3

Policy Framework for BPCA and PREA

The incentives of the Best Pharmaceuticals for Children Act (BPCA) and the requirements of the Pediatric Research Equity Act (PREA) and their predecessor policies apply within a broader framework of statutes and regulations that are intended to protect public health by ensuring the safety and effectiveness of medications. The foundations of BPCA and PREA are the Federal Food, Drug, and Cosmetic Act (FDC Act), elements of which apply to biologics as well as conventional drugs, and the Public Health Service Act (PHS Act), which includes additional requirements specific to biologics. When Congress passed the Biologics Price Competition and Innovation Act (BPCIA) (as part of the Patient Protection and Affordable Care Act of 2010, PL 111-148), it extended the provisions of BPCA to cover biological drugs.

Although both BPCA and PREA refer to the pediatric population, neither statute nor the implementing regulations define the age range or subgroups to which they apply. As noted in Chapter 1, the Food and Drug Administration (FDA) has described the pediatric population as including individuals ages “birth to 16 years, including age groups often called neonates, infants, children, and adolescents” (CDER/CBER, 2005, p. 8). Elsewhere, the agency has proposed age ranges for these groups. In application, when it requests or requires pediatric studies of specific products, FDA considers what age ranges are appropriate given the medical condition to be studied, the research questions and procedures, and, possibly, the characteristics of the drug in question.

This chapter begins with a brief overview of the regulatory context for BPCA and PREA, including definitions of key terms, procedures govern-



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3 Policy Framework for BPCA and PREA T he incentives of the Best Pharmaceuticals for Children Act (BPCA) and the requirements of the Pediatric Research Equity Act (PREA) and their predecessor policies apply within a broader framework of statutes and regulations that are intended to protect public health by ensur- ing the safety and effectiveness of medications. The foundations of BPCA and PREA are the Federal Food, Drug, and Cosmetic Act (FDC Act), ele- ments of which apply to biologics as well as conventional drugs, and the Public Health Service Act (PHS Act), which includes additional requirements specific to biologics. When Congress passed the Biologics Price Competition and Innovation Act (BPCIA) (as part of the Patient Protection and Afford- able Care Act of 2010, PL 111-148), it extended the provisions of BPCA to cover biological drugs. Although both BPCA and PREA refer to the pediatric population, neither statute nor the implementing regulations define the age range or subgroups to which they apply. As noted in Chapter 1, the Food and Drug Administration (FDA) has described the pediatric population as includ- ing individuals ages “birth to 16 years, including age groups often called neonates, infants, children, and adolescents” (CDER/CBER, 2005, p. 8). Elsewhere, the agency has proposed age ranges for these groups. In applica- tion, when it requests or requires pediatric studies of specific products, FDA considers what age ranges are appropriate given the medical condition to be studied, the research questions and procedures, and, possibly, the char- acteristics of the drug in question. This chapter begins with a brief overview of the regulatory context for BPCA and PREA, including definitions of key terms, procedures govern- 63

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64 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN ing the study and approval of new drugs and biologics and their labeling, and mechanisms for monitoring drug safety after products are approved for marketing. It then describes major features of BPCA and PREA. The discussion of PREA includes a short comparison of differences in require- ments for pediatric drug studies between the United States and Europe. The chapter concludes with some suggestions for policy makers as they consider the reauthorization of BPCA and PREA in 2012.1 Chapter 4 describes an- other part of the regulatory framework for pediatric studies—regulations concerning the protection of human participants in research. Chapter 8 provides more information about BPCIA, the implementation of which was still in its early stages at the time this report was being completed. BASIC REGULATORY FRAMEWORK FOR DRUG DEVELOPMENT, APPROVAL, AND SURVEILLANCE Definition of Drugs and Biologics As defined in the FDC Act, drugs are articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C). (21 USC 321(g)(1)) This definition encompasses both small-molecule chemical compounds (what are conventionally called “drugs”) and biologics.2 For regulatory purposes under the PHS Act, as amended by BPCIA in 2010, a biologic is “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically synthesized polypeptide), or analogous product, or ars- phenamine 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” (42 USC 262(i)). A few biologics have been and still are regulated under the FDC Act. These include a small 1 After this report was released in February 2012, Congress reauthorized BPCA and PREA in June 2012. The FDA Safety and Innovation Act changed several provisions described in this chapter. A comparison of the previous and current legislation can be found in AAP, 2012. 2 In 1972, the Secretary of what is now the Department of Health and Human Services gave FDA the explicit authority to apply the requirements of the FDC Act to biologics (37 FR 4004, cited in Carver et al., 2010).

