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Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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-

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 requirements 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 2012.1Chapter 4 describes another 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 arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound) applicable to the prevention, treatment, or cure of a disease or condition of human beings” (42 USC 262(i)). A few biologics have been and still are regulated under the FDC Act. These include a small

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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).

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 recombinant 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 designed and conducted to meet agency criteria for approval of new drugs, new indications, new formulations, or use by new populations. These communications may lead to modifications of research protocols as studies are planned or initiated.

FDA may initiate discussions of pediatric studies during the IND application 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 diagnosed 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 manufacturing, processing, packing, and analytical testing; proposed labeling; and reports of clinical and other investigations. These investigations are conducted to show whether the product is safe and effective under the pro-

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 approve 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 labeling 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 after 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 research 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 information show that (1) the product will be safe for use under the conditions

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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 facility 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 demonstration 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 labeling 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 prescribers. 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

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 populations (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 populations 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 labeling). 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 approved 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 periodic 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-

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

porting System.) In addition, drug and biologic sponsors operate under obligations to report significant new information (including from the published 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 voluntary 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 studies 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, following 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 requirements or voluntary agreements for sponsors to undertake specified further investigations of a drug or biologic following its approval. The FDA Amendments Act of 2007 (FDAAA; PL 110-85) strengthened FDA’s authority 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 serious 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 studies 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

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 “pediatric 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 component 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 sponsor 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 delegation to FDA):

1. determines that information about the use of a new drug by the pediatric population may produce health benefits in that population;

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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).

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 investment 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 exclusivity. 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

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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 approvals in 2010, this pathway is at an early stage of implementation within FDA (see Chapter 8).

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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TABLE 3-1 Underlying Patent or Exclusivity Incentives That Can Be Extended with Pediatric Exclusivity


Underlying Incentive Type of Innovator Applications Eligible for Underlying Incentive Original Period of Protection Based on Underlying Incentive Market Protection if Pediatric Exclusivity Is Earned

Patent protection (gives the sponsor the ability to exclude others from making, using, or selling a patented invention; pertinent patents may cover the drug substance, formulation, or an approved method of using the drug) NDAa Varied (patent life may be up to 20 years) Patent life + 6 months
New chemical entity exclusivity (covers the first NDA approval for a particular active chemical moiety in the United States) NDA FDA may not accept or begin to review a follow-on application that relies on the innovator NDA until 5 years after the innovator’s approval was issued (the timeline may be 4 years if certain patent scenarios exist) 5 years + 6 months
New conditions of use exclusivity (protects an innovator’s new conditions of use for a previously approved active moiety when clinical research was required to be performed to achieve the new approval, e.g., FDA approves a new indication for use, potentially including a pediatric indication, or certain other changes) NDA FDA may accept and review a follow-on application during the 3-year period but may not formally approve that application for the protected conditions of use until 3 years after the innovator’s new conditions were approved 3 years + 6 months
Orphan drug exclusivity (covers drugs and biologics for rare diseases) NDA, BLA FDA may accept and review a competitor application (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 7 years + 6 months
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

Underlying Incentive Type of Innovator Applications Eligible for Underlying Incentive Original Period of Protection Based on Underlying Incentive Market Protection if Pediatric Exclusivity Is Earned

Biologic product exclusivity (covers innovator biologics; see Chapter 8 for further discussion) BLA FDA may accept and review a biosimilar product application during part of the 12-year period but may not approve the biosimilar product application until 12 years after the first licensure of the reference (innovator) product 12 years + 6 months
Timeline for submission of biosimilar product application (provides period of time during which a biosimilar product applicant may not seek FDA approval that is based on reference to an existing, licensed biologic) BLA An applicant for a product biosimilar to an approved biologic may not submit its application until 4 years after the date on which the reference product was first licensed 4 years + 6 months

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 approvals 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 exclusivity determinations at least 9 months prior to the expiration of the underlying 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 reports on pediatric studies more than a year before the scheduled expiration of underlying patent and market exclusivity.

