Regulatory Rights & Legal Vehicles in Medical Product Development

Transcription

1 Regulatory Rights & Legal Vehicles in Medical Product Development From Discovery to Commercialization: Strategizing for Success FLC 2015 National Meeting, Denver Colorado Jeremiah J. Kelly, Esq., MPP Attorney for Medical Product Development & Regulation OSJA, USAMRMC

2 Agenda Part I: Understanding the Risks Part II: The FDA Regulatory Landscape Part III: Comparison of Legal Agreement Vehicles & Associated Rights Part IV: Best Practices

3 Understanding the Risks Product development and Tech Transfer missions require strategic thinking regarding: Proper evaluation of the FDA regulatory landscape (sponsor responsibilities, unique approval mechanisms, marketing exclusivity) Correct selection of legal instrument (assistance agreement, contract, CRADA, OTA or a combination) Including proper terms/clauses in our legal agreements to ensure protection of intellectual property (patents, technical data, etc.) or ability to recover rights licensed Failure in any one of these areas creates risk to the product development effort or the tech transfer mission.

4 Understanding the Risks Ideally, an advanced developer has the Trifecta : Patent rights Technical Data rights FDA Sponsorship/Holdership We don t always operate in ideal world: We leverage private resources to achieve mission Collaborators fail, terminate programs for business reasons, are acquired/merged, go bankrupt Our authorities are cumbersome & not ideally built for the regulatory environment.

5 Understanding the Risks Goals: Maximize the use of existing authorities to secure best position possible for the investment made Take innovative approaches to protect the government s interest and achieve the mission. Combining legal instruments Innovative clauses Use current authorities correctly

6 Part I: Know the Regulatory Landscape

7 What are Regulatory Rights? General term used to describe the benefits that accrue to the Sponsor or Holder of a regulatory application. Includes: exclusive standing and control before FDA special designations or review mechanisms given to the regulatory application marketing exclusivity awarded upon approval priority review vouchers that are transferrable upon approval ability to supplement applications

8 Statutory Framework for FDA Regulated Products Drugs Investigational Use Application IND Pre-market Approval Applications 505(b)(1) NDA 505(b)(2) NDA 505(j) ANDA Biologics Investigational Use Application IND Pre-market Approval Applications 351(a) BLA (PHSA) 351(k)(2)(A) Biosimilar 351(k)(2)(B) Interchangeable Biosimilar

9 Statutory Framework for FDA Regulated Products Medical Devices Investigational Use Application IDE (21 CFR 812) Abbreviated IDE Exempt Pre-market Approval Applications 510(k) Pre-marketing Notification (21 CFR 807(e)) Some Class I (general), ost Class II (general & special controls) SE, NSE, Revised de novo process 515 Pre-market Approval Application (PMA) (21 CFR 814) Class III (special controls insufficient) Exempt Humanitarian Device Exemption

10 What is it? Marketing Exclusivity If marketing exclusivity granted, FDA will not approve certain applications for same drug product until the expiration of exclusivity period Each exclusivity differs in what type of application it will bar. Exclusivity vs. Patent Term Goal: balance innovation vs. competition Can present unique benefits and challenges to product developers.

11 Marketing Exclusivity Marketing Exclusivity for Drugs New Chemical Entity (NCE) 5 years (21 CFR ) New Clinical Information or Other 3 years Pediatric (PED) 6 months add-on exclusivity Orphan Drug 7 years (21 CFR ) Qualified Infectious Disease Product (QIDP) 5 years add-on exclusivity (*NEW*) Generic Drug Exclusivity (available for 505(j) applicant only) 6 months Marketing Exclusivity for Biologics New Biologic 12 years Interchangeable Biosimilar 1 year

12 Marketing Exclusivity Marketing Exclusivity for Drugs New Chemical Entity (NCE) 5 years (21 CFR ) BAR: 505(b)(2) or 505(j) applicant; not full 505(b)(1) NDA (see 505(c)(3)(E)(ii); 21 CFR (b)(2)) Request in NDA New Clinical Information or Other 3 years Available to 505(b)(2) [21 CFR (b)(4)] Applicant or as Supplement [21 CFR (b)(5)] BAR: 505(b)(2) or 505(j) applicant; not full 505(b)(1) NDA Pediatric (PED) 6 months add-on exclusivity Awarded for conduct of pediatric clinical studies in response to written request Only extends; does not create additional bars

13 Marketing Exclusivity Marketing Exclusivity for Drugs Orphan Drug 7 years (21 CFR ) First approval of drug or biologic approved BARS: any application [included full-scale NDA or BLA] that includes the active ingredient for that indication Request before filing of NDA/BLA, as early as possible. Generic Drug Exclusivity 6 months BARS: subsequent 505(j) ANDA for 180 days/6 months.