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65 POLICY FRAMEWORK FOR BPCA AND PREA group of older products such as insulin and human growth hormone that were originally derived from human or other animal sources but that may be produced today using recombinant DNA technology. Some of these products have been the subject of written requests and pediatric exclusivity under BPCA. Examples include insulin glargine (ribosomal DNA origin) (Lantus), somatropin recombinant (Omnitrope), and hyaluronidase recom- binant human (Hylenex). Investigational New Drug Application Under the FDC Act and the PHS Act, an early regulatory step on the pathway to product approval is the filing of an Investigational New Drug (IND) application by the sponsor (in essence, the owner) of a promising drug or biologic product. The application describes the indications (clinical uses) to be investigated, the existing data on the drug or biologic (e.g., from animal studies), and the proposed strategy for clinical testing with humans. The IND application process is an important mechanism by which sponsors and FDA may communicate about how studies should be de- signed and conducted to meet agency criteria for approval of new drugs, new indications, new formulations, or use by new populations. These com- munications may lead to modifications of research protocols as studies are planned or initiated. FDA may initiate discussions of pediatric studies during the IND ap- plication process if such studies are not already being conducted under the application. These discussions may, for example, make clear that PREA requirements will be waived because the condition being studied is not diag- nosed in children. Alternatively, FDA may signal to sponsors that pediatric studies will be required, and it may encourage them to start planning for those studies and to be ready to begin them as early as possible taking safety into account (see discussion of the pediatric plan below). New Drug Application or Biologics License Application Before a product may be marketed, the sponsor typically must submit a New Drug Application (NDA) or Biologics License Application (BLA). These applications encompass volumes of documentation for FDA review and scrutiny. FDA reviews and approves a range of details related to the drug or biologic. These details cover the active and inactive ingredients of the components of the drug or biologic; packaging materials; container- closure systems; methods, facilities, and controls for product manufactur- ing, processing, packing, and analytical testing; proposed labeling; and reports of clinical and other investigations. These investigations are con- ducted to show whether the product is safe and effective under the pro-

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66 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN posed conditions of use (for products covered by NDAs) or is safe, pure, and potent under the proposed conditions of use (for products covered by BLAs). Chapter 5 discusses FDA’s protocols for staff assessments of safety, efficacy, and other studies submitted by sponsors to support product approvals. Once an original NDA or BLA has been approved, FDA may ap- prove supplemental NDAs or BLAs. Among other changes, supplemental applications may cover such disparate modifications as the addition of a new indication to a product’s labeling; the expansion of an indication to a new population of patients; the availability of a new form of the product; a change in the dosing regimen; the addition of new safety information to labeling; and a modification involving component specifications, suppliers, or manufacturing processes. Under the FDC Act, sponsors of original and supplemental applications must provide substantial evidence of a product’s safety and effectiveness for its intended use. As described in the statute, substantial evidence means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts 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 label- ing or proposed labeling thereof. (21 USC 355(d)) In the FDA Modernization and Accountability Act of 1997 (FDAMA; PL 105-115), Congress clarified that data from one adequate and well- controlled study, together with confirmatory evidence obtained before or af- ter that study, can constitute “substantial evidence” of effectiveness for any new drug. FDA regulations specify that studies and study reports should • provide a clear statement of purpose; • permit a valid comparison of the experimental group with a control group; • employ suitable methods to assign study and control groups and otherwise to minimize bias; • use clear, reliable methods to define and assess responses of re- search participants; and • employ appropriate methods to analyze study results (21 CFR 314.126; see also CDER/CBER, 1998b). In the case of a drug reviewed under the NDA process, FDA’s approval determination is based on judgment that the submitted data and informa- tion show that (1) the product will be safe for use under the conditions

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67 POLICY FRAMEWORK FOR BPCA AND PREA described in the proposed labeling; (2) substantial evidence exists that the drug will have the effect that it purports to have under the conditions of use described in the proposed labeling; and (3) the methods, facilities, and controls used for the manufacture, processing, and packing of the drug are adequate to maintain its identity, strength, quality, and purity (21 USC 355; 21 CFR Part 314). Although similar in substantive underpinnings, FDA approval of a biological drug in the BLA process is based on the sponsor’s demonstration that the product is safe, pure, and potent and that the facil- ity in which the product is manufactured, processed, packed, or held meets standards designed to ensure that the product continues to be safe, pure, and potent (42 USC 262(a)). In addition, FDA has incorporated concepts of the FDC Act into the BLA approval process by holding that a demon- stration of “potency” includes demonstration of effectiveness (see 21 CFR 600.3(s) and CDER/CBER, 1998b). Labeling Requirements The sponsor technically owns and holds copyright to a product’s la- beling information, and it normally proposes and participates in labeling changes subject to close FDA oversight. The labeling of NDA and BLA products is governed by a common set of regulations (21 CFR Part 201) that are designed to make detailed and clear information available to pre- scribers. This prescribing information covers these broad topics: • Drug name, dosage forms, and strengths • Indications and usage • Dosage and administration • Contraindications • Warnings and precautions • Adverse reactions • Drug interactions • Use by specific populations (including pregnant women, pediatric populations, and geriatric patients) • Drug abuse and dependence (if a concern) • Overdosage • Clinical pharmacology • Nonclinical toxicology • Clinical studies • Storage and handling • Patient counseling In 2006, FDA initiated the use of a structured format and content for drug labeling that includes, among many other required elements, a front

