The United States And Europe

4. 1 INTRODUCTION The United States and the European Union have distinct but overlapping schemes for the regulation of biologics, ranging from the definition of a biologic itself to the technical requirements for approval. In the United States, the definition of “biological product” was developed over time, and historical context continues to inform its interpretation.

In the European Union, biologics are largely defined in terms of their active substances and methods of manufacture. Despite these differ- ences, both jurisdictions recognize that biologics warrant special treatment because of their distinct characteristics, such as their complex structures and susceptibility to variation during manufacturing.

Whereas in the United States, Congress enacted a separate statute for biologics, in the EU, the general approval scheme and certain specific requirements apply to biologics. Nevertheless, US and EU authorities have undertaken harmonization efforts with respect to some technical requirements for biologics applications; thus, there is significant overlap in requirements imposed by both regions. This chapter provides an overview of the US and EU regulatory schemes, from nonclinical trials through clinical trials to approval.

It then discusses considerations for global development of biologics, and it ends by discussing special issues for developing vaccines. 1 The chapter uses both the terms “drug” and “medicine” as they are used in the US and EU regulatory schemes, respectively. 2 Mr. Kingham is a partner at Covington & Burling LLP in Washington, DC, and London; Ms. Carver is an associate in the firm’s Washington, DC, office; and Ms. Klasa is an associate in the firm’s Brussels office. The views expressed here are solely those of the authors and do not necessarily reflect the views of the firm or its clients. 75.

Biological Drug Products: Development and Strategies, First Edition. Edited by Wei Wang and Manmohan Singh. O2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc. 4. 2 GENERAL UNITED STATES REGULATORY SCHEME 4. 2. 1 The Definition of “Biological Product” and Its Significance In the United States, “biological products” are subject to a different premarket pathway and differing intellectual property protections than products regulated only as “drugs. ”

3 Whereas a biological product must be licensed pursuant to a biologics license application (BLA) showing it is “safe, pure, and potent,” the sponsor of a nonbiologic drug must submit a New Drug Application (NDA) showing the drug is safe and effective.

4 Certain new biological products receive 12 years of data protection, but new drugs receive up to 5 years of this protection. 5 Biologic and drug legislation also provide different schemes for resolving patent issues regarding entry of follow-on products. 6 Thus, determining whether a product meets the definition of “biological product” is enormously important. Unfortunately, this inquiry is not straightforward. Drug and biologic legislation developed separately, and Congress did not provide detailed guidance for distin-guishing biologics from other drugs.

As a result, the Food and Drug Administration (FDA) and other agencies administering the biologics law over time have made these distinctions mostly on an ad hoc basis based on history and relevant precedents. 7 The FDA has recently proposed a bright-line rule for distinguishing “proteins” that qualify for treatment as biologics from certain other products that do not. This approach remains in the proposal stages, however, and history and precedent continue to play important roles in product jurisdiction determinations.

This section outlines that relevant history. In 1902, Congress passed the Biologics Control Act, which applied to “any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention and cure of diseases of man” and required licensure of facilities making these products. 8 Over the next hundred-plus years, Congress expanded this list of covered products to include, among other things, the following products and those “analogous” to them: vaccines, blood, blood products, allergenic products, and proteins (except chemically synthesized polypeptides). 9 Despite all of these 3.

Products meeting the “biological product” definition also meet either the definition of “drug” or “device” under the Federal Food, Drug, and Cosmetic Act (FDCA). Intercenter Agreement Between CDER and CBER (effective October 31, 1991) [hereinafter ICA], § II. 4 Public Health Service Act (PHSA) § 351(a)(2)(C)(i)(I); FDCA § 505(b) & (d). 5 PHSA § 351(k)(7); FDCA §§ 505(c)(3)(E), 505(j)(5)(F). 6 PHSA § 351(l); see, e. g. , FDCA §§ 505(b)(1), 505(c)(2), 505(c)(3)(A)-(D), 505(j)(2)(A)(vii) and (B), 505(j)(5). 7 Michael S. Labson, Krista Hessler Carver, and Marie C. Boyd, FDA Regulation of Biological Products, in THE PHARM. REGULATORY PROCESS 103, 110 (Ira R. Berry & Robert P. Martin, eds. , 2008).

