preapproval and approval: navigating the approval process ...€¦ · •market exclusivities 1....

ACI’s 29th FDA BOOT CAMP

Preapproval and Approval:Navigating the Approval Process of Drugs and Biologics

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Scott M. Lassman

Partner, Goodwin

slassman@goodwinlaw.com

Game Plan

• Overview of Basic Approval Concepts

• NDAs and BLAs

• FDA Approval Process

• Market Exclusivities

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Overview of Basic Approval Concepts

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What is a drug?

Statutory Definition:

Articles recognized in the official United States Pharmacopeai (USP), Homeopathic Pharmacopeia of the US, or National Formulary (NF)

Articles intended for use in the diagnosis, treatment, prevention, mitigation, or cure of disease in man or other animals

Articles (other than food) intended to affect the structure or function of the body of man or other animals

Articles intended for use as a component of any of the above

Federal Food, Drug and Cosmetic Act (FFDCA) §201(g)(1)

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What is a biological product?

• “Biological product” is defined in the Public Health Service Act (PHSA)

• It means “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide) or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

• Most biological products are also considered to be drugs

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Examples of Biological ProductsInclude:

• Vaccines

• Blood and blood components

• Allergenics

• Somatic cells

• Gene therapy

• Tissues

• Recombinant therapeutic proteins

Can be composed of:

• Sugars

• Proteins

• Nucleic acids

• Complex combinations of these substances

• Living entities such as cells and tissues

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Why do definitions matter?

• Drugs and biological products have the most burdensome review and approval standards –Bracco case

• Extraordinary time and cost to market- 10-15 years to develop and win approval for a new

Rx medicine- Hundreds of millions of dollars

• Significant post-approval requirements for drugs and biological products

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What is a “new” drug?• Any drug:

- not generally recognized . . . as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling, or

- generally recognized as safe and effective, but has not been used to a material extent or for a material time under such conditions.

• GRAS/E = Generally recognized as safe and effective

• FFDCA § 201(p)

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Why does it matter?

• FDA approval is required only for “new drugs”

• Approval is not required for:- Most OTC drugs- “Grandfathered” drugs- Some DESI drugs

• Generic drugs typically are considered to be “new drugs” even if they contain a previously approved and long marketed active ingredient because of the new formulation

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OTC Drugs

• Most (but not all) are legally marketed without FDA approval under an OTC Monograph

• OTC Monographs are regulations that define the conditions under which FDA considers an OTC drug product to be GRAS/E (and not misbranded)

• OTC drugs that do not comply with a monograph are “new drugs” and thus must be approved by FDA

- Rx-to-OTC switch- Direct-to-OTC approval (very few drugs are approved this way)

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NDAs and BLAs

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Types of Applications

• “Full” New Drug Application (NDA) – FFDCA § 505(b)(1)

• 505(b)(2) Application – FFDCA § 505(b)(2)

• Abbreviated New Drug Application (ANDA) – FFDCA § 505(j)

• “Full” Biologics License Application (BLA) – PHSA § 351(a)

• Abbreviated Biologics License Application (aBLA) - PHSA § 351(k)

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What is a Full NDA

• A type of application used to obtain approval of a new drug

• Must include full reports of studies to prove safety and effectiveness

• In other words, the applicant must conduct or have a right of reference to all studies necessary to demonstrate that the drug is safe and effective

• Usually used to approve New Chemical Entities (NCEs), i.e., drugs with novel active moieties

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What is a 505(b)(2) Application?

A type of full New Drug Application (NDA) where some of the required safety and effectiveness studies were: NOT conducted by or for the 505(b)(2) applicant; and For which the applicant has no right of reference

In other words, it’s an NDA that relies in part upon somebody else’s data for approval

Often viewed as a hybrid between a full NDA and an ANDA

• Typically used for approval of changes to a previously approved drug, e.g., new dosage form, new indication

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505(b)(2) Examples

• New formulation requiring clinical studies

• New dosage regimen

• Different salt of previously approved active

• New combination of previously approved actives

• New indication

• Rx-to-OTC switch

• Complex drugs where clinical investigations necessary to show “same” active

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What is a BLA?

• A type of application used to obtain licensure of a biological product

• Requirements similar to NDA requirements

• The PHSA uses the “safe, pure, and potent” standard but FDA generally interprets it the same as the “safe and effective” standard used for drugs

• Generally, increased focus on the manufacturing facility

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NDA/BLA Contents

• Form 356h

- Signed form certifying to the truth and accuracy of the application

• Nonclinical data

• Clinical data

• Chemistry, manufacturing and control information

• Labeling

• Administrative information

- E.g., patent information, various certifications

• Summaries (e.g., Integrated Summary of Effectiveness (ISE))

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NDA Approval Standards

• Drug is safe under the proposed conditions of use

• There is substantial evidence of effectiveness of the drug for the labeled indications

• Manufacturing operations comply with current Good Manufacturing Practices (cGMPs); and

• Labeling is not false or misleading

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Substantial Evidence• The NDA applicant must provide “substantial evidence that the drug will

have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling”

• Substantial evidence = evidence from adequate and well-controlled clinical studies (FFDCA § 505(d))

• Typically requires two adequate and well-controlled studies but FDA can approve a drug on the strength of only one clinical trial, plus confirmatory evidence (FFDCA § 505(d))

• Evidence of effectiveness must be both statistically and clinically significant