14 Marketing Exclusivity Marketing Exclusivity for Drugs Qualified Infectious Disease Product (QIDP) 5 years add-on exclusivity Title VIII of FDASIA entitled Generating Antibiotic Incentives Now (GAIN) QIDP = "an antibacterial or antifungal drug (*) for human use intended to treat serious or life-threatening infections, including those caused by: (1) an antibacterial or antifungal resistant pathogen, including novel or emerging infectious pathogens; or (2) qualifying pathogens." BARS: same as underlying exclusivity period; BUT applicable to drugs only (potentially even in instance where it s a biologic obtaining orphan status); not applicable to 3-year New Clinical Information exclusivity; issue w/ interpreting re: supplements where original NDA was eligible, but came before GAIN. Rulemaking due July 2014

15 Marketing Exclusivity Marketing Exclusivity for Biologics New Biologic 12 years Biologics Price Competition and Innovation Act of 2009 (BPCI), Public Law , enacted as part of the Affordable Care Act on March 23, 2010, amended 351 of the Public Health Service Act (PHSA) BAR: licensure of biosimilar or interchangeable version of a reference product. 42 USC 262(k)(7)(A); bars any abbreviated application for 4 years; does not bar submission of full-scale BLA Interchangeable with Reference Biologic 1 year BAR: subsequent interchangeable product for that reference product (42 USC 262(k)(6) Decouples from patent litigation, unlike Hatch-Waxman Duration may extended up to 3.5 years if patent litigation is ongoing

16 Special Review Designations & Approval Pathways Special Designations Fast Track Breakthrough Therapy Priority Review (including voucher programs) Orphan Drug Special Approval Pathways Accelerated Approval Animal Rule Guidance for Industry: Expedited Programs for Serious Conditions Drugs and Biologics (Draft), U.S. Food and Drug Administration, June 2013

17 Special Review Designations Fast Track Designation Where: 506(b) of the FD&C Act, part of FDAMA in 1997, amended by Section 901 of the Food and Drug Safety and Implementation Act (FDASIA) Qualifying Criteria: Drug intended to treat a serious condition AND non-clinical or clinical data demonstrate the potential to address an unmet medical need or a drug has been designated as a qualifying infectious disease product (QIDP). Request w/ind, no later than pre-nda/bla meeting, FDA response w/in 60 days Features: expedited development and review through rolling review process.

18 Special Review Designations Breakthrough Therapy Designation Where: 506 (a) of the FD&C Act, added by 902 of FDASIA Qualifying Criteria: Drug intended to treat a serious condition AND preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies. Request: w/ind, no later than End of Phase 2 Mtg., FDA response w/in 60 days Features: all fast-track features, intensive guidance on efficient drug development during IND, as early as Phase 1, organizational commitment w/ senior leadership ( all hands on deck approach )

19 Special Review Designations Priority Review Where: Prescription Drug User Fee Act (PDUFA) of 1992 Qualifying Criteria: Application (original or efficacy supplement) for drug that treats a serious condition AND if approved would provide a significant improvement in safety or effectiveness OR Supplement for labeling change pursuant to a report on a pediatric study under Pediatric Research Equity Act OR QIDP OR any application or supplement submitted with a Priority Review Voucher Request with BLA, NDA or efficacy supplement, FDA response in 60 days Features: 6 month review clock vs. normal 10 month

20 Special Review Designations Orphan Drug Designation Where: 526 of the FD&C Act, added by Orphan Drug Act, 21 CFR (b)(8) 21 CFR Qualifying criteria: Sponsor must submit documentation demonstrating that the disease or condition for which the drug is intended affects fewer than 200,000 people in the United States or, if the drug is a vaccine, diagnostic drug, or preventative drug, the persons to whom the drug will be administered in the United States are fewer than 200,000. Features: no PDUFA fee, 7 years of marketing exclusivity (active ingredient + indication), will typically receive fast track and/or priority review, but this is not automatic.

