COMBINATION PRODUCTS A RECENT FDA PERSPECTIVE. Sugato De

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1 COMBINATION PRODUCTS A RECENT FDA PERSPECTIVE Sugato De Principal Consultant Integrated Product Development PAREXEL Consulting June 29, 2018 GLOBAL BIO CONFERENCE PAREXEL INTERNATIONAL CORP.

2 SUGATO DE PRINCIPAL CONSULTANT Seasoned engineer and regulatory professional with specialized expertise with combination products and digital health technology Over 11 years of recent experience at FDA/CDRH Former Branch Chief of Respiratory Devices Branch Former Senior Policy Advisor in Office of Center Director Comprehensive knowledge of cutting-edge regulatory strategies for combination products Extensive experience in designing and evaluating clinical studies for medical devices and combination products Led development and implementation of several CDRH-wide policy initiatives, including early stage clinical trials, digital health, and the utilization of RWE and patient preferences in regulatory decision making 2018 PAREXEL INTERNATIONAL CORP. / 2

3 AGENDA Current Regulatory Framework 21st Century Cures Definitions Procedural Mechanisms Additional Provisions FDA Initiatives PDUFA Commitments Global Regulatory Strategies Personalized Medicine 2018 PAREXEL INTERNATIONAL CORP. / 3

4 EVOLVING REGULATORY PARADIGMS FOR COMBINATION PRODUCTS TOKYO, JAPAN 2018 PAREXEL INTERNATIONAL CORP. / 4

5 A RENEWED FDA PRIORITY Combination products account for a growing proportion of products submitted for review, and FDA will continue to pursue new approaches to collaboration that ensure, safe, effective, and innovative medical products are made available to patients as quickly as possible. Robert Califf, M.D. Former FDA Commissioner December 2, PAREXEL INTERNATIONAL CORP. / 5

6 COMBINATION PRODUCT REGULATORY DEFINITION Under 21 CFR 3.2 (e): Single-entity combination product A product comprised of two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and produced as a single entity Co-packaged combination product Two or more separate products packaged together in a single package or as a unit and comprised of device products, device and biological products, or biological and drug products Cross-labeled combination product A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an only with an approved individually specified drug, device or biological product PAREXEL INTERNATIONAL CORP. / 6

7 EXAMPLES Source: PAREXEL INTERNATIONAL CORP. / 7

8 PRIMARY MODE OF ACTION DEFINITION The Lead Center for a combination product is based on the primary mode of action (PMOA) The single mode of action of a combination product expected to make the greatest contribution to the overall intended therapeutic effects of the combination product (FDA 503(g)(1)9C), 21 CFR 3.2(m)) 2018 PAREXEL INTERNATIONAL CORP. / 8

9 ALGORITHM FOR ASSIGNING LEAD CENTER Submit a Request for Designation (RFD) to the Office of Combination Products A. If the PMOA of a combination product is attributable to: drug constituent part, CDER has primary jurisdiction. device constituent part, CDRH has primary jurisdiction. biological product constituent part, CBER or CDER has primary jurisdiction. B. If unable to determine PMOA: Precedent Expertise 2018 PAREXEL INTERNATIONAL CORP. / 9

10 21ST CENTURY CURES: 3038 COMBINATION PRODUCT INNOVATION New Procedural Mechanisms In determining the Lead Center for review of a combination product, FDA may not determine that a product s PMOA is that of a drug or biologic solely because it has any chemical action within or on the human body. If a combination product sponsor disagrees with FDA s PMOA determination, the sponsor may request, and FDA must provide, a substantive rationale for the determination that references the scientific evidence relied upon by FDA. The sponsor then may propose 1 or more studies (which may be clinical, nonclinical, or both) to establish the relevance, if any, of chemical action in achieving the PMOA of the combination product. If the sponsor and FDA agree on the study design and the sponsor conducts such studies, then FDA must consider the data in reevaluating the PMOA PAREXEL INTERNATIONAL CORP. / 10

11 21ST CENTURY CURES New Procedural Mechanisms, Cont. If a combination product sponsor submits a written meeting request, FDA generally must meet with the sponsor within 75 calendar days. This meeting may address the standards and requirements for market approval or clearance, post-market modifications, and applicable good manufacturing practices for the combination product. FDA may, however, defer addressing issues if scientific or other information is not available or agreement is not feasible when the meeting is requested. Any agreement reached in the meeting must remain in effect except upon: (1) the written agreement of FDA and the sponsor; or (2) a decision by the director of the review division of the primary agency center (or someone more senior) that an issue essential to determining whether the standard for market clearance or another applicable statutory standard is met was identified after the agreement or that deviating from the agreement is otherwise justifiable based on scientific evidence, for public health reasons PAREXEL INTERNATIONAL CORP. / 11