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

Eligible Products

Under BPCA, FDA may issue written requests for pediatric studies for already-marketed products and may grant exclusivity to sponsors who meet the terms of those requests. The statute also authorizes FDA to issue requests for products that are still under initial development (i.e., still in their first IND application period). A sponsor can conduct the requested studies and submit them either as part of an initial NDA or as part of a supplemental NDA (or, as a result of provisions in BPCIA, as part of a new or supplemental BLA).

As noted in Table 3-1, exclusivity is approved for an active moiety. The definition of active moiety focuses on chemical structures. As defined in regulations, the active moiety is “the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt … or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance” (21 CFR 314.108(a)). Different active ingredients may thus have a common active moiety.

As an example, amlodipine maleate and amlodipine besylate are considered different active ingredients, but they have the common active moiety amlodipine. It is responsible for the physiological action of the drugs, which are used to treat hypertension. After the sponsor conducted studies requested under BPCA, FDA granted pediatric exclusivity for the moiety in 2001 and a labeling change for a product containing amlodipine besylate (Norvasc) in 2004 (Throckmorton, 2004).5

Written Requests

FDA’s written request for a pediatric study is a critical component of BPCA that determines when and how a product will become eligible for pediatric exclusivity. FDA may issue a written request at any time (i.e., it need not be linked to an NDA, BLA, or supplement). A request may specify separate and different studies for different pediatric age groups. The specified studies may cover a product’s pharmacokinetics (i.e., how it is absorbed, distributed, metabolized, and eliminated from the body), phar-

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5 Under limited circumstances, an active moiety that has previously been approved and has already been the subject of a pediatric exclusivity award may qualify for a second period of pediatric exclusivity. FDA must issue a second written request that differs from the first request, and the sponsor must fulfill the requirements on a timely basis. The scope of the second pediatric exclusivity reward is more limited, however, and attaches only to a period of 3-year market exclusivity that may be granted for the new conditions of use studied. A second period of pediatric exclusivity would not extend any patent or other protections (e.g., orphan drug exclusivity) that may exist.

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

macodynamics (i.e., how a product affects the body), safety, or efficacy. The basic features of a written request, as currently outlined by the Center for Drug Evaluation and Research (CDER), are listed in Box 3-1.

Drug sponsors may submit to FDA a Proposed Pediatric Study Request that outlines their ideas for pediatric studies. FDA may modify or reject the proposal. Approximately 80 percent of issued requests start as sponsor proposals. Alternatively, FDA may initiate a written request of its own accord.

Under BPCA, FDA may request a pediatric study to evaluate the same indications intended or approved for adults, but it may also request that a sponsor conduct a pediatric study for a different indication, including one not approved for adults. The latter authority is a key feature that distinguishes BPCA from PREA. As described below, FDA may (except in rare situations) mandate pediatric assessments under PREA only when making a determination about an indication(s) that it is proposed by the sponsor in an NDA or BLA submission.

FDA may amend a written request at its own initiative or in response to problems encountered by a sponsor (e.g., problem with enrolling numbers of children sufficient to match the sample size originally expected). Many

BOX 3-1
Basic Elements of a Written Request

• Types and objectives of studies to be performed

• Indications to be studied

• Age groups and numbers of patients to be studied; ethnic/minority representation

• Study endpoints, including pharmacokinetic, pharmacodynamic, safety, and efficacy endpoints (as appropriate)

• Known drug safety concerns and monitoring

• Reporting of extraordinary (unexpected) findings

• Drug information, including dosage form, route of administration, regimen, need for development of age-appropriate formulation, and documentation requirements

• Statistical information, including the power of a study(ies) and statistical analyses to be performed

• Provisions for labeling that may result from the study(ies)

• Format of reports to be submitted

• Time frame for submitting reports

• Time table to respond to the written request

• Provisions for public information about studies

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SOURCE: CDER (2011c).

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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requests that were issued before the passage of FDAAA were amended to incorporate provisions of that law, for example, provisions about the addition of information to the labeling.