8 Pub. L. No. 57-244, 32 Stat 728, 728 (1902). Congress added a product licensure requirement in 1944 and then replaced the dual license requirement with a single requirement for a BLA in 1997. Pub. L. No. 78- 410, § 351, 58 Stat. 682, 702 (1944); Pub. L. No. 105-115, § 123(a), 111 Stat. 2296, 2323 (1997). 9 Pub. L. No. 111-148, Title VII, Subtitle A, § 7002 (b)(2), 124 Stat. 119, 814 (2010); Pub. L. No. 105-115, § 123(d), 111 Stat. 2296, 2324 (1997); Pub. L. No. 91-515, § 291, 84 Stat. 1297, 1308 (1970); Pub.

L. No. 78-410, 58 Stat. 682, 702 (1944). 76 KEY REGULATORY GUIDELINES FOR THE DEVELOPMENT OF BIOLOGICS amendments, Congress never defined the listed terms and, in particular, never defined “analogous,” so the scope of the biological product definition remained unclear. The overlapping definition of “drug” added to this complexity. The Food and Drugs Act of 1906 and the Federal Food, Drug, and Cosmetic Act of 1938 (FDCA) defined “drug” broadly to include, among other things, substances intended for use in the cure, mitigation, or prevention of disease, and the latter statute mandated submission of an NDA before marketing of a drug.

10 Although these “drug” definitions encompassed many biologics, the statutes did not provide concrete parameters for distinguishing nonbiological drugs from biological products. In 1944, when Congress revised and recodified the 1902 Act in the Public Health Service Act (PHSA), it clarified that the NDA requirement did not apply to biologics, but it did not elucidate the scope of the biological product definition. 11 Regulators attempted to fill this gap by promulgating regulatory definitions of virus, therapeutic serum, toxin, antitoxin, and analogous product.

12 For example, the 1947 regulations, which are essentially similar to the current regulations, 13 defined products “analogous” to a toxin or antitoxin as those intended for preventing, treating, or curing diseases or injuries “through specific immunization. ” 14 The 1947 definition of products analogous to therapeutic serums excluded hormones. 15 Hormones such as insulin and human growth hormone were approved under the FDCA, not the PHSA. 16 Despite the 1947 regulations, differentiating biologics from drugs remained challenging at the margins. 10 Pub. L. No. 59-384 § 6, 34 Stat 768 (1906); Pub. L. No. 75-717 §§ 201(g)(2), 52 Stat.

1040, 1041, 1052-53 (1938). 11 See Pub. L. No. 78-410 § 351(g), 58 Stat. 682, 703 (1944) (“Nothing contained in this Act shall be construed as in any way affecting, modifying, repealing, or superseding the provisions of the [FDCA]”); H. R. Rep. No. 1364, 78th Cong. , at 23 (1944) (“Subsection (g) is an explicit statement, confirming the present legal situation, that products subject to this section are not exempted from the [FDCA], except for the provision of that act relating to the licensing of new drugs”). 12 42 C. F. R. § 73. 1(g) (1949); see, e. g. , Treasury Dep’t, U. S. Pub.

Health & Marine-Hospital Serv. , Regulations for the Sale of Viruses, Serums, Toxins, and Analogous Products, Miscellaneous Publication No. 20, {16 (1909). 13 21 C. F. R. § 600. 3(h) (2012). The FDA has not updated 21 C. F. R. § 600. 3(h) to reflect that the statutory definition of biological product now includes products applicable to the prevention, treatment, or cure of “condition[s]” of human beings. For this reason, one court has concluded that the regulation is invalid “to the extent that [it] purports to eliminate the application… to ‘conditions. ’” United States v. Livdahl, 459 F. Supp. 2d. 1255, 1261 (S. D. Fla. 2005). 14 42 C. F. R. § 73.