12 21ST CENTURY CURES: ADDITIONAL PROVISIONS Approved Constituent Part FDA may require that the sponsor of a combination product containing an approved constituent part submit only those data and information that FDA deems necessary to meet the statutory standard for marketing authorization. FDA must consider any incremental risks and benefits posed by the product, using a risk-based approach and taking into account prior findings of safety and effectiveness or substantial equivalence for the relied-upon approved constituent part PAREXEL INTERNATIONAL CORP. / 12

13 21ST CENTURY CURES Approved Constituent Part, Cont. Device submissions that rely on an approved drug constituent part must include patent certifications or statements as are required for section 505(b)(2) applications and comply with the notice provisions regarding paragraph IV certifications. The timeline for approval of these applications will depend on the type of patent certification made by the applicant. Approval of the combination product also must await expiry of any blocking new chemical entity exclusivity, three-year Hatch- Waxman exclusivity, pediatric exclusivity, qualified infectious disease product ( QIDP ) exclusivity, and orphan drug exclusivity applicable to the approved drug PAREXEL INTERNATIONAL CORP. / 13

14 21ST CENTURY CURES Approved Constituent Part, Cont. Section 520(h)(4) of the FDCA previously authorized FDA to rely on data in a PMA six years after its approval in approving a subsequent device or reclassifying a device. This section was amended to provide that no information in a PMA may be used to approve or clear another device submission for a combination product containing an approved drug constituent part unless the submitter complies with the patent certification and notice requirements that would apply to a section 505(b)(2) applicant, and that the subsequent device submission is subject to the exclusivity rights applicable to the approved drug PAREXEL INTERNATIONAL CORP. / 14

15 21ST CENTURY CURES Separate Marketing Applications FDA shall conduct the premarket review of any combination product under a single application, whenever appropriate. Section 503(g)(1)(B) of the Act. Nothing in this subsection shall be construed as prohibiting a sponsor from submitting separate applications for the constituent parts of a combination product, unless FDA determines that a single application is necessary. Section 503(g)(6) of the Act. The designation of one agency component as having primary jurisdiction does not preclude in appropriate cases, the requirement by FDA of separate applications. 21 CFR 3.4(c) for most combination products, a single marketing application is sufficient for the combination product s approval, clearance or licensure. In some cases, however, a sponsor may choose to submit two marketing applications for a combination product when one application would suffice. In certain circumstances a single marketing application is the only feasible option, such as: combination products that are chemically, physically, or otherwise combined Drugs and devices are generally approved or cleared only as finished products, not as components for further manufacture. Number of Market Applications Concept Paper 2018 PAREXEL INTERNATIONAL CORP. / 15

16 21ST CENTURY CURES Office of Combination Products In order to assure timely and effective premarket review, OCP must: oversee the alignment of feedback regarding reviews involving multiple agency centers, ensure that there is a designated primary point of contact in the lead center for a combination product sponsor, ensure that meetings between FDA and a combination product sponsor are attended by each agency center involved in the review as appropriate, and that each consulting center follows applicable guidance, and ensure that each consulting center completes its premarket review and provides the results to the lead center in a timely manner. Communications from the primary agency center shall be considered communications from the FDA on behalf of all agency centers involved in the review to the extent consistent with other provisions of law and the requirements of all affected agency centers PAREXEL INTERNATIONAL CORP. / 16

17 21ST CENTURY CURES Required Guidance & GMP Within 4 years after enactment and after public comment, FDA must issue final guidance addressing: (1) the structured process for managing pre-submission interactions with sponsors developing combination products; (2) best practices for ensuring that agency feedback in such interactions represents FDA s best advice based on the information provided; and (3) procedural matters for the meetings described above and agreements reached therein. Within 18 months of enactment, FDA must publish a proposed list of combination products and manufacturing processes for which GMP requirements may vary from 21 C.F.R. section 4.4 or for which the requirements of section 4.4 can be satisfied through alternative or streamlined mechanisms. After a public comment period, FDA must publish a final list in the Federal Register and then periodically review it PAREXEL INTERNATIONAL CORP. / 17

18 FDA INITIATIVES Combination Product Policy Council (Est. April 2016) The Combination Products Policy Council provides a senior-level forum to establish combination product policy across the FDA and ensures that policy is implemented in a consistent manner throughout the Agency. The Council is chaired by the Deputy Commissioner for Medical Products and Tobacco (OMPT) or his/her designee, comprised of the following members: the Center Directors or their designee and one representative from CDER, CDRH, and CBER the Office Directors or their designee from the Office of Combination Products and the Office of Special Medical Programs PAREXEL INTERNATIONAL CORP. / 18

