Introduction to FDA Review and Approval of Biological Products

Introduction to FDA Review and Approval of Biological Products Jason Conaty Hogan Lovells US LLP October 14, 2020 Agenda • Basic principles; definitions and jurisdiction – What a biologic is and where it fits relative to drugs, devices, etc. • Pathways to market • Requirements for approval • Expedited programs • Marketing exclusivity Sources of Law • Public Health Servises Act (PHSA) (1944) – Biological products (biologics) – Biosimilars (2010) • Food, Drug, and Cosmetics Act (FDCA) (1938) – Food – Drugs – Medical devices – Cosmetics – Tobacco (2010) Centers • Center for Biologics Evaluation and Research (CBER) • Center for Devices and Radiological Health (CDRH) • Center for Drug Evaluation and Research (CDER) • Center for Food Safety and Applied Nutrition • Center for Tobacco Products • Center for Veterinary Medicine Intended Use

• Intended use is the objective intent of the person legally responsible for the product’s labeling • Evidence of intended use – Expressions of the person responsible for labeling or circumstances surrounding the product’s distribution – Look to, e.g., labeling claims, advertising, statements by company or its representatives Drugs FDCA 201(g) • The term “drug” means – articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary; and – articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and – articles (other than food) intended to affect the structure or any function of the body of man or other animals; and – articles intended for use as a component of any [such] article Biologic PHSA 351(i) • The term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product, . . . applicable to the prevention, treatment, or cure of a disease or condition of human beings Drug vs Biologic • Similar to a drug, is “applicable to the prevention, treatment, or cure of a disease or condition of human beings” • A subset of articles – Often thought to mean a product derived from a living source (animal or plant), as opposed to chemically synthesized, but not quite so – Some products that fall within the definition of “biological product” have been approved as drugs, but they were “deemed to have been licensed” as biologics in March 2020 Device FDCA 201(h) • Medical devices, like drugs, are articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect structure/function of the body • Subset of articles – Distinguished from a drug in that it does not achieve its primary intended purpose through chemical action within or on the body, or by being metabolized Cosmetic FDCA 201(i) • Article intended to be applied to, or introduced into, the body to cleanse (but not a soap), beautify, promote attractiveness or alter appearance – Claims of effect on structure/function can be problematic, which is why you see claims to “reduce the appearance of wrinkles and fine lines” – FDA has taken the position that the presence of certain ingredients that are active ingredients in drugs make a product a drug, regardless of claims Dietary Supplement FDCA 201(ff) • A product intended to supplement the diet that contains certain types of ingredients (e.g., vitamin, mineral, herb) and is intended for ingestion • Permitted to include structure/function claims subject to disclaimer Tobacco FDCA 201(rr) • A product made or derived from tobacco and intended for human consumption, or any component, part or accessory, but not any such product that meets the statutory definition of drug, device or combination product – Distinction is based on intended use; product intended for use in diagnosis, cure, mitigation, treatment or prevention of disease, or to affect structure/function is not a tobacco product supplement

drug device

biologic

cosmetic

tobacco Pathways • Biologics License Application (BLA) – 351(a) BLA – branded innovator pathway – 351(k) biosimilar • New Drug Application (NDA) – 505(b)(1) NDA – branded innovator pathway – 505(j) abbreviated NDA (ANDA) – generic drugs – 505(b)(2) NDA hybrid pathway • Medical devices – Pre-Market Approval (PMA) – 510(k) clearance Combination Products

• Therapeutic and diagnostic products that combine drugs, devices, and/or biological products 21 CFR 3.2(e) – Physically, chemically, or otherwise combined or mixed and produced as a single entity; – Packaged together in a single package or as a unit – Packaged separately, but specifically labeled for use with one another • The constituent components (e.g., drug, biologic, device) can be approved under separate marketing applications (NDA, BLA, PMA/510(k)), or under a single marketing application Jurisdiction