1(g)(5)(iii) (1949). 15 Id. § 73. 1(g)(5)(ii) (defining a product as analogous to a serum if it was “composed of whole blood or plasma or containing some organic constituent or product other than a hormone or an amino acid, derived from whole blood, plasma, or serum and intended for administration by a route other than ingestion”) (emphasis added). 16 Letter of Steven K. Galson, M. D. , M. P. H. , Director, CDER, to Kathleen M. Sanzo, Esq. , Morgan, Lewis & Bockius LLP; Stephan E. Lawton, Esq. , BIO; and Stephen J. Juelsgaard, Esq. , Genentech, Docket No. 2004P-0231, PDN1 (May 30, 2006) (2006 Consolidated Response), at 44 & n.

82; FDA, Ever Approved Drug Products Listed by Active Ingredient, at 2291 (printout dated August 2, 1989) (obtained via FOIA request) (listing NDA 1-754 for Sterling Drug Inc. ’s insulin suspension product, approved November 27, 1939). GENERAL UNITED STATES REGULATORY SCHEME 77 The advent of biotechnology, along with agency organizational disputes, brought this issue to the forefront of FDA’s focus. In 1986, the FDA issued a policy statement stating that it would determine whether biotechnology products constituted biologics “based on the intended use of each product on a case-by-case basis. ” 17

Thus, the FDA continued to make product-specific determinations informed by history and precedent, and different units of the FDA had to agree on the approval pathway for a given product. This proved to be difficult, with press reports of “turf battles” between the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) for jurisdiction over blockbuster biotechnology products 18 and claims that the deci- sions were “inconsisten[t]. ”

19 For example, epidermal growth factors were regu- lated as drugs because their first approved indications were traditionally drug indications. 20 Most monoclonal antibodies (mAbs) were licensed as biologics because of their biological source material and immunologic function. 21 Recom- binant insulin and human growth hormone, similar to their naturally derived counterparts, were approved pursuant to NDAs. 22 CDER and CBER subsequently executed an Intercenter Agreement (ICA) that attempted to clarify the governing authorities for products derived from living material.

The agreement provided that the following products, among others, were subject to licensure under the PHSA: vaccines; proteins, peptides, and carbohydrates produced by cell culture (other than hormones and products previously derived from human or animal tissue and approved as drugs); proteins made in transgenic animals; blood and blood products; and allergenic products. 23 NDAs were required for, among other things, hormones (regardless of method of manufacture), synthetic mono- nucleotide and polynucleotide products, and naturally derived products other than vaccines or allergenics.

24 Twelve years later, the FDA consolidated review of most therapeutic proteins in CDER, but this transfer did not modify the governing statutory scheme for any ICA product, and the FDA continued to decide whether new products were biological products or nonbiologic drugs on a case-by-case basis using the principles of the ICA and historical precedent.

25 In February 2012, the FDA issued draft guidance aimed at implementing recent legislation that added “protein (except any chemically synthesized polypeptide)” to the biological product definition. 26 In this draft guidance, the FDA proposed a 17 51 Fed. Reg. 23309, 23310 (June 26, 1986). 18 FDA Triage System for Drugs/Biologics Questioned, U. S. REGULATORY REPORTER (November 1990), at 3. 19 FDA’s Handling of Biotech Approvals,SCRIP (August 26, 1988), at 14. 20.

The FDA and Drug-Biologic Classifications, U. S. REGULATORY REPORTER (August 1988), at 6. 21 Id. 22 Suzanne White Junod, Ph. D. , FDA Historian, Celebrating a Milestone: FDA’s Approval of First Genetically-Engineered Product,U PDATE, September/October 2007, at 43, 44; 2006 Consolidated Response, at 44 and n. 82. 23 ICA, § III(B)(1). 24 Id. § III(A). 25 68 Fed. Reg. 38067, 38068 (June 26, 2003). 26 Patient Protection and Affordable Care Act (PPACA), Pub. L. No. 111-148 § 7002(b)(2), 124 Stat 119, 814 (2010) (amending section 351(i) of the PHSA). 78 KEY REGULATORY GUIDELINES FOR THE DEVELOPMENT OF BIOLOGICS.

bright-line rule distinguishing proteins from “peptides” and “chemically synthesized polypeptide[s]” that the FDA proposes to approve under the FDCA. 27 The agency proposed to define “protein” as “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size. ” 28 According to the draft guidance, “peptides” have 40 or fewer amino acids and are not “proteins. ” 29 The agency also proposed to define “chemically synthesized polypeptide” as an alpha amino acid polymer that is made entirely by chemical synthesis and that has fewer than 100 amino acids. 30.