Scope of Exclusivity

FDA has interpreted pediatric exclusivity to attach to any patent or exclusivity protections covering any of a sponsor’s products containing the active moiety that was studied in children. For example, if a liquid formulation must be developed to perform a requested pediatric clinical study, the sponsor’s tablets and other dosage forms containing the same moiety, for any indication, also will be awarded pediatric exclusivity (assuming that they are subject to patents or other applicable market protections that can be extended as summarized in Table 3-1). Because exclusivity attaches to the moiety and product and not the particular indication for which studies are requested, it affects all indications for which the product is already approved. Thus, when exclusivity was granted for studies of risedronate (Actonel) for children with osteogenesis imperfecta, the additional 6 months of marketing protection restricted generic competition with the product when used for its three approved indications for different forms of osteoporosis in adults.

Policy makers believed that this broad interpretation—combined with no requirement that the studies yield positive results—was necessary for pediatric exclusivity to serve as an effective market-based incentive. Given the very recent extension of BCPA to biologics and the more complex nature of biologic product molecules, it remains to be seen how FDA will interpret the scope of pediatric exclusivity in the context of biologics.

Requests for Studies of Off-Patent Products

As mentioned in Chapter 1, BPCA created a role for the National Institutes of Health (NIH) in supporting pediatric drug studies for both on-patent and off-patent drugs.6 For drugs that are off-patent, BPCA directed NIH to create a list of pediatric therapeutic priorities and to propose written requests for studies to FDA. (The National Institute for Child Health and Human Development [NICHD] has the lead on these activities.) If FDA then issues a written request and the sponsor declines it, the agency may refer the request to NIH for study. If NIH funds the study, the entity that

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6 According to the Government Accountability Office, one sponsor accepted a written request for study of an off-patent drug between 2002 and the end of 2005 (GAO, 2007), and no sponsor has accepted a written request for study of an off-patent drug since BPCA was reauthorized in 2007 (GAO, 2011).

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

conducts the study would submit the results and suggested labeling to FDA for assessment. The results of at least five NIH-funded studies have been submitted to FDA (personal communication, Anne Zajicek, Chief, Obstetric and Pediatric Pharmacology Branch, NICHD, December 1, 2011). Any labeling change resulting from a submission would have to be worked out with relevant drug manufacturers.

For drugs that remain on-patent, if the sponsor declines a written request, FDA may refer the request to the Foundation for the National Institutes of Health (FNIH) for funding. (FNIH is an independent, nonprofit, congressionally created organization that raises private funds and works with for-profit, nonprofit, and government agencies to undertake research in support of NIH’s mission.) If the Foundation does not fund the studies, BPCA directs FDA to decide whether it should require the study under PREA on the basis of criteria specified by Congress. FDA has not required any PREA studies under this provision (GAO, 2011). According to the Foundation’s website, which lists BPCA activities as a “past program,” the Foundation raised $4 million in 2004 to support the study of on-patent drugs, and those studies are under way (FNIH, 2011).

PEDIATRIC RESEARCH EQUITY ACT

FDA promulgated its Pediatric Rule—the predecessor of PREA—in 1998. The objective was to increase the labeling information relevant to pediatric use by requiring manufacturers to provide data and information on such use under certain circumstances. When it published the Rule, FDA noted the pediatric exclusivity provisions of FDAMA but also noted perceived limitations on their scope (63 FR 66631 at 66633). Specifically, they provided no incentive for sponsors to conduct studies on certain types of products, including antibiotics and other biologics regulated under the PHS Act. In addition, given limited resources, FDA perceived that it was likely that manufacturers would choose to undertake preferentially studies of drugs for which 6 months of exclusivity would be the most valuable. This would tend to exclude drugs with relatively small markets. Sponsors would also tend to decline requests that involved expensive studies with neonates, infants, and young children. Further, the agency noted that the statute did not ensure that results of studies would be incorporated into and improve labeling. The Pediatric Rule became effective on April 1, 1999.

As described in Chapter 1, in October 2002, the U.S. District Court for the District of Columbia determined that the Pediatric Rule exceeded FDA’s authority under the FDC Act and invalidated its application. In December 2003, Congress passed PREA, which included many of the provisions of the Pediatric Rule.

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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The Requirement

PREA applies to marketing applications involving a new active ingredient, 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 indications claimed in all relevant pediatric subpopulations and

2. to support dosing and administration of the product for each pediatric 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 development of an age-appropriate formulation. It should address whether and, if so, under what grounds, the applicant plans to request a waiver or deferral under PREA.… Early consultation and discussions are particularly important for products intended for life-threatening or severely debilitating 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

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7 A 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).