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68 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN page or leading section with Highlights of Prescribing Information that cover key information about indications, usage, dosing; safety warnings and cautions of various sorts; and use by children and other special popu- lations (FDA, 2006b). The requirements for use of this format are being phased in through 2013. They are not fully retroactive to NDAs or BLAs approved before June 2001, so some labels may remain in the old format (established in 1979), unless sponsors voluntarily revise them. Even with the new format, information relevant to use of a product by pediatric popu- lations may be located in several sections of the structured label (e.g., in sections on dosage, clinical pharmacology, and adverse reactions as well as in the highlights section that now appears at the start of prescription label- ing). This can complicate efforts to find, assess, and summarize pediatric information in product labeling. As discussed in Chapter 1, drug and biologic labeling historically did not include consistent, substantive information about the use of drug and biologic products in pediatric patients because that information was, for the most part, not available. Although FDA required as early as 1979 that drug labels include a pediatric subsection (as part of the section on precautions), the rules did not require the development of pediatric data for inclusion in labeling. Congress passed BPCA and PREA and their predecessor policies to respond to that information deficit. Postmarket Studies and Surveillance FDA’s role in ensuring drug safety does not end when a product is ap- proved for marketing. (See Chapter 5 for a discussion of recent changes to requirements for reporting of adverse events during clinical trials of a product.) To monitor and learn more about drug safety in actual use, FDA uses two general strategies. The first strategy for postmarket safety monitoring involves the peri- odic reporting of new safety information to FDA. Through its MedWatch system, FDA receives spontaneous reports (i.e., reports not associated with a planned clinical study) about adverse drug events. Sponsors of drugs and biologics have specific requirements for surveillance and reporting of adverse events associated with the use of a drug, particularly events that are unexpected (e.g., not described in the product’s labeling). In addition, health care professionals, patients, parents, and others may voluntarily report problems. Adverse event reports to MedWatch are compiled in a computerized database, the Adverse Event Reporting System, which FDA monitors for indications of safety problems that warrant further analysis and possible response. (FDA and the Centers for Disease Control and Prevention monitor vaccine safety through the Vaccine Adverse Event Re-

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69 POLICY FRAMEWORK FOR BPCA AND PREA porting System.) In addition, drug and biologic sponsors operate under obligations to report significant new information (including from the pub- lished literature) that might affect the safety, effectiveness, or labeling of an approved product. This information could be included in a sponsor’s annual report to FDA or provided in an expedited report. Depending on the nature of the problem identified, the sponsor’s or FDA’s analysis of vol- untary and mandatory safety reports and other information (e.g., literature reviews) may lead to safety advisories to clinicians and consumers, to the addition of new safety information to a product’s labeling, to further stud- ies or data analyses, or to other product changes. For example, in 2009, based on analyses of adverse event reports over a 10-year period, FDA first reported on a possible association between certain cancers in children and young adults and the use of tumor necrosis factor blockers; in 2009, fol- lowing further investigation and analysis, the labeling was revised to add new safety warnings (FDA, 2009b). In rare cases, a sponsor withdraws a product from the market. A second strategy for postmarket safety monitoring involves require- ments or voluntary agreements for sponsors to undertake specified fur- ther investigations of a drug or biologic following its approval. The FDA Amendments Act of 2007 (FDAAA; PL 110-85) strengthened FDA’s author- ity to require sponsors to conduct postmarket studies, including studies to “assess a known serious risk related to the use of the drug; assess signals of serious risk related to the use of the drug; [or] identify an unexpected seri- ous risk when available data indicate the potential for a serious risk” (21 USC 355(o)(3)(B)). In 2009, FDA adopted internal policies and procedures for developing such postmarket study requirements (CDER/CBER, 2009), and in 2011 FDA issued guidance for industry on the topic (CDER/CBER, 2011). These required safety investigations may involve pediatric studies but are separate from any requirements under PREA. For example, in 2009, when FDA approved guanfacine (Intuniv) for treatment of attention deficit hyperactivity disorder in children ages 6 up to 17 years, it required postmarket studies of cardiac toxicity in rats and reproductive toxicity in juvenile rats (Laughren, 2009b). These requirements were separate from the requirements that the agency imposed under PREA for additional stud- ies in the 6- to 17-year-old age group (including one for a long-term study of efficacy and safety and a second one to more fully evaluate safety and efficacy in adolescents). Both sets of studies could result in the addition of information to product labeling. FDAMA required sponsors to report annually on their progress in meeting certain types of postmarket study requirements, which now include the required safety studies just described as well as studies required under

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70 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN PREA. It likewise directed FDA to provide annual summaries based on these reports.3 The importance of postmarket strategies for expanding pediatric safety information is discussed further in Chapter 5. That chapter also describes the process for 1-year safety reviews that Congress initially established in 2002 for products with labeling changes resulting from studies requested under BPCA and then extended in 2007 for products with changes resulting from studies required under PREA. BEST PHARMACEUTICALS FOR CHILDREN ACT History of the Exclusivity Provision The substance of BPCA predates that statute that bears the name. Congress first established the concept and rules for what is called “pedi- atric exclusivity” in 1997 in FDAMA. This legislation provided incentives and FDA authority to encourage the study of drug products in pediatric patients. FDAMA included a sunset, or expiration, provision that largely limited its application to NDAs submitted on or before January 1, 2002. In 2002, Congress enacted BPCA (PL 107-109) to amend and reauthorize the pediatric exclusivity program for NDAs filed on or before October 1, 2007. BPCA was again renewed and amended in September 2007 as a com- ponent of FDAAA. The current iteration of BPCA is scheduled to expire in October 2012. As explained earlier, in 2010, Congress extended the provisions of BPCA to cover biological drugs. This legislation is discussed further in Chapter 8. The Incentive BPCA establishes a voluntary incentive program through which a spon- sor may gain the benefit of market protection (exclusivity) as a reward for having performed pediatric studies as specified in a written request from FDA. The core incentive is a 6-month period of pediatric exclusivity that is awarded if the Secretary of Health and Human Services (through delega- tion to FDA): 1. determines that information about the use of a new drug by the pe- diatric population may produce health benefits in that population; 3 An FDA website allows a status search by product and type of requirement (e.g., PREA) (http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm).

