43
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

Regulatory Rights & Legal Vehicles in Medical …globals.federallabs.org/pdf/2015-national-meeting/regulatory... · Regulatory Rights & Legal Vehicles in Medical Product Development

  • Upload
    vudan

  • View
    218

  • Download
    0

Embed Size (px)

Citation preview

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

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

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.

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.

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

Part I: Know the Regulatory Landscape

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

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

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

Marketing Exclusivity

• What is it?

– 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.

Marketing Exclusivity

• Marketing Exclusivity for Drugs– New Chemical Entity (NCE) – 5 years (21 CFR 314.108)

– New Clinical Information or “Other” – 3 years

– Pediatric (PED) – 6 months’ add-on exclusivity

– Orphan Drug – 7 years (21 CFR 316.31)

– 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

Marketing Exclusivity

• Marketing Exclusivity for Drugs– New Chemical Entity (NCE) – 5 years (21 CFR 314.108)

• BAR: 505(b)(2) or 505(j) applicant; not full 505(b)(1) NDA (see

§505(c)(3)(E)(ii); §21 CFR 314.108(b)(2))

• Request in NDA

– New Clinical Information or “Other” – 3 years

• Available to 505(b)(2) [21 CFR 314.108(b)(4)] Applicant or as

Supplement [21 CFR 314.108(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

Marketing Exclusivity

• Marketing Exclusivity for Drugs– Orphan Drug – 7 years (21 CFR 316.31)

• 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.

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

Marketing Exclusivity

• Marketing Exclusivity for Biologics– New Biologic – 12 years

• Biologics Price Competition and Innovation Act of 2009 (BPCI),

Public Law 111-148, 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

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

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.

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”)

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

Special Review Designations

• Orphan Drug Designation

– Where: §526 of the FD&C Act, added by Orphan Drug Act, 21

CFR 316.20(b)(8) – 21 CFR 316.21.

– 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.

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

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)

Special Approval Pathways

• Animal Rule

– Where: 21 CFR §314.600 (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 314.600

– 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

314.610.(b)(1)

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)

Part II: Selecting the Right Legal Vehicle

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

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 §32.36 (nonprofit); 32 CFR §34.25 (for profit)

• Process: Funding Opportunity Announcement (PA or BAA);

merit-based/competitive

– “Best efforts” if awarded in a research area

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

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

Contracts

• Utilize the Correct Clauses

– For patents, use FAR 52.227-11 (FAR 52.227-13 is never

used; exceptional circumstances)

– DoD does not use FAR 27.4 for technical data, but rather the

guidance at DFAR 227.71 and 227.72 (48 CFR §227.400)

• DFAR Non-commercial Technical Data Rights Clause 252.227-

7013/7014

• SBIR Technical Data Rights Clause 252.227-7018

• DFAR Commercial Technical Data Rights Clause 252.227-7015

– Government receives 1 of 3 licenses (but may negotiate

license as part of the contract, see DFAR 227.7102-2(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)

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

Contracts: DFAR 252.227-7013

• Technical Data (48 CFR 252.227-7013(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 252.227-7013(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 252.227-7013(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.”

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

Contracts

• What technical data do I need to consider:

– Non-clinical Data

• GLP certificate of compliance

• Study report

• Site/staff qualification

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

Contracts: DFAR 252.227-7013

• Best Practices

– Have contactor assert rights in technical data prior to award in

an assertion list (DFAR 252.226-7013(e))

– Explore specifically negotiated rights (DFAR 252.226-7013(b)(4))

– Ensure unlimited rights coverage (DFAR 252.226-7013(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

Contracts: DFAR 252.227-7013

• 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 252.227-7037)

– Deferred Delivery & Order

• DFAR 252.227-7026

• Expensive

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 70-57 (T2), DODI 5535.8

• 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

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

Part IV: Best Practices

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

Best Practices to Mitigate Risk

• Aggressive Evaluation Sub-Factors for Open Data Rights

– Higher Rating for Open Data Rights Proposals (DFARS

227.7103-10(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

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

e-mail: [email protected]

phone: (301) 619-6554