19 FDA INITIATIVES Pre-RFD Submission Guidance (February 2018) A Pre-RFD is a clear and concise written submission that a sponsor may submit to OCP to request FDA s preliminary, nonbinding assessment of: (1) the regulatory identity or classification of a product as a drug, device, biological product, or combination product, and/or (2) whether CBER, CDER, or CDRH will regulate the product if it is a noncombination product, or which of those Agency Centers will have primary jurisdiction for the premarket review and regulation, if it is a combination product. OCP will determine if the submission contains information to make an assessment within business 5 days and will provide a written preliminary classification and/or jurisdictional assessment of the product within 60 calendar days of receipt PAREXEL INTERNATIONAL CORP. / 19

20 PDUFA COMMITMENTS Advancing Combination Product Development Expand staff capacity and capability in Centers and OCP: cgmp, engineering, HF, bridging studies and labeling. Streamline consult processes, develop internal standard operating policies. Identify Points of Contact in OCP, Centers. Review HF protocols within 60 days. Train staff in CP development Publish new draft guidance on bridging studies and IFU PAREXEL INTERNATIONAL CORP. / 20

21 TOKYO, JAPAN GLOBAL REGULATORY STRATEGIES 2018 PAREXEL INTERNATIONAL CORP. / 21

22 CLINICAL BRIDGING CDER Primary focus is on evidence Each drug-device combination product should have: A complete chemistry, manufacturing, and controls database Device design and development A substantially complete clinical development program to support efficacy and safety of the entire combination product [Draft Guidance for Industry Rheumatoid Arthritis: Developing Drug Products for Treatment] 2018 PAREXEL INTERNATIONAL CORP. / 22

23 CLINICAL BRIDGING CDRH Primary focus is on risk Provisions of the FDA Modernization Act (1997): The basis for all regulatory decisions will be found in sound science and the spirit and the letter of the law Information unrelated to the regulatory decision should not be part of the decision-making process Alternative approaches to regulatory issues should be considered to optimize the time, effort, and resources involved in resolving the issue consistent with the law and regulations All reasonable measures should be used to reduce review times and render regulatory decisions within statutory timeframes. [The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles; Final Guidance for FDA and Industry] 2018 PAREXEL INTERNATIONAL CORP. / 23

24 CLINICAL BRIDGING EMA Greater focus is on risk Accepts equivalence of subcutaneous delivery devices No need to generate additional clinical data for bridging prefilled pen to manual syringe as the differences in exposure are expected to be minimal; clinical data would be nice to have, but not required for registration purposes [EMA Scientific Advice Meeting: Manual syringe to pre-filled pen; June 2013] 2018 PAREXEL INTERNATIONAL CORP. / 24

25 BIOEQUIVALENCE/PK FDA generally requires bioequivalence studies and with narrow limits. For example, a transition from a prefilled syringe to an auto-injector (AI) delivery system involves the following, at a minimum: (2) a pharmacokinetic bridging study that demonstrates similar delivery of the drug product to the same biospace across a range of body weights. [Draft Guidance for Industry Rheumatoid Arthritis: Developing Drug Products for Treatment] This guidance recommends that the traditional BE limit of 80 to 125 percent for non-narrow therapeutic range drugs remain unchanged for the bioavailability measures (AUC and Cmax) of narrow therapeutic range drugs. [Guidance for Industry, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products General Considerations] 2018 PAREXEL INTERNATIONAL CORP. / 25

26 BIOEQUIVALENCE/PK EU: Not always required (e.g., PFS to AI). In the case of other parenteral routes, e.g. intramuscular or subcutaneous, if the product is of the same type of solution (aqueous or oily), contains the same concentration of the same active substance and the same or comparable excipients as the medicinal product currently approved, then bioequivalence testing is not required. [EMA Note for Guidance: The investigation of bioavailability and bioequivalence (2000); Committee for Proprietary Medicinal Products (CPMP)] Recommendation: Provide justification for clinical comparability based on therapeutic window and available safety data PAREXEL INTERNATIONAL CORP. / 26

27 HUMAN FACTORS STUDIES FDA New protocols (along with IFUs) are expected to be submitted for FDA review; feedback is generally helpful but can add delays to the program. May not be needed if same or similar delivery device is bridged to a new drug. Final reports must be submitted along with HFS summaries. Human Factors Validation Study results for the combination product should be located in ectd section Other Study Reports with links from appropriate Module 3 files. Additionally, you may cross reference from Module 5 to Module 3 as applicable. [Guidance for Industry: ectd Technical Conformance Guide] OUS HFS summaries are sufficient in most cases PAREXEL INTERNATIONAL CORP. / 27