21 Incentives Priority Review Vouchers Applications for drugs for the treatment or prevention of certain tropical diseases under 524(a)(3) and (4) of the FD&C Act Applicable to both 505(b)(1) NDAs or 351 BLAs Enumerated tropical disease includes malaria, cholera, dengue, leishmaniasis, and any other infectious disease for which there is no significant market in developed nations and that disproportionately affects poor and marginalized populations Not applicable to any active ingredient approved under 505(b)(1) NDA or 351 (BLA). Transferable by contract; 1 year notice before use Applications for drugs to treat of rare pediatric diseases as defined under 529(a)(3) of the FD&C Act

22 Special Approval Pathways Accelerated Approval Where: 21 CFR 314, Subpart H (for drugs); 21 CFR 601, Subpart E (for biologics); 506(c) of the FD&C Act as amended by 901 of FDASIA. Qualifying Criteria: A drug that treats a serious condition AND provides meaningful advantage over available therapies AND demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit OR on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit (i.e., intermediate clinical endpoint). Discuss w/review division as early as possible Features: based on surrogate; post-marketing study commitments to verify (Phase IV)

23 Special Approval Pathways Animal Rule Where: 21 CFR (Subpart I) Qualifying Criteria: new drug or biologic that intended to treat or prevent serious or life threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances and where human efficacy studies cannot be conducted because it would be unethical.and field trials have not been feasible. 21 CFR Discuss w/review division as early as possible Features: FDA will rely on animal studies to show efficacy when, inter-alia, effect is demonstrated in more than 1 animal species predictive of the response in humans; Animal study endpoint is related to the desired endpoint in humans, Post-market studies when exigency emerges. See 21 CFR (b)(1)

24 Regulatory Considerations Know the full value of your regulatory position (likely designation, exclusivity) before conceding Sponsorship to a development partner Avoid conceding regulatory sponsorship too early; best to retain control of the development effort until partner s effort is mature enough to engender confidence Be clear about who is the Sponsor If Sponsorship is conceded, leverage contributions to effort to ensure ability to (i) remain actively involved in FDA meetings and communications; (ii) assume Sponsorship/Holdership if there are product development failures; and (iii) obtain necessary licenses to IP and technical data for commercial development. Align plan with mission (advanced development or both)

25 Part II: Selecting the Right Legal Vehicle

26 Choosing the Correct Legal Vehicle USAMRMC utilizes five (5) types of legal instruments to accomplish its product development mission: Assistance Agreements (grants and cooperative agreements) Contracts Cooperative Research and Development Agreements (CRADAs) Other Transaction Authority (OTAs) License of Federal Technology (covered by other presentations) Agreements Differ on: Purpose and use of funds Allocation of Technical Data Rights Restricted Federal or Government Purpose Unlimited

27 Assistance Agreements Purpose: Includes grants and cooperative agreements. Cooperative agreements require substantial involvement by the awarding agency; grants do not. A mechanism to provide government funding to a project, the completion of which is in the public interest. inappropriate for the acquisition of a good or service. Where: 10 USC 2358(b)(1), 15 USC 3701, DoDGARS, 32 CFR (nonprofit); 32 CFR (for profit) Process: Funding Opportunity Announcement (PA or BAA); merit-based/competitive Best efforts if awarded in a research area

28 Assistance Agreements Features & Limitations: Money out Federal Purpose Rights (FPR) in technical data (1) obtain, reproduce, publish or otherwise use the data directly produced under an award; and (2) [a]uthorize others to receive, reproduce, publish, or otherwise use such data for Federal purposes. 32 CFR 32.36(c) Federal purposes ill-defined Ability to require delivery of data is limited Best efforts if awarded in a research area

29 Contracts Purpose: A contract is a legal instrument used for the acquisition of goods or services. Where: 10 USC 2358(b)(1) Process: Full and open competition with exceptions for Broad Agency Announcement (BAA) and Sole/Limited Source Justification Features & Limitations: Money out Unlimited Rights in Technical Data Cumbersome and Lengthy Process Must be utilized correctly to obtain full benefit of vehicle

30 Contracts Utilize the Correct Clauses For patents, use FAR (FAR is never used; exceptional circumstances) DoD does not use FAR 27.4 for technical data, but rather the guidance at DFAR and (48 CFR ) DFAR Non-commercial Technical Data Rights Clause /7014 SBIR Technical Data Rights Clause DFAR Commercial Technical Data Rights Clause Government receives 1 of 3 licenses (but may negotiate license as part of the contract, see DFAR (b)); license generally determined by the source of funds used. Unlimited (developed exclusively at government expense) Government Purpose/Use (mixed funding) Limited/Restricted (developed exclusively at private expense)

31 Contracts Ensure Data Order & Delivery Order and delivery accomplished by Contract Data Requirements List (CDRL), DD Form 1423, combined with the appropriate Data Item Description (DID), DD Form 1664 CDRL = data order form DID = describe data format and content requirements Getting it Right From RFP Forward: Include Section C, Statement of Work Include in Section F (Deliveries or Performance, CLINs) Include Section L (Instructions, Conditions and Notices to Offerors) Include Section M (Evaluation Factors for Award) Cite CDRL in Section J (List of Attachments) Prepare to Review Markings: Nonconforming, Unjustified

32 Contracts: DFAR Technical Data (48 CFR (a)(15)) recorded information, regardless of the form or method of the recording of a scientific or technical nature (including computer software information). The term does not include computer software or data incidental to contract administration, such as financial or management information. Detailed Manufacturing or Process Data (48 CFR (a)(6)) technical data that describe the steps, sequences and conditions of manufacturing, processing or assembly used by the manufacturer to produce an end item or component or to perform a process. Form, Fit and Function Data (48 CFR (a)(11)) technical data that describes the required overall physical, functional, and performance characteristics (along with the qualification requirements, if applicable) of an item, component, or process to the extent necessary to permit identification of physically and functionally interchangeable items.