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71 POLICY FRAMEWORK FOR BPCA AND PREA 2. makes a written request for pediatric studies of the drug (including a timetable for the completion of the studies); and 3. concludes that the studies submitted have been completed within the specified timetable and meet the other terms of the written request. The law does not require that studies demonstrate that a drug is safe and effective for the specified pediatric use. Indeed, in some cases, pediatric studies have yielded important negative findings and labeling changes that warn that a drug or biologic is not safe and should not be administered in specific pediatric settings. Pediatric exclusivity is not a freestanding protection. Instead, it attaches to one or more existing periods of patent or statutory market protections. The primary objectives of these legal protections are to encourage invest- ment in costly and unpredictable research within a legal framework that also enables broader use of existing research findings. The latter benefit is provided for by an abbreviated approval pathway that allows sponsors of generic and other follow-on products to rely on a demonstration of the similarity of their product to products that have already been shown to be safe and effective for specific uses. In essence, exclusivity is an incentive because it delays the time at which the sponsor of a generic or other follow- on product may secure FDA approval and begin marketing a competing product for the protected use.4 Table 3-1 identifies the patent and statutory market protections that can be extended by 6 months with an award of pediatric exclusivity. Only the first relates to a product’s patent(s). Many drugs approved under NDAs have multiple patents that can be effectively extended by pediatric exclusiv- ity. In contrast, as a result of more limited statutory provisions applicable to biologics approved under BLAs, pediatric exclusivity does not extend the market protective effect of patents covering such products. Independent of patents are several types of market exclusivity that may be extended for 4 In general, delayed approval affects a generic or other follow-on product application that expressly refers to an approved innovator product as part of the basis for the second product’s approval. For example, instead of having to reassess the safety and effectiveness of a product for an established use, a competitor producing a generic product may (1) demonstrate that its product has the same active ingredient, dosage form, strength, route of administration, and labeling as the innovator product and (2) provide data to demonstrate that the product is bioequivalent (i.e., has the same rate and extent of absorption) to the innovator drug. Upon this demonstration, FDA may deem the generic product to have a safety and effectiveness profile comparable to that of the innovator product for the same labeled use. Although the BPCIA established a legal pathway for the use of abbreviated “biosimilar” biologics approv- als in 2010, this pathway is at an early stage of implementation within FDA (see Chapter 8).

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72 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE 3-1 Underlying Patent or Exclusivity Incentives That Can Be Extended with Pediatric Exclusivity Type of Innovator Market Applications Protection Eligible for if Pediatric Underlying Original Period of Protection Exclusivity Underlying Incentive Incentive Based on Underlying Incentive Is Earned NDAa Patent protection (gives Varied (patent life may be up to Patent the sponsor the ability 20 years) life + 6 to exclude others from months making, using, or selling a patented invention; pertinent patents may cover the drug substance, formulation, or an approved method of using the drug) New chemical entity NDA FDA may not accept or begin to 5 years + exclusivity (covers the review a follow-on application 6 months first NDA approval for a that relies on the innovator particular active chemical NDA until 5 years after the moiety in the United States) innovator’s approval was issued (the timeline may be 4 years if certain patent scenarios exist) New conditions of use NDA FDA may accept and review a 3 years + exclusivity (protects an follow-on application during 6 months innovator’s new conditions the 3-year period but may of use for a previously not formally approve that approved active moiety application for the protected when clinical research was conditions of use until 3 years required to be performed to after the innovator’s new achieve the new approval, conditions were approved e.g., FDA approves a new indication for use, potentially including a pediatric indication, or certain other changes) Orphan drug exclusivity NDA, BLA FDA may accept and review 7 years + (covers drugs and biologics a competitor application 6 months for rare diseases) (including that of another innovator) during the 7-year period but (with certain exceptions) may not approve another application for the same product and the orphan indication until 7 years after the innovator product’s approval

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73 POLICY FRAMEWORK FOR BPCA AND PREA TABLE 3-1 Continued Type of Innovator Market Applications Protection Eligible for if Pediatric Underlying Original Period of Protection Exclusivity Underlying Incentive Incentive Based on Underlying Incentive Is Earned Biologic product exclusivity BLA FDA may accept and review a 12 years + (covers innovator biologics; biosimilar product application 6 months see Chapter 8 for further during part of the 12-year discussion) period but may not approve the biosimilar product application until 12 years after the first licensure of the reference (innovator) product Timeline for submission BLA An applicant for a product 4 years + of biosimilar product biosimilar to an approved 6 months application (provides period biologic may not submit its of time during which a application until 4 years after biosimilar product applicant the date on which the reference may not seek FDA approval product was first licensed that is based on reference to an existing, licensed biologic) a By statute, patents for BLA products cannot be extended by pediatric exclusivity. 6 months by an award of pediatric exclusivity (e.g., a 7-year orphan drug exclusivity becomes a 7.5-year exclusivity). Over time, Congress has tightened the time frame for sponsors to complete requested pediatric clinical studies and submit reports. Originally, a sponsor might have submitted its report at a time close to the time of expiration of the underlying patent or market exclusivity to be extended by pediatric exclusivity. That created a de facto delay of competitor ap- provals while FDA determined whether exclusivity had been earned. (The law authorized a 90-day period for FDA review, to be counted as part of the 6-month extension if pediatric exclusivity was ultimately awarded.) In 2007, Congress revised BPCA to require that FDA make pediatric exclusiv- ity determinations at least 9 months prior to the expiration of the underly- ing patent or market exclusivity to be extended. The agency is permitted up to 180 days to make its determination whether pediatric exclusivity has been earned. As a result, sponsors now must complete and submit their re- ports on pediatric studies more than a year before the scheduled expiration of underlying patent and market exclusivity.