28 ACTUAL USE STUDIES FDA generally requires real-life patient handling experience (incorporated into clinical studies). Since Human Factors studies (i.e., simulated injections) may not fully capture adverse events and medical errors that occur with actual use, we recommend that you conduct an actual use study in patients and caregivers who may be administering the injections. For example, users may be more prone to incomplete injection when the device is penetrating their skin, or there may be difficulties manipulating the device when the device is used for an actual injection at the target site(s). One approach could be to collect information through questionnaires that ask about the patient and/or caregiver s experience using the device for injections. [Nov 2015, DGIEP/CDRH] OUS: Not required PAREXEL INTERNATIONAL CORP. / 28

29 PREVIOUSLY APPROVED/CLEARED DEVICES FDA Frequent requests for combination product performance testing even with 510(k) clearance is applicable. Example: Cleared Needle Safety Device/Guard FDA(CDRH) can ask about drug-specific test data for verification testing recommended in the Guidance for Industry and FDA Staff, Medical Devices with Sharps Injury Prevention Features. Typically, studies with ISO conformant PFS are sufficient not drug dependent. EU Significantly scaled back device review. EMA has taken the position that, if a platform device has prior approval with another drug, the device information (e.g., in the 3.2.R regional section) need not be reassessed.(i.e., not reflected in the assessment report.) 2018 PAREXEL INTERNATIONAL CORP. / 29

30 ESSENTIAL PERFORMANCE REQUIREMENTS FDA In NDA/BLA reviews, FDA is currently asking for a traceability matrix for all the essential performance requirements, which should include the location of the verification and/or validation testing documents. The essential quality aspects and the regulatory requirements, such as safety, performance, and dependability of a product (whether hardware, software, services, or processed materials) are established during the design and development phase. Deficient design can be a major cause of quality problems. [FDA Design Control Guidance For Medical Device Manufacturers] FDA may provide a sample traceability matrix for completion upon request. OUS This term is not used typically used OUS. EMA requires an assessment of particular Essential Requirements in accordance with the Medical Devices Directive (MDD) PAREXEL INTERNATIONAL CORP. / 30

31 FDA CFR PART 4 COMPLIANCE US-Only Requirement (GMP/Quality Systems Compliance) Summarize compliance with: Management responsibility Design controls Purchasing controls Corrective and preventive actions Installation Servicing. FDA will often accept adequate summaries where SOPs have been requested in the past 2018 PAREXEL INTERNATIONAL CORP. / 31

32 TAIPEI, TAIWAN NEW FRONTIERS IN PERSONALIZED MEDICINE 2018 PAREXEL INTERNATIONAL CORP. / 32

33 WHAT ARE PERSONALIZED MEDICINES? Leverage biomarkers, often genetic, to determine who is most likely to benefit from a treatment, who is at higher risk of a side effect, or who needs a different dose. Without Personalized Medicine Some benefit, some do not. Patients Therapy With Personalized Medicine Each patient receives the right medicine for them. Patients Biomarker Diagnostics Therapy 1 Therapy 2 Therapy 3 Benefit No Benefit Adverse Effects Each patient benefits from individualized treatment. Minimize Adverse Effects Source: Adapted from Bayer Healthcare, Personalized Medicine. (accessed May 2105) PAREXEL INTERNATIONAL CORP. / 33

34 RISE AND IMPACT OF PERSONALIZED MEDICINES? Interactive Review 2018 PAREXEL INTERNATIONAL CORP. / 34

35 THE RIGHT REASONS TO INCLUDE GENOMICS IN DRUG DEVELOPMENT 2018 PAREXEL INTERNATIONAL CORP. / 35

36 A JOURNEY WITH GREAT PROMISE AND CHALLENGES, TOO Clinical trials for personalized medicines may look very different from traditional drug trials. Hard to have breadth of expertise needed to capitalize on turning: Genes > Targets > Precision Medicines Complex trial designs including codevelopment of companion test. Regulatory requirements are emerging in global markets. Reimbursement considerations for drug and test. Ethics and local laws pose challenges for sampling and testing. Storage and computational resources for big data. Ensuring accuracy of results from evolving technologies such as NGS. Making big data accessible and understandable to drug development scientists. Creating and communicating reproducible workflows for complex analyses PAREXEL INTERNATIONAL CORP. / 36