Until the draft guidance is finalized, these definitions must be considered proposals. Nevertheless, they signal that the FDA might be shifting from its traditional, ad hoc approach to jurisdictional decisions to a new approach guided by bright-line rules. 31 4. 2. 2 Nonclinical Studies for Biologics Similar to other drugs, biologics must undergo laboratory and animal testing to define their pharmacologic and toxicologic effects before they can be studied in humans. 32 The legal framework for preclinical testing of biologics is essentially similar to that for drugs; for example, the FDA’s good laboratory practice (GLP) regulations typically apply.

33 Nevertheless, biologics present special issues, necessitating a “flexible, case-by-case, science-based approach” to preclinical testing. 34 For biotechnology-derived pharmaceuticals, the FDA has adopted the Interna- tional Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) S6 guidance, which describes the unique 27 FDA, Draft Guidance for Industry: Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 13 (February 2012) (Q&A Draft Guidance).

Sponsors of certain transitional proteins will remain eligible to submit their applications as NDAs during a transition period that ends on March 23, 2020. PPACA § 7002(e), 124 Stat. at 817. This option is available if a protein is the same “product class” as a biological product that was approved under the FDCA on or before March 23, 2010. Id. § 7002(e)(2). In the draft guidance, the FDA proposes to consider two products to be in the same product class if they “are homologous to the same gene-coded sequence,” with allowances “for additional novel flanking sequences. ” Q&A Draft Guidance, at 14.

Under the draft guidance, two products may be in the same product class even if their differences result in changes in pharmacokinetics, but not if the changes “alter[] a biological target or effect. ” Id. at 14–15. 28 Q&A Draft Guidance, at 13. 29 Id. 30 Id. 31 The FDA also has special rules for determining the regulatory status of tissue engineering and cell processing products. See 21 C. F. R. Parts 1270 & 1271. Detailed discussion of these rules is beyond the scope of this chapter. 32 FDA, Guidance for Industry: S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharma- ceuticals 3 (July 1997) (S6 Guidance). 33 21 C. F. R. Part 58.

For some studies using specialized test systems, it may be impossible to fully comply with GLP, but this might not preclude use of the studies to support clinical trial initiation and marketing authorization. S6 Guidance, at 3. 34 S6 Guidance, at 1. GENERAL UNITED STATES REGULATORY SCHEME 79 approach needed to selection of animal species and immunogenicity testing as overarching considerations and outlines typical preclinical testing. 35 Also, in May 2012, the FDA adopted the addendum to that ICH guidance.

36 Because Europe’s Committee for Medicinal Products for Human Use (CHMP) approved that guidance nearly a year earlier, in July 2011, the addendum is discussed in Section 3. 1, infra, but it is now equally applicable in the United States. Therefore, for a full under- standing of nonclinical testing standards in the United States, readers should also review Section 3. 1 of this chapter. 4. 2. 2. 1 Relevant Species Many biologics cannot be tested in commonly used animal species, such as rats and dogs, because of their biological activity and species- or tissue-specific activity.

37 Instead, sponsors must use a variety of tests, such as invitro binding assays and functional tests, to identify a “relevant species,” that is, “one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies). ” 38 Generally, a sponsor should identify two relevant species, although one species may suffice when the product’s biological activity is well understood or only one relevant species exists. 39 In some cases, the chimpanzee—which cannot be sacrificed at the end of the study—is the only relevant species, and in other cases, identifying a relevant species might be impossible.

40 In these situations, the sponsor might need to consider alternative approaches to gathering animal data, such as the use of homologous proteins (which recognize the target protein or epitope in the animal), 41 transgenic animals that express the human receptor, or other animal models. 42 4. 2. 2. 2 Immunogenicity Many biologics elicit immune responses, which can affect preclinical study results. 43 In some cases, these effects are desired (e. g. , with a vaccine), but unwanted immunogenicity might be harmful. Potential undesired effects include neutralizing or prolonging the biologic’s activity, forming immune complexes, or cross-reacting with endogenous substances. 44.