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78 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN The Requirement PREA applies to marketing applications involving a new active ingredi- ent, indication, dosage form,7 dosing regimen, or route of administration. It requires sponsors to submit, as part of an NDA or a BLA, an assessment containing data that are adequate 1. to assess the safety and effectiveness of the product for the indica- tions claimed in all relevant pediatric subpopulations and 2. to support dosing and administration of the product for each pe- diatric age group for which the product is safe and effective. Studies must use an appropriate formulation for each age group for which an assessment is required. That may require the sponsor to develop and test a new formulation. Products with an orphan drug designation for a rare disease or condition are exempt from PREA requirements, whether or not the product has been approved for the designated indication. As described below, FDA may waive or defer pediatric studies. The Pediatric Plan PREA refers to but does not define the term pediatric plan. In draft guidance for industry on compliance with PREA, FDA describes a pediatric plan as a statement of intent submitted by the applicant outlining the pediatric studies (e.g., pharmacokinetics/pharmacodynamics, safety, efficacy) that the applicant plans to conduct. The plan should also address the develop- ment of an age-appropriate formulation. It should address whether and, if so, under what grounds, the applicant plans to request a waiver or defer- ral under PREA. . . . Early consultation and discussions are particularly important for products intended for life-threatening or severely debilitat- ing illnesses. For these products, FDA encourages applicants to discuss the pediatric plan at pre-investigational new drug (pre-IND) meetings and end-of-phase 1 meetings. . . . For products that are not intended for treatment of life-threatening or severely debilitating illnesses, applicants are encouraged to submit and discuss the pediatric plan no later than the end-of-phase 2 meeting. (CDER/CBER, 2005, p. 6) FDA recommends that drug or biologic sponsors discuss their plans for pediatric assessment, potential studies, and possible PREA waiver or deferral requests early in the drug development process. If sponsors seek a deferral or waiver of pediatric studies at the time that they submit particular 7A dosage form (e.g., tablet, capsule, solution, or topical cream) is not identical to a drug formulation (i.e., the specific ingredients and composition of an individual product).

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79 POLICY FRAMEWORK FOR BPCA AND PREA NDAs or BLAs that request the approval of products for adults only, the sponsors must then (as part of the marketing application) describe planned or ongoing studies, which FDA will review. The timing of the development and confirmation of the pediatric plan has become more of an issue since the European Medicines Agency (EMA, formerly the European Agency for the Evaluation of Medicinal Products [EMEA]) issued its policies for pediatric studies. As described below, EMA requires determination of a specific plan for pediatric studies shortly after Phase I studies with adults are completed. Deferral of Pediatric Assessments FDA is authorized, on its own initiative or upon the request of an applicant, to defer the submission of required pediatric assessments for completion at some time after the drug or biologic is approved for market- ing. A deferral may be authorized when • the drug or biologic is ready for approval for use by adults before pediatric studies are complete; • additional safety or effectiveness data should be collected before pediatric studies are initiated; or • another appropriate reason exists. A sponsor requesting the deferral of a pediatric assessment must cer- tify to FDA the grounds for deferral, describe planned or ongoing studies, provide evidence that the required studies are being conducted or will be conducted with due diligence, and submit a schedule for completing the studies. The sponsor must then report on its progress annually. If the studies have not progressed, the sponsor is required to document that the studies will be conducted in a timely and diligent way. Since the reauthorization of PREA in 2007, as an accountability measure, information from the annual update on deferred studies must be made available to the public, including through FDA’s website. (See the discussion in Chapter 7 of the status of deferred studies.) FDA has limited practical options for compelling the conduct or sub- mission of a study required under PREA. For example, although FDA may declare a product misbranded, it cannot withdraw marketing approval. The Inspector General of the Department of Health and Human Services has recommended that FDA seek additional authority and options (e.g., monetary fines) that might “send a signal to drug applicants that there are consequences when postmarketing study commitments are not fulfilled” (OIG/HHS, 2006, p. 21).

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80 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN Waiver of Pediatric Assessment Requirements FDA is authorized, on its own initiative or upon request of a drug or biologic sponsor, to fully or partially waive the pediatric assessment requirement for all or specific pediatric age groups. Table 3-2 cites the statutory bases for such waivers and provides recent examples. (In years past, approval letters were often not specific about the rationales for a waiver or deferral.) FDAAA specified that if FDA grants a waiver on the basis of evidence that a drug or biologic would be ineffective or unsafe in TABLE 3-2 Reasons for Waiver of Pediatric Assessment Requirements Authorized Under PREA with Examples from Recent NDA or BLA Approvals Reason for Waiver Example Necessary studies are impossible or highly FDA waived the pediatric study requirement impracticable (because, for example, the for gabapentin (Gralise), which was approved number of patients overall or in a specific for treatment of postherpetic neuralgia. It age group is so small or the patients are concluded that the necessary studies were geographically dispersed). impossible or highly impracticable because “[p]ostherpetic neuralgia is generally not a condition that occurs in pediatric patients” (Rappaport, 2011b, p. 2). Evidence strongly suggests that a drug or FDA waived the pediatric study requirement biologic would be ineffective or unsafe in for tesamorelin for injection (Egrifta), which all or specific pediatric age groups. was approved for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. It concluded that using the drug in “a patient population that has not yet completed growth may result in adverse events associated with supraphysiologic levels of growth hormone, including excessive linear growth” (Rosebraugh, 2010, p. 2). The drug or biologic does not represent FDA waived pediatric study requirements for a meaningful therapeutic benefit over the biologic azficel-T (Laviv), a suspension of existing therapies for pediatric patients autologous cultured fibroblasts expanded from or specific pediatric age groups and is not a patient’s skin biopsy specimen, finding that likely to be used in a substantial number the product “has very limited applicability of pediatric patients. PREA does not define to pediatric patients for the improvement of “substantial number of pediatric patients,” nasolabial fold wrinkles because this condition but FDA has historically used 50,000 as a occurs only in the adult population” (Witten reference number (63 FR 66631 at 66636). and Malarkey, 2011, unpaged). The applicant can demonstrate that No examples through June 2010 (GAO, reasonable attempts to produce a pediatric 2011). formulation necessary for a specific age group have failed.

