Industry Experience: Early Collaboration with FDA on Combination Products

Kristi Kistner, Amgen Inc.

CMC Strategy Form

January 26, 2015

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)

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

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

Example of a Potential Challenge for Meeting Success

Pre-clinical Phase 1 Phase 2 Phase 3 Filing Launch/

Post-Launch

Critical Device

Development

Design Inputs are

Needed For

Planning Phase

Device

Concept Development Verification/ Validation

Feasibility Planning

Proposed

Commercial

Equivalent Device

is Needed for

Phase 3 Clinical

Study

1 - 4 years

6 – 9

months

Transfer to Life Cycle Management

Drug

Unaligned Drug and Device Development Processes Pre-IND Mtg EOP1 Mtg EOP2 Mtg Pre-NDA/BLA Mtg

Post-approval

Feedback Mtg

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)

Indirect Access via Coalition and

Industry Groups (examples follow)

Agency Meetings CDRH: Informational, Pre-Submission (Pre-Sub),

Agreement, Determination, Study Risk

Determination

CDER – Type B (clinical & CMC): Pre-IND (pre-

human 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])

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

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

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

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

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

Examples of Meeting Questions (End Of Phase 2 through Pre-Submission)

Explanation of Context/Purpose Question

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.

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)?

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.

Does the Agency agree that the plan to evaluate the

device in accordance with ISO 10993-1 requirements and

the primary container in accordance with compendial

testing requirements is sufficient?

Regarding software verification and validation, FDA

guidance and IEC 62304 are being followed and a Level

of Concern is indicated in the briefing document.

Does the Agency agree with this classification

assignment?

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.

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?

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.

Does the Agency agree that the proposed stability

strategy for drug substance and the drug combination

products are appropriate to support commercial

registration?

Examples of Meeting Questions (EOP through Pre-Submission)

Explanation of Context/Purpose Question

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.

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?

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.

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?

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.

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?

continued

Additional questions may include topics such as clinical bridging study

Plans or type(s) of clinical and/or marketing applications

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)

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~

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; http://www.fda.gov/RegulatoryInformation/Guidances/ucm126050.htm)

• Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants (CDER/CBER, May 2009; http://www.fda.gov/downloads/Drugs/Guidances/ucm153222.pdf)

• Guidance for Industry: IND Meetings for Human Drugs and Biologics – Chemistry, Manufacturing, and Controls Information (CDER/CBER, May 2001; http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070568.pdf)

• CDER 21st Century Review Process – Desk Reference Guide (http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/UCM218757.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; http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM311176.pdf)