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Safety – Balancing Benefit and Risk

• Demonstrate “by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions of use prescribed, recommended, or suggested” in the proposed labeling

• Safety is not defined in the FFDCA

• Safety assessment involves a balancing of the risks and benefits of a drug

- Sliding scale approach to safety assessment – even significant risks will be accepted if the drug is intended to treat a serious or life-threatening disease

• Risk minimization tools- Labeling- Post-market studies- Risk Evaluation and Mitigation Strategies (REMS)

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FDA Review Process

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FDA Review Process• Pre-review activities

- FDA regulations and guidance provide opportunity for numerous pre-submission meetings (e.g., pre-IND, End of Phase 2, pre-NDA)

• Submit NDA/BLA

• FDA “Filing” decision made within 60 days

- Is the application sufficiently complete to allow FDA to conduct a substantive review?

• 74-Day Letter

- Provides FDA’s initial thoughts from filing review

• Information Requests and amendments

• Advisory committee meeting may be held

• FDA inspection of manufacturing facilities and some clinical trial sites

• Action Letter

- Approval letter, or

- Complete Response Letter

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Prescription Drug User Fee Act (PDUFA)

• Enacted in 1992 to speed FDA review of NDAs – highly successful- Must be reauthorized every 5 years

• Fees paid by biopharmaceutical companies are earmarked for drug review activities

• Establishes timelines for review activities (longer than statutory requirement)- 10 months for standard applications- 6 months for priority applications

• Three Types of User Fees (FY2017)- Application - $2 Million- Manufacturing Facility – $512,200- Product - $97,750

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Expedited Programs

• There are several programs designed to expedite the approval of drugs intended to treat serious conditions for which there is an unmet need

• Expedited Programs- Fast Track Designation- Breakthrough Therapy Designation- Accelerated Approval- Priority Review

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Features of Expedited Programs

• Early and frequent interactions with FDA

• Intensive FDA guidance on drug development

• Senior management involvements

• Rolling review of NDAs

• Approval based on surrogate endpoints or intermediate clinical endpoints

• Shorter review goals (6 months versus 10 months)

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Special Cases• Fixed-Dose Combination Drugs

- Combines two or more active ingredients into a single dosage form

- Combination Rule: each active ingredient must contribute to the claimed effect

- Examples: HIV drugs, abuse-deterrent opioids

• Complex Drugs- Some large molecule products (including biological products)

are approved via NDAs- Examples: insulin, human growth hormone, enoxaparin- After 2020, all NDAs for biological products will be converted

to BLAs- Some drugs are so complex that an ANDA cannot be

submitted and an applicant must use the 505(b)(2) process

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Marketing Exclusivities

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Exclusivity Overview

• Several types of exclusivity were established by the Hatch-Waxman Act to maintain incentives for innovative research (NDAs) and to encourage competition (ANDAs)

• Since then, other, more targeted types of exclusivity have been created to incentivize particular types of research (e.g., pediatric, orphan drug)

• Exclusivity works by preventing the submission or approval of competing products for specified time periods even when FDA has determined the product is safe and effective

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Main Types of Exclusivity

• Non-patent exclusivity

- NCE exclusivity – 5 years

- New clinical study – 3 years

• Orphan drug exclusivity – 7 years

• Pediatric exclusivity – 6 months (add-on only)

• Biologic Reference Product exclusivity

- 4 years

- 12 years

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NCE Exclusivity

• Granted to drug products containing an active drug molecule that has never been approved before, i.e., a “new chemical entity” (NCE)

• Blocks submission of 505(b)(2) applications and ANDAs for five years

- 4 years if subsequent application contains a “paragraph IV” certification

- Effectively provides 6-7 years of exclusive marketing

• Umbrella Policy: exclusivity protects all versions of the drug containing the same active moiety

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3-Year Exclusivity

• Granted for changes to previously approved drugs requiring the submission of new clinical studies

• Blocks approval of 505(b)(2) applications and ANDAs for three years

• Protects only the change supported by the new studies, e.g., extended release dosage form

- Carve outs may be possible

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Orphan Drug Exclusivity

• Provides incentives for developing drugs to treat rare diseases or conditions

• Rare disease or condition- Affects less than 200,000 in U.S.; or- No reasons reasonable expectation of recovering costs from U.S.

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• 7-year exclusivity period - Blocks approval of NDAs, 505(b)(2) applications, ANDAs, and Biologics

License Applications (BLAs), even if supported by full clinical trials

- Limited to “same drug” for same indication

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Pediatric Exclusivity

• Intended to provide incentives to conduct pediatric research

• Adds 6 months to existing exclusivity periods

• Granted if an applicant conducts pediatric studies requested by FDA in a Written Request

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Biologic Reference Product Exclusivity

• Two Types:- 4 Year: No aBLA can be submitted for 4 years after approval

of the reference product- 12 Year: No aBLA can be approved for 12 years after approval

of the reference product

• Pediatric exclusivity can extend these exclusivity periods for 6 months

• FDA is publishing a “Purple Book” (similar to the Orange Book) intended to contain exclusivity information for biological reference products

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Questions?

34203338741.

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Contact Information

Scott M. Lassman is a partner at Goodwin, where he specializes in FDA legal, regulatory and policy issues, including product approval, lifecycle management, and biosimilars.

Contact Information901 New York Avenue, NW

Washington, D.C. 20001202-346-4134 (o)

slassman@goodwinlaw.com

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