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81 POLICY FRAMEWORK FOR BPCA AND PREA pediatric populations, then the labeling for the product must present that information. If a waiver is granted because it is not possible to develop a pediatric formulation, the waiver is limited to the pediatric age groups that require the formulation. The applicant must also document why a pediatric for- mulation cannot be developed and the applicant’s documentation must be made public, including by posting on FDA’s website. As Table 3-2 indicates, FDA had not granted any waivers on this basis as of June 2010. Relationship to the Pediatric Rule PREA established that its provisions retroactively applied to an ap- plication submitted to FDA on or after April 1, 1999 (the effective date of the Pediatric Rule). The statute gave effect to waivers and deferrals that had been issued under the Pediatric Rule, and it extended deferral periods to take into account the period between the court decision overturning the Pediatric Rule and the date of enactment of PREA. A 1-year period was established for the submission to FDA of required pediatric assessments for applications submitted between April 1, 1999, and the enactment of PREA. The committee did not find that FDA has reported on the application of this retroactive feature. Communications by FDA with sponsors about this feature are not public. Relationship to Pediatric Exclusivity FDA has consistently worked to allow drug sponsors to qualify for pediatric exclusivity on the basis of the performance of clinical studies that it requires under PREA. Congress affirmed its desire for this interpretation as early as the BPCA reauthorization in 2002. BPCA expressly states that, if any pediatric study is required by law and such study meets the complete- ness, timeliness, and other requirements established in a written request is- sued under BPCA, the study will be deemed to satisfy the requirements for pediatric exclusivity (and the exclusivity incentive may be earned). Relationship to European Requirements for Pediatric Studies As noted in Chapter 1 and above, the laws and policies administered by FDA differ from those of the EMA as they relate to requirements for pedi- atric drug studies. In both jurisdictions, requirements and guidance are de- signed to encourage and facilitate pediatric medicinal product development. For example, EMA policies provide for a 6-month Supplementary Protec- tion Certificate extension that is equivalent to pediatric exclusivity under BPCA. Policies differ in the timing and the scope of the required analyses.

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82 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN These differences have practical implications for sponsors and regulators and are the subject of ongoing communication and harmonization efforts. Another difference between U.S. and European policies involves the timing for development and submission of a pediatric study plan. EMA policies require that sponsors submit a pediatric investigation plan (PIP) at an early stage, that is, when Phase I studies with adults are completed. A PIP considers all age groups and conditions for which a product may have utility. It includes a structured description of studies needed, waiver or de- ferral issues, clinical and nonclinical requirements, and formulation issues. Without a PIP, a sponsor’s marketing authorization application (similar to an NDA or BLA in the United States) will not be accepted for filing. As described earlier, FDA encourages discussions of plans for pediatric studies relevant to PREA requirements by the end of Phase II of clinical development. Under current policy, however, the formal assessment of the pediatric study plan and any request for waivers or deferrals occurs at the time that a marketing application is filed. Approval of the plan and any waivers or deferrals occurs when FDA approves an NDA or BLA. The committee heard that the mismatch in timing of submission re- quirements in the United States and Europe was a problem for sponsors and a concern of FDA (BIO, 2011; Dunne and Murphy, 2011; Frattarelli, 2011; PhRMA, 2011b).8 EMA regulations may drive planning decisions too early (before sufficient safety information from studies with adults is available). U.S. regulations—despite FDA encouragement of earlier discussions—may allow sponsors to delay the focused consideration of the pediatric study plan and the initiation and completion of studies that would provide im- portant information to clinicians who treat children. Moreover, sponsors attentive to EMA requirements may devise plans that have to be revised as information from Phase II trials in adults is evaluated. Beyond the differences in timing of the pediatric plan, the U.S. and European systems differ in other ways. For example, EMA provides a clearer description of what is expected in a pediatric plan than is provided by U.S. statutes or regulations. Further, the U.S. feasibility criterion does not exist in legislation from the European Union. As a result, a study may be required in the European Union but waived in the United States under PREA. Drugs with orphan designations, which are exempt from mandatory assessment requirements under PREA in the United States, are covered by 8 In its statement to the IOM committee, BIO presented results of a survey of its members (BIO, 2011). Approximately 60 percent of respondents reported that they prepared the relevant pediatric documents at the end of Phase I. Although respondents cited a goal of simultaneous regulatory submissions to EMA and FDA, that goal had not been achieved for various reasons, including variable responses from FDA divisions.

