for combination product (or combined product ) topics. Meeting topics have primarily focused on CMC, design verification/design validation, and clinical study requirements Meeting participants (or meeting prep participants) have varied based on the topics: Amgen staff, consultants, development partners + CDER and CDRH and OCP representation Most meeting requests have been granted [in-person, teleconference, or written response only (WRO)]; preliminary comments supplied prior to the scheduled meetings with timely/accurate issuance of minutes Examples of extended engagement timeframes: 2011 through 2014 (approval in 2014, BLA) 2011 through planned meetings in 2015 (filing planned for 2015, BLA) 2012 through 2014 (filing in 2014, BLA)

13 There are opportunities for reducing the challenges facing industry and the Agency Potential areas for improvement in clarity and consistency: Intra-center coordination/transparency on acceptable study designs (e.g., clinical home use and bridging study requirements) OCP/CDER/CBER/CDRH guidance documents for combination products Increased acceptance/reliance on device-specific non-clinical evidence (greater utilization of consensus standards/bench and HFE/UE testing) Better communication from industry on specific issues: Ensure OCP is informed in a timely way of not only the issue(s) but implication/context for the issue(s) Collaborate with the Agency on opportunities to Apply platform knowledge to future programs Utilize consensus standards drafting forums to informally discuss issues (allows for global scope to be included) Ask! ~Thank you~

14 U.S. FDA Interaction and Meeting Guidance (Examples) Guidance for Industry and FDA Staff: Early Development Considerations for Innovative Combination Products (Office of Combination Products, September 2006; Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants (CDER/CBER, May 2009; Guidance for Industry: IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and Controls Information (CDER/CBER, May 2001; ances/ucm pdf) CDER 21 st Century Review Process Desk Reference Guide ( ocedures/ucm htm) Guidance for Industry and FDA Staff: Requests for Feedback on Medical Device Submissions The Pre-Submission Program and Meetings with Food and Drug Administration Staff (CDRH/CBER, February 2014; ancedocuments/ucm pdf)