As a result, sponsors 35 Id. at 1 n. 1. This guidance applies to biotechnology-derived proteins and peptides, their derivatives, and products of which they are components. It may also apply to recombinant DNA protein vaccines, chemically synthesized peptides, and plasma-derived products, among other things.

It does not apply to allergenic extracts, cellular blood components, conventional bacterial or viral vaccines, DNA vaccines, or cellular and gene therapies. Id. at2. 36 FDA, Guidance for Industry S6 Addendum to Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (May 2012) as adopted by FDA at 77 Fed. Reg.

29665, 29666 (May 18, 2012). 37 S6 Guidance, at 4. 38 Id. 39 Id. 40 Andrea B. Weir, Ph. D. , DABT, Pharmacologist/Toxicologist, Office of Drug Evaluation VI, CDER, FDA, Preclinical Safety Assessment of Therapeutic Proteins and Monoclonal Antibodies,inBIOLOGICS DEVELOPMENT:AREGULATORY OVERVIEW17, 19 (Mark Mathieu, ed. , 3rd ed. , 2004).

41 Id. 42 S6 Guidance, at 4–5. 43 Weir, supra note 40, at 19. 44 Id. at 20. 80 KEY REGULATORY GUIDELINES FOR THE DEVELOPMENT OF BIOLOGICS should obtain necessary samples for antibody testing during repeat-dose toxicity studies and, when interpreting the data, should consider the effects of antibody formation on pharmacokinetics (PK), pharmacodynamics (PD), and adverse events.

45 Detection of antibodies should not prompt termination of a preclinical study unless the immune response neutralizes the biologic’s effects in “a large proportion” of the test animals. 46 Finally, sponsors should be aware that animals’ immune responses are not indicative of those in humans. 47 4. 2. 2. 3 Typical Preclinical Testing Sponsors usually must conduct PD studies, such as in vitro binding assays and in vivo studies that assess the product’s pharmacologic activity and define its mechanism of action. 48

Biologics typically undergo single- and repeat-dose toxicity studies using relevant species, as noted earlier. 49 Safety pharmacology studies, which evaluate the product’s functional effects on major body systems and specific organs, and local tolerance testing can be done separately or subsumed in toxicity testing. 50 Sponsors also usually conduct single- and multiple-dose PK and/or toxicokinetic studies to assess absorption, disposition, exposure, and clearance (in particular, antibody-mediated clearance) and explore dose–response relationships.

51 This information is used to predict margins of safety for human studies. Immunogenicity testing might include screening and mechanistic studies, but animal models are not highly predictive of human immunogenicity. 52 Typical carcinogenicity bioassays are “generally inappropriate” for biologics, although the S6 guidance calls for assessment of carcinogenicity when warranted based on the “duration of clinical dosing, patient population, and/or biological activity. ”

53 If concern exists regarding carcinogenic potential, the sponsor can consider several approaches to assess risk, including testing in a variety of malignant and normal human cells and further testing in relevant species. 54 According to ICH S6, reproductive and developmental toxicity studies may or may not be recom- mended, depending on “the product, clinical indication, and intended patient population. ”

55 Such studies using primate species pose challenges because of these animals’ heterogeneous drug responses, high background abortion rate, and low number of offspring. 56 45 S6 Guidance, at 6. 46 Id. 47 Id. 48 Weir, supra note 40, at 20; S6 guidance, at 4. 49 Weir, supra note 40, at 21. 50 S6 guidance, at 7, 10. 51 Id. at 7–8; Weir, supra note 40, at 21. 52 Weir, supra note 40, at 22; S6 guidance, at 9. 53 S6 guidance, at 10. 54 Id. 55 Id. at9. 56.

Weir, supra note 40, at 22. GENERAL UNITED STATES REGULATORY SCHEME 81 Because biologics generally degrade into peptides and amino acids, classic biotransformation studies are unnecessary. 57 Genotoxicity studies also usually are not applicable to biotechnology-derived drugs because they are not expected to interact with DNA or chromosomes. 58 4. 2. 3 Clinical Studies for Biologics 4. 2. 3. 1 The Investigational New Drug Application If a sponsor plans to perform clinical testing of a biologic in the United States, it must first have an investigational new drug application (IND) in effect.