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83 POLICY FRAMEWORK FOR BPCA AND PREA European requirements. (Orphan drugs may be the subject of voluntary, written requests from FDA under BPCA.) The European Union’s Pediatric Committee (PDCO) is the counterpart to FDA’s Pediatric Review Committee (PeRC; see below). PDCO exercises decision-making authority under requirements for PIPs. Unlike the FDA committee, however, PDCO makes binding determinations in the regula- tory process. FDA and EMA have developed a framework to encourage the regular exchange of information and perspectives on scientific, policy, ethical, and other issues related to pediatric drug development in the United States and Europe. One objective is to avoid exposing children to unnecessary or pre- mature trials; another is to harmonize global pediatric drug development plans to the extent feasible (EMA, 2009b). Individuals from FDA and EMA may attend each other’s pediatric committee meetings so that they can bet- ter understand each other’s policies and operations and thus communicate better. Information exchanges between PeRC and PDCO encompass • issues specific to particular products (e.g., details of trial design, such as choice of comparator and efficacy endpoint, and plans for long-term safety monitoring); • general issues related to pediatric drug development (e.g., early sharing of draft guidance documents); and • safety issues (e.g., reports of adverse drug reactions and postmarket surveillance statistics and analyses). Communication does not, however, mean that pediatric drug develop- ment programs will have identical pediatric study protocols. It also does not mean that FDA and EMA will reach the same regulatory decisions. FDA ADMINISTRATION OF BPCA AND PREA A variety of FDA entities are involved in the administration of BPCA and PREA. These include the review divisions within the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The review divisions, which are divided according to therapeutic areas, bear responsibility for the review of and decision making over whether to approve individual product applications. Following establishment of a requirement in BPCA in 2002, FDA established and maintains the Office of Pediatric Therapeutics within the Office of the Commissioner. This office coordinates and supports all activi- ties within FDA involving pediatric issues. Congress specified that the staff include one or more pediatric experts and also one or more experts on ethical issues in the conduct of pediatric clinical research (see Chapter 4).

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84 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN In addition, two advisory committees currently participate in the analy- sis of pediatric drug issues. One is the publicly deliberating Pediatric Advi- sory Committee, which was created in 2004 as required by Congress. It is one of FDA’s formal advisory committees and comprises external advisors. This committee makes recommendations to FDA on a number of matters, including (1) pediatric research conducted under NDAs, BLAs, and certain other provisions of law; (2) research priorities for pediatric therapeutics; (3) ethics, design, and analysis of pediatric clinical trials; (4) certain pedi- atric labeling changes and labeling disputes under BPCA; (5) adverse event reports for products approved under BPCA or PREA and certain other safety issues; (6) other pediatric issues or disputes involving FDA-regulated products; (7) research involving child research participants; and (8) other pediatric matters related to FDA’s regulatory responsibilities. The second committee is the internal previously mentioned PeRC, which was mandated by FDAAA and is led by CDER to support quality and consistency across FDA. The PeRC includes representatives of CDER, CBER, and the Office of the Commissioner. Congress specified several ar- eas of expertise for the committee, including pediatrics, biopharmacology, statistics, chemistry, legal issues, and pediatric ethics (see Chapter 4). The PeRC consults on and reviews a wide range of pediatric issues related to BPCA and PREA. As specific examples, the PeRC • reviews all written requests under BPCA before they are issued; • may review the findings of studies submitted in response to such requests and make recommendations about the granting of exclusivity; • consults with review divisions on pediatric plans and assessments under PREA and reviews requests for waivers or deferrals; and • consults on the tracking and public availability of information about pediatric studies and labeling changes. PUBLIC ACCESS TO INFORMATION Congress has increasingly required FDA to provide public access to information concerning the application of BPCA or PREA. Originally, documents such as written requests and, often, FDA review memoranda were not accessible to the public except through the lengthy and onerous Freedom of Information Act process. Congress and others have come to view public access to these documents to be useful to promote consistent decision making, information sharing, and accountability of both FDA and sponsors. In addition, Congress has acted to ensure that information from pediatric studies—whether positive or negative—is, in most cases, reflected in product labeling. Moreover, as part of FDAAA, Congress required that the sponsor (or principal investigator) of FDA-regulated drugs trials (except