• Primary mode of action (PMOA) – An investigational product will be assigned to CDER/CBER or CDRH for lead review depending on the PMOA of the product – If the PMOA is “chemical action” then the combination will typically be reviewed as a drug (or biologic as the case may be) • One marketing application, or two? – When a drug or biologic is combined with a device, there is a strong policy preference for the combination drug/device or biologic/device to be approved under a single marketing authorization, typically an NDA or a BLA • Request for Designation (RFD) – The sponsor of an investigational product can submit a RFD to the Office of Combination Products • Intercenter Agreements – Historically, jurisdictional questions had been the subject of three “Intercenter Agreements” that were entered into by CDER, CBER and CDRH in 1991 – Much of what the agreements covered has since been formalized by rulemaking and guidance Biological Products Protein Therapeutics, BLAs, Biosimilars Biologics Price Competition and Innovation Act (BPCIA) • Enacted on March 23, 2010, as part of the ACA • Created a pathway for the approval of biosimilars in the U.S. • Created a pathway for making interchangeability determinations for biosimilars • Established 12-year reference biologic exclusivity • Established a system for pre-approval patent litigation between pioneers and biosimilars • The BPCIA also amended the definition of biological product to include added the terms “protein (except any chemically synthesized polypeptide)” • Established a 10 year transition mechanism for consolidating the approval of all biological products under the biologics system (= Protein products) • In December 2019, Congress made a further amendment, striking the exception for “chemically synthesized polypeptides” • As of March 23, 2020, NDAs for protein products were “deemed to be a licensed” under BLAs Proteins • The term “biological product” means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein, or analogous product . . . . Proteins Previously Regulated as • insulin products Drugs • somatropin products • chorionic gonadotropin products • desirudin products • follitropin products, urofollitropin products, and menotropins products • hyaluronidase products • imiglucerase products • mecasermin products • pancrelipase products • pegademase products • pegvisomant products • sacrosidase products • somatropin products • taliglucerase alfa products and velaglucerase alfa products • thyrotropin alfa products Regulatory Definition of Protein • “A protein is any alpha amino acid polymer with a specific, defined sequence that is greater than 40 amino acids in size.” • “When two or more amino acid chains in an amino acid polymer are associated with each other in a manner that occurs in nature, the size of the amino acid polymer . . . will be based on the total number of amino acids in those chains, and will not be limited to the number of amino acids in a contiguous sequence.” 21 CFR 600.3(h)(6 “Full” 351(a) BLA • Under 351(a), a BLA will be approved if it:

– Demonstrates the product is safe, pure, and potent – Demonstrates the manufacturing facility meets standards designed to assure that the product continues to be safe, pure, and potent • The regulations add only that the applicant “Shall submit data from nonclinical and clinical studies which demonstrate that the manufactured product meets prescribed requirements of safety, purity and potency.” 21 CFR 601.2 Historical Fexibility

• Diversity of products, from blood to vaccines to allergens • Biologics Act (1902): regulated manufacturing and labeling but not the products themselves • Recodified as PHSA (1944): “safety, purity, and potency” • FDCA (1938) and its major amendments left the regulation of biologics untouched • Administration shunted about before landing at FDA in 1972, while philosophy and standards of biologics regulation remained nebulous • FDAMA (1997), Congress instructed FDA to “minimize differences in the review and approval” of biologics and drugs Standard for Approval of a “Full” BLA

• The substantive content of a BLA for a modern therapeutic protein is generally seen as coincident with that of a full NDA under 505(b)(1) • In practice, a BLA is expected to conform to the ICH standards for preparing the Common Technical Document (ICH-CTD) • The CTD includes placeholders for specific kinds of preclinical and clinical data • Must contain sufficient data to show that the product is safe, pure, and potent • Each product is approved with a labeling and claims, and each claim must be supported by “substantial evidence” “Substantial Evidence” of Effectiveness • “Substantial evidence” means “evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts . . . On the basis of which it could fairly and responsibly be concluded by such experts” that the drug will be effective (FDCA 505(d)) • Typically, this means at least two Phase III clinical trials, but the standard can be met by a single study “and confirmatory evidence” • Safety and effectiveness (safety, purity, potency) are not absolute – FDA balances the benefits and risks in relation to the severity of the condition and the intended population “Abbreviated” Biosimilar 351(k) BLA • 351(k) of the PHS Act: Allows for a finding of safety, purity and potency that relies on the prior approval of a reference biological product • A biosimilar must be – “highly similar” to the reference product – must have the same mechanism of action if known – have the same route of administration, dosage form and strength as the reference product, and – must be approved for a condition of use previously approved for the reference product Interchangeable Biosimilar • Sponsor must provide sufficient evidence to demonstrate biosimilarity • Sponsor must demonstrate that the biological product can be expected to produce the same clinical result as the reference product in any given patient • If the product is administered more than once to an individual, “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch” PHSA 351(k)(4) Innovator Product Expedited Programs Fast Track • Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need • Benefits – More frequent meetings with FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval – More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers – Eligibility for Priority Review and Accelerated Approval – Possible Rolling Review Breakthrough Therapy • A sponsor may request breakthrough therapy designation for a drug or biologic if: – It is intended to treat a serious or life-threatening disease or condition; and – Preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints • Benefits of the program – Additional meeting with the sponsor and the review team throughout the development of the drug – Collaborative, cross-disciplinary review • Timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable • FDA will take steps to ensure that the design of the clinical trials is as efficient as practicable, when scientifically appropriate, such as by minimizing the number of patients exposed to a potentially less efficacious treatment – Possible rolling review; Priority review Accelerated Approval