33 Contracts What technical data do I need to consider: Manufacturing Data GMP or QSR certificate of compliance Batch/production records Tech transfer report for process development, validation reports All testing reports, certificates of analysis Stability reports Cold chain documents Equipment identification Cross reference to Drug Master Files (DMFs) The types of DMFs are:» Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel (no longer applicable)» Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product» Type III Packaging Material» Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation» Type V FDA Accepted Reference Information

34 Contracts What technical data do I need to consider: Non-clinical Data GLP certificate of compliance Study report Site/staff qualification

35 Contracts What technical data do I need to consider: Clinical Data (typically in Clinical Trial Agreement) GCP certificate of compliance IRB approval Monitoring reports Protocol & amendments Regulatory filings, correspondence Site/staff qualification Clinical database, data sets Statistical Analysis Plan & Data Management Plan Objectives, endpoints, sample size, tables-listings and figures (TLF) Case Report Forms Final Clinical Study Reports

36 Contracts: DFAR Best Practices Have contactor assert rights in technical data prior to award in an assertion list (DFAR (e)) Explore specifically negotiated rights (DFAR (b)(4)) Ensure unlimited rights coverage (DFAR (b)) (i) data related to item, component or process developed exclusively at government expense (ii) studies, analysis, test data or similar data produced for this contract when the [ data or similar work] was specified as an element of performance (iii) created exclusively with government funds in performance of a contract that does not require development, manufacture, construction or production of items, components, or process. (iv) Form, fit and function data (v) operation, maintenance, installation or training data (other than detailed manufacturing or process data) (vi) Corrected or changed data from the government

37 Contracts: DFAR Best Practices Ensure unlimited rights coverage Note potential conflict between subsection (ii) and (iii)/(v); there seems to be greater protection for detailed manufacturing or process data Proper Markings & Legends Must conspicuously and legibly mark GPR, Limited or Special on each page Unjustified vs. Non-Conforming Validation of Restrictive Marking clause (DFAR ) Deferred Delivery & Order DFAR Expensive

38 CRADA Purpose: A Cooperative Research and Development Agreement (CRADA) is a unique legal mechanism for the government to partner with any outside entity for a stated research collaboration. Where: 15 USC 3710a, AR (T2), DODI Process: Discretionary and flexible, no competition, ORTA Features & Limitations: No money out (but goods and services out); money and nearly everything else in Regulatory rights and Technical Data rights subject to negotiation Must be a defined research collaboration Limited to designated federal laboratories w/crada authority

39 OTA Purpose: Transactions where assistances agreements and contracts are not suitable (these are no procurement contracts) Where: 10 USC 2371 (see also 845 of the NDAA of 1994 and subsequent NDAAs) Process: flexible, competition to the maximum extent practicable Features & Limitations: money out Prototype projects, but recently opened to larger application No FAR-based cost-accounting standards No FAR-based restrictions on Bayh-Dole and Technical Data Rights subject; generally, subject to negotiation Nontraditional defense contractors Novel, untested

40 Part IV: Best Practices

41 Best Practices to Mitigate Risk Remember to: Know the regulatory landscape, properly value the potential Know your IP, Technical Data Needs Know the agreements you need and how to use them to their maximum utility Innovate within legal boundaries: Combining legal instruments for seamless approach Innovative clauses (get deviations where needed) Use current authorities correctly

42 Best Practices to Mitigate Risk Aggressive Evaluation Sub-Factors for Open Data Rights Higher Rating for Open Data Rights Proposals (DFARS (a)(5)) Separate Costing/Proposals Increased and Efficient Use of Contract Vehicle over Assistance Agreement Use the contract vehicle to its maximum utility Cost-sharing Approach Transition Cooperative Agreements to Sole/Limited Source Contracts

43 Contact Information Jeremiah J. Kelly, Esq., MPP Attorney for Medical Product Development & Regulation, Office of the Staff Judge Advocate, U.S. Army Medical Research and Materiel Command Building 521, Room 13A, Fraim Street, Ft. Detrick, MD phone: (301)