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85 POLICY FRAMEWORK FOR BPCA AND PREA for Phase I trials) register the trials at ClinicalTrials.gov and report the basic results of completed trials. Table 3-3 describes the publication requirements of BPCA and PREA as they have evolved over time. Today, publication often means the posting TABLE 3-3 Selected Public Information Requirements of BPCA and PREA Through 2007 Reauthorizations Statute Publication Requirements FDAMA FDA is required to publish notice only when pediatric exclusivity has been (1997) awarded. It is not required to publish a written request, the fact that a request has been made, or the fact that a report on requested studies has been submitted. BPCA FDA must make available to the public a summary of the medical and clinical (2002) pharmacology reviews of pediatric studies conducted for an NDA supplement. PREA If FDA grants a full or partial waiver because of evidence that a drug or biologic (2003) would be ineffective or unsafe in pediatric populations, the information must be included in the labeling for the drug or biologic product. No requirement to publish summaries of PREA reviews exists. BPCA FDA must publish notice that pediatric exclusivity has been awarded no later (2007) than 30 days after the determination is made. It must also make public a copy of the written request. FDA must publish a notice identifying any drug for which a pediatric formulation was developed, studied, and found to be safe and effective in the pediatric population (or specified subpopulation) if the pediatric formulation of the drug is not introduced on the market within 1 year after exclusivity has been awarded and notice of exclusivity has been published. FDA may order certain product labeling to include information about the results of a study. FDA must track and make available to the public, in an easily accessible manner (including posting on the FDA website), information, including statistical information, concerning • ediatric studies conducted; P • pecific drugs and uses, including on-label and off-label indications, studied S under BPCA or PREA; • ypes of studies conducted under such sections (including trial design, number T of pediatric patients studied, and number of centers and countries involved); • umber of pediatric formulations developed, number of pediatric formulations N not developed, and the reasons that formulations were not developed; • abeling changes made as a result of studies conducted under such sections; L and • eports submitted on or after the date of enactment of the BPCA of 2007. R Not later than 210 days after the date of submission of a report, FDA must make available to the public the medical, statistical, and clinical pharmacology reviews of pediatric studies conducted. continued

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86 SAFE AND EFFECTIVE MEDICINES FOR CHILDREN TABLE 3-3 Continued Statute Publication Requirements PREA Annually, following the approval of a PREA deferral, the drug or biologic (2007) sponsor must submit status or progress information on the pediatric assessment. The information must promptly be made available to the public in an easily accessible manner, including through the FDA website. If FDA grants a PREA waiver because a pediatric formulation cannot be developed for particular pediatric groups requiring such a formulation, the applicant’s submission (detailing why a pediatric formulation cannot be developed) “shall promptly be made available” to the public in an easily accessible manner, including through the FDA website. If the Secretary of the Department of Health and Human Services grants a full or partial waiver because of evidence that a drug or biologic product would be ineffective or unsafe if it was used by pediatric populations, the information shall be included in the labeling for the drug or biologic product. FDA must track and make available to the public certain statistical information, including the number of times that the Pediatric Review Committee made a recommendation about priority review, the number of times that FDA followed or did not follow such a recommendation, and, if it was not followed, the reasons why the recommendation was not followed. Not later than 210 days after the date of submission of a pediatric assessment, FDA must make available to the public in an easily accessible manner the medical, statistical, and clinical pharmacology reviews of such pediatric assessments, including through the FDA website. of information online. Chapter 4 discusses public access to information as an ethical issue. CONCLUSIONS During the past 15 years, Congress has created a flexible framework of incentives and requirements to increase the study of drugs and biologics for use by children. It has also responded to emerging concerns about aspects of the framework by adding or amending provisions, in particular, to en- sure that information from pediatric studies becomes public and, except in unusual situations, is reflected in drug labeling. Changes have also incorpo- rated more pediatric expertise into the review of requests and requirements for pediatric studies and the findings of the studies submitted in response. As the 2012 reauthorization of BPCA and PREA is debated, one ques- tion is whether both policies should now be made permanent (i.e., not be subject to further time-limited extensions). Industry and others have criticized the requirement for reauthorization of BPCA (and PREA) after relatively short 5-year periods on the ground that it creates uncertainty for sponsors that are planning drug studies that will not be completed or

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87 POLICY FRAMEWORK FOR BPCA AND PREA perhaps even initiated before new legislation that could significantly change the incentives or requirements is passed (see, e.g., BIO, 2011; GAO, 2011; PhRMA, 2011b). The GAO has reported that for the 50 drugs approved between September 27, 2007, and June 30, 2010, the average time from is- suance of a written request to the FDA’s completed review of the submitted studies was 6 years (GAO, 2011). Although Congress might grandfather studies already under way to insulate them from some features of future reauthorizations, such an approach cannot be assumed. Another possible benefit of making this reauthorization permanent is that FDA might feel more confident about expending the considerable re- sources that are required to update and make final the guidance documents that it has issued for BPCA and PREA. This process of updating and other- wise reexamining old documents not only could result in better information for sponsors and other interested external parties but also could contribute to consistent interpretations of both laws across FDA divisions and centers. A major advantage of retaining the reauthorization strategy (whether for 5-year or longer periods) is that it provides a stimulus for Congress and others to consider explicitly the experience with BPCA and PREA fol- lowing the previous legislative action and to evaluate the need for further adjustments in the policies and their administration. Statutory change does not depend on a reauthorization process, but that process likely facilitates serious examination of the kinds of problems and possible responses de- scribed in this report. Congress might also evaluate the arguments for harmonizing U.S. and EMA regulations on the timing of the submission of the pediatric plan. Harmonization of the requirements would require action by both Congress and European authorities, but Congress could act independently to require earlier submission of pediatric plans in the United States (e.g., at the end of Phase II studies with adults). If Congress is not prepared to create such a requirement, it could direct FDA to study and report on the consequences of the differences in plan submissions requirements. For example, do FDA’s preferences for pediatric drug studies have less weight with sponsors now than they might if requirements were harmonized? Even if the U.S. require- ment were changed, FDA would continue to defer many pediatric studies, as it does now, because a product is ready for approval for adult use. A requirement for earlier submission should, however, encourage the timely planning, conduct, and submission of pediatric studies. The next chapter reviews policies for the protection of child partici- pants in research and discusses ethical issues in pediatric studies conducted under BPCA and PREA. It concludes with further suggestions for modifica- tions to FDA policies and procedures.

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