• FDA may grant accelerated approval to a drug if: – It is intended to treat a serious or life-threatening disease or condition; – It provides a meaningful advantage over available therapies; and – It 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 irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit • FDA says that with accelerated approval, there generally will be fewer, smaller, or shorter clinical trials than is typical for a drug receiving traditional approval • However, FDA will likely require post-marketing confirmatory trials to verify and describe the anticipated effect on IMM or other clinical benefit Innovator Product Marketing Exclusivity 12 Year “First Licensure” Exclusivity

• FDA may not license a biosimilar application until 12 years after the date on which the reference product was “first licensed” under PHSA 351(a) • Includes a 4-year period during which a biosimilar application cannot be submitted • Exclusivity only blocks a biosimilar application – Does not block a full BLA • Exclusivity is limited to the specific reference product with exclusivity – Does not block a biosimilar application that uses a different reference product “First Licensure”

• “First licensure” excludes the following types of applications: – A supplemental application – A subsequent application filed by the same sponsor of the reference product (or a licensor, predecessor in interest, or other related entity) for: • A change (not including a structural modification) that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength • A structural modification that does not result in a change in safety, purity, or potency • Few real-world examples – FDA makes “first licensure” decisions only when necessary or requested by the reference product sponsor Orphan Exclusivity

• Blocks the approval of another sponsor’s marketing application for the “same drug for the same indication or use” for seven years • Broad exclusivity: Blocks BLAs and biosimilars • Same drug means: – Small molecule drug: “same active moiety as a previously approved drug … for the same use … except that if the subsequent drug can be shown to be clinically superior to the first drug…” – Large molecules (macromolecules): “the same principal molecular structural features (but not necessarily all of the same structural features)” unless clinically superior • To avoid a first product’s orphan exclusivity, a second product can be (a) different drug/biologic (b) for a different indication, or (c) clinically superior Orphan “Sameness” for Biologics

• Cellular therapies, e.g., chimeric antigen receptor (CAR) engineered T-cell, viral vectors – Which large molecule definition applies? Which components are relevant? • Monoclonal antibodies – compare to 12-year exclusivity – Considered to be the “same drug” if amino acid sequences of the “complementarity-determining regions” (CDRs) are the same or if there are only minor amino acid differences between them. – By contrast, two antibody conjugates would be considered the “same drug” if “both the CDR sequences of the antibody and the functional element of the conjugated molecule were the same.” • Drug-biologic combinations? • PEGylation? Pediatric Exclusivity

• Pediatric exclusivity will be awarded to a sponsor that conducts pediatric studies in accordance with a “Written Request” issued by FDA • A sponsor must submit reports of the pediatric studies as part of a marketing application to add labeling regarding the pediatric use. – The studies are not required to show safety or efficacy in the pediatric population(s) – Do not have to support a new pediatric indication in the drug product’s labeling – Study results may demonstrate that the drug is not safe or effective for pediatric population(s), or even be inconclusive • Pediatric exclusivity extends underlying regulatory exclusivity periods by 6 months – 7-year orphan exclusivity extended to 7.5 years – 12-year reference product exclusivity for biologics extended to 12.5 years Questions Jason Conaty Hogan Lovells US LLP [email protected]