59 An IND generally goes into effect 30 days after the FDA receives it. 60 During this 30-day time period, the FDA reviews the IND for any safety issues and may place a clinical hold on the study if, among other things, it presents an “unreasonable” risk to patients. 61 The IND must contain “[a]dequate” information from preclinical studies, on which the sponsor bases its conclusion that clinical trials are reasonably safe. 62 For well-characterized therapeutic biotechnology products, the IND should describe the product’s pharmacologic effects and mechanism of action and provide information on its absorption, distribution, metabolism, and excretion. 63.

Sponsors must include a description of the overall investigational plan and a protocol for each planned study; protocols not submitted in the initial IND should be submitted as protocol amendments. 64 The IND also must contain chemistry, manu- facturing, and controls information sufficient to allow evaluation of safety. 65 This information is particularly important for many biologics, which may raise concerns because of their impurity profiles or the use of materials with unknown components in their manufacture. 66 The FDA recognizes that sponsors likely will change their manufacturing processes as development progresses. Section 2. 3.

4, infra, dis- cusses the effects of these changes on product development. 4. 2. 3. 2 Good Clinical Practices Traditionally, the FDA used the phrase “good clinical practices” (GCP) to collectively describe a number of regulations and guidance documents with two overarching goals: (1) to ensure the integrity of data collected in clinical trials and (2) to protect clinical trial subjects. 67 In the mid 57 S6 guidance, at 8. 58 Id. at 9–10. 59 21 C. F. R. § 312. 20(a) & (b);

21 C. F. R. § 312. 40(b)(1); FDA, Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-Derived Products 2 (November 1995) (Phase 1 Guidance).

60 21 C. F. R. § 312. 40(b)(1). 61 21 C. F. R. § 312. 42(b)(i). 62 21 C. F. R. § 312. 23(a)(8). 63 Phase 1 Guidance, at 10. 64 21 C. F. R. § 312. 23(a)(3)(iv) & (6). 65 21 C. F. R. § 312. 23(a)(7); Phase 1 Guidance, at 4. 66 Phase 1 Guidance, at 4–5. This Guidance applies only to well-characterized therapeutic biotech products. Id. at2. 67 Good Clinical Practices (GCP),inBIOLOGICS DEVELOPMENT:AREGULATORY OVERVIEW 115, 115 (Mark Mathieu, ed. , 3rd ed. , 2004); see also 62 Fed. Reg. 25691, 25692 (May 9, 1997).

82 KEY REGULATORY GUIDELINES FOR THE DEVELOPMENT OF BIOLOGICS 1990s, however, the ICH developed a consolidated GCP guideline, known as the E6 guidance, to harmonize standards for clinical study design, conduct, reporting, and recordkeeping. 68 The FDA has adopted this guidance.

The agency recommends that sponsors use it when generating data for submission to the agency 69 and has stated that it will deem studies complying with ICH GCP as meeting the FDA’s GCP standards. 70 This guidance supplements and clarifies FDA regulations on institu- tional review boards (IRBs) (21 C. F. R. Part 56), informed consent (Part 50), and clinical studies for drugs and biologics (Part 312).

It describes the overarching principles for conducting clinical trials, the responsibilities of various parties involved with the clinical trial (IRB, sponsor, investigator), and the necessary documents for conducting a clinical study (e. g. , the study protocol and investigator’s brochure). 71 Sponsors should consider it in combination with the above-cited regulations, more recent FDA regulations (such as Part 54 on financial disclosures for clinical investigators), and more recently released FDA guidance on specific GCP topics. 4. 2. 3.

3 Study Design Considerations As with new drugs, clinical development of biologics typically involves three phases, which may or may not overlap. Biologics present several unique clinical considerations, however. Often, their clinical devel- opment programs must include an assessment of immunogenicity, which is typically not an issue for small molecule drugs. Also, because many biologics treat serious or life-threatening illnesses, their development may be compressed. 72 Phase 1 studies involve the “initial introduction” of the biologic into a small number of humans to assess the product’s metabolism, pharmacology, and safety at escalating doses.