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 marketing. 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 certify 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 submission 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).

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 impracticable (because, for example, the number of patients overall or in a specific age group is so small or the patients are geographically dispersed).     FDA waived the pediatric study requirement for gabapentin (Gralise), which was approved for treatment of postherpetic neuralgia. It concluded that the necessary studies were 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 biologic would be ineffective or unsafe in all or specific pediatric age groups.     FDA waived the pediatric study requirement for tesamorelin for injection (Egrifta), which 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 a meaningful therapeutic benefit over existing therapies for pediatric patients or specific pediatric age groups and is not likely to be used in a substantial number of pediatric patients. PREA does not define “substantial number of pediatric patients,” but FDA has historically used 50,000 as a reference number (63 FR 66631 at 66636).     FDA waived pediatric study requirements for the biologic azficel-T (Laviv), a suspension of autologous cultured fibroblasts expanded from a patient’s skin biopsy specimen, finding that the product “has very limited applicability to pediatric patients for the improvement of nasolabial fold wrinkles because this condition occurs only in the adult population” (Witten and Malarkey, 2011, unpaged).
         
The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for a specific age group have failed.     No examples through June 2010 (GAO, 2011).
         

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 formulation 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 application 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 completeness, timeliness, and other requirements established in a written request issued 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 pediatric drug studies. In both jurisdictions, requirements and guidance are designed to encourage and facilitate pediatric medicinal product development. For example, EMA policies provide for a 6-month Supplementary Protection Certificate extension that is equivalent to pediatric exclusivity under BPCA. Policies differ in the timing and the scope of the required analyses.

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 deferral 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 requirements 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 important 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

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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.

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 regulatory 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 premature 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 better 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 development 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 activities 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).

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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In addition, two advisory committees currently participate in the analysis of pediatric drug issues. One is the publicly deliberating Pediatric Advisory 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 pediatric 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 areas 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

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 (1997)     FDA is required to publish notice only when pediatric exclusivity has been 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 (2002)     FDA must make available to the public a summary of the medical and clinical pharmacology reviews of pediatric studies conducted for an NDA supplement.
           
PREA (2003)     If FDA grants a full or partial waiver because of evidence that a drug or biologic 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 (2007)     FDA must publish notice that pediatric exclusivity has been awarded no later 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
           
         

• Pediatric studies conducted;

• Specific drugs and uses, including on-label and off-label indications, studied under BPCA or PREA;

• Types of studies conducted under such sections (including trial design, number of pediatric patients studied, and number of centers and countries involved);

• Number of pediatric formulations developed, number of pediatric formulations not developed, and the reasons that formulations were not developed;

• Labeling changes made as a result of studies conducted under such sections;

• Reports submitted on or after the date of enactment of the BPCA of 2007.

           
          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.
           
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Statute     Publication Requirements

PREA (2007)     Annually, following the approval of a PREA deferral, the drug or biologic 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 ensure that information from pediatric studies becomes public and, except in unusual situations, is reflected in drug labeling. Changes have also incorporated 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 question 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

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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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 issuance 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 resources that are required to update and make final the guidance documents that it has issued for BPCA and PREA. This process of updating and otherwise 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 following 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 described 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. requirement 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 participants in research and discusses ethical issues in pediatric studies conducted under BPCA and PREA. It concludes with further suggestions for modifications to FDA policies and procedures.

Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 81
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 82
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 83
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 84
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 85
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
Page 86
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Page 87
Suggested Citation:"3 Policy Framework for BPCA and PREA." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Page 88
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The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) were designed to encourage more pediatric studies of drugs used for children. The FDA asked the IOM to review aspects of pediatric studies and changes in product labeling that resulted from BPCA and PREA and their predecessor policies, as well as assess the incentives for pediatric studies of biologics and the extent to which biologics have been studied in children. The IOM committee concludes that these policies have helped provide clinicians who care for children with better information about the efficacy, safety, and appropriate prescribing of drugs. The IOM suggests that more can be done to increase knowledge about drugs used by children and thereby improve the clinical care, health, and well-being of the nation's children.

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