73 Unlike phase 1 trials for nonbiologic drugs, phase 1 studies of biologics frequently involve administration to patients rather than healthy volunteers who will not derive benefit from them to ensure the risk–benefit profile of the product is acceptable for ethical purposes. 74 For example, studies may enroll patients when the biologic is known or suspected to be “unavoidably toxic,” when there is a risk of antibody development to a native protein or mAb, or when the product’s bioactivity is disease specific.

75 Phase 1 studies should determine the maximum tolerated dose and assess the product’s bioactivity and PK to determine the optimum biological dose. 76 With respect to immunogenicity, these studies should assess subjects’ antibody 68 62 Fed. Reg. at 25692. 69 Id. ; FDA, Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance (E6 Guidance) 1 (April 1996).

70 Good Clinical Practices (GCP),supra note 67, at 118. 71 See generally E6 Guidance. 72 See Barbara G. Matthews, M. D. , M. P. H. , Clinical Testing of Biologically Derived Therapeutics,in BIOLOGICS DEVELOPMENT:AREGULATORY OVERVIEW 79, 84 (Mark Mathieu, ed. , 3rd ed. , 2004). 73 21 C. F. R. § 312.

21(a)(1) & (2). 74 FDA, Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers 3 (July 2005) (MRSD Guidance); Matthews, supra note 72, at 83. 75 MRSD Guidance, at 3; Matthews, supra note 72, at 83. 76 Matthews, supra note 72, at 81–82, 83. GENERAL UNITED STATES REGULATORY SCHEME 83 development, both directly after administration and at least 28 days thereafter, and determine whether these results are linked to adverse events, PK, or PD.

77 Phase 2 trials are controlled studies that evaluate short-term adverse events and effectiveness for a specific use in several hundred patients. 78 These studies further explore exposure–response relationships and the biologic’s PK, PD, and immuno- genicity, and they provide information to help refine the phase 3 protocol, including with respect to size, population, and endpoints. 79 Biologics sponsors often combine phase 2 studies with phase 1 or phase 3 studies. 80 Phase 3 studies enroll patients and provide primary evidence for labeling claims and risk–benefit assessment.

81 They are larger than phase 2 studies, but their size ranges considerably depending on the patient population and the availability of alternative therapies. 82 They typically are randomized, double blinded, controlled, and performed at multiple study centers. 83 Placebo controls are used when ethical considerations permit, but in some cases (e. g. , when effective treatment is already available and withholding treatment would expose subjects to unreasonable risks), active controls are used.

84 The studied patient population, as defined in the protocol’s exclusion and inclusion criteria, should be representative of the population for which the sponsor seeks approval. 85 Endpoint selection is critical to a successful phase 3 trial.

The endpoint must demonstrate clinical benefit in the intended patient population. 86 Ideally, the endpoint is an established clinical outcome measure, although validated surrogate endpoints may be used in some cases. 87 If the endpoint is not well defined, the sponsor might have to combine use of several effectiveness outcomes. 88 Several alternatives to traditional endpoints are available.

Under the accelerated approval scheme, eligible sponsors may obtain approval based on either (1) a surrogate endpoint that is “reasonably likely to predict clinical benefit” or (2) a clinical endpoint that is measurable earlier than irreversible morbidity or mortality and that is “reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit. ” 89.

The evidence supporting an endpoint’s 77 Id. 78 21 C. F. R. § 312. 21(b). 79 Matthews, supra note 72, at 84–85, 90–92. 80 Id. at 84. 81 21 C. F. R. § 312. 21(c). 82 See id. ; Matthews, supra note 72, at 80. 83 Matthews, supra note 72, at 85–86. 84 Id. ; FDA, Inside Clinical Trials: Testing Medical Products in People, http://www. fda. gov/Drugs/ ResourcesForYou/Consumers/ucm143531. htm (last accessed November 29, 2012). 85.

Matthews, supra note 72, at 85. 86 Id. 87 Id. at 85–86. 88 Id. at 85. 89 FDCA § 506(c)(1)(A). In July 2012, Congress amended the criteria for accelerated approval as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). Pub. L. No. 112-144 §§ 901-902, 126 Stat. 993, 1082-1088 (2012). The amended statutory provisions are discussed here. The FDA has not yet updated its accelerated approval regulations to reflect these statutory changes. See 21 C. F. R. Part 601, Subpart E.


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