安渡分享 | FDA儿科研究公平法案合规性指南草案摘要

How to Comply with 

the Pediatric Research Equity Act

• This draft guidance, issued September 2005, provides recommendations on how to interpret the pediatric study requirements of the Pediatric Research Equity Act (Public Law 108-155) (PREA). PREA amends the Federal Food, Drug, and Cosmetic Act (the Act) by adding section 505B (21 U.S.C. 355B).  PREA requires the conduct of pediatric studies for certain drug and biological products

• Specifically, PREA requires new drug applications (NDAs) and biologics licensing applications (BLAs) (or supplements to applications) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment

• This guidance addresses the pediatric assessment, the pediatric plan (see section V.A), waivers and deferrals, compliance issues, and pediatric exclusivity provisions

• PREA is the most recent of more than a decade of legislative and regulatory attempts to address the lack of pediatric use information in drug product labeling.  In PREA, Congress codified many of the elements of the Pediatric Rule, a final rule issued by FDA on December 2, 1998 (63 FR 66632) and suspended by court order on October 17, 2002

• The Pediatric Rule was designed to work in conjunction with the pediatric exclusivity provisions of section 505A of the Act (21 U.S.C. 355a), an incentive signed into law to encourage sponsors or holders of approved applications to voluntarily perform the pediatric studies described in a Written Request issued by FDA, in order to qualify for an additional 6 months of marketing exclusivity

A.  PREA Statutory Requirements

• PREA requires all applications (or supplements to an application) submitted under section 505 of the Act (21 U.S.C. 355) or section 351 of the Public Health Service Act (PHSA) (42 U.S.C. 262) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration to contain a pediatric assessment unless the applicant has obtained a waiver or deferral (section 505B(a) of the Act)

• In general, PREA applies only to those drugs and biological products developed for diseases and/or conditions that occur in both the adult and pediatric populations.  Products intended for pediatric-specific indications will be subject to the requirements of PREA only if they are initially developed for a subset of the relevant pediatric population

B.  Scope of Requirements

1. Applications Affected by PREA

• Because section 4(b) of PREA makes the legislation retroactive, all approved applications for new active ingredients, new indications, new dosage forms, new dosing regimens, and new routes of administration submitted on or after April 1, 1999 (including those approved when the Pediatric Rule was suspended), are subject to PREA

• Under PREA, holders of such approved applications that did not previously include pediatric assessments, waivers, or deferrals must submit their pediatric assessments or requests for waiver or deferral (section 4(b)(2)(B) of PREA).  If a waiver request is denied and/or studies are deferred, FDA will require the applicable studies as post marketing studies

2. Orphan Drugs

• Submission of a pediatric assessment is not required for an application to market a product for an orphan-designated indication, and waivers are not needed at this time.  However, if only one indication for a product has orphan designation, a pediatric assessment may still be required for any applications to market that same product for the non-orphan indication(s)

3. Generic Drugs Under 505(j) of the Act (21 U.S.C. 355(j))

Because

• PREA applies only to applications (or supplements to applications) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration,

• PREA does not impose pediatric assessment requirements on ANDAs for generic drugs.

• PREA is retroactive, all approved and pending ANDAs submitted on or after April 1, 1999 (when the Pediatric Rule became effective) and prior to December 3, 2003 (when PREA was enacted) under suitability petitions for changes in dosage form, route of administration, or active ingredient in combination products are subject to PREA.

• ANDAs submitted under suitability petitions after April 1, 1999, and prior to December 3, 2003, which have not been approved or obtained waivers must submit post approval pediatric studies or a request for a waiver or deferral of the pediatric assessment requirement (section 505B(a)(2) of the Act)

A. What Is the Pediatric Assessment?

Under PREA, the pediatric assessment contains data gathered from pediatric studies using appropriate formulations for each age group for which the assessment is required, and other data that are adequate to:

• Assess the safety and effectiveness of the drug or the biological product for the claimed indications in all relevant pediatric subpopulations

• Support dosing and administration for each pediatric subpopulation for which the drug or the biological product has been assessed to be safe and effective

B.  When to Submit the Pediatric Assessment in Compliance with PREA

• Under PREA, a pediatric assessment must be submitted at the time an application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is submitted to the Agency, unless the requirement for the assessment has been deferred or waived.  If a deferral has been granted, the pediatric assessment will be due on or before the date specified by the Agency

• PREA is retroactive and requires pediatric assessments for all applications submitted between April 1, 1999, and the present.  To address potential gaps in pediatric information for applications approved between April 1, 1999, PREA provides for waivers or deferrals in cases where pediatric study requirements were never addressed and for extensions of certain deferrals issued previously under the Pediatric Rule

C. What Types of Data Are Submitted as Part of the Pediatric Assessment?

• The data submitted under PREA will depend on the nature of the application, what is known about the product in pediatric populations, and the underlying disease or condition being treated.  PREA does not require applicants to conduct separate safety and effectiveness studies in pediatric patients in every case

• If the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, the Secretary may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults, usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies

• If extrapolation from adult effectiveness data is inappropriate, adequate and well controlled efficacy studies in the pediatric population may nevertheless be required.  Additional information, such as dosing and safety data, could also be important to support pediatric labeling decisions

A.  When to Develop a Pediatric Plan

• A Pediatric Plan is a statement of intent that outlines the pediatric studies that the applicant plans to conduct. The plan should also address the development of an age-appropriate formulation

• Applicants are encouraged to submit their pediatric plans to the Agency as early as possible in the drug development process, Phase 1, and to discuss these plans with the Agency at critical points in the development process for a particular drug or biologic specially for treatment of life-threatening or severely debilitating illnesses

• 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.

• The review division will provide its best judgment about (1) the pediatric assessment that will be required for the product, (2) whether its submission can be deferred, and (3) if deferred, the date studies will be due

• When a decision to waive or defer pediatric studies is made at key meetings, the minutes from those meetings reflecting the decision generally will be provided to applicants for their records

B.  What Ages to Cover in a Pediatric Plan

• PREA requires, unless waived or deferred, the submission of a pediatric assessment for certain applications for the claimed indications in all relevant pediatric populations

• PREA requires the pediatric assessment to evaluate safety and effectiveness for the claimed indication(s) for each age group in which the drug or biological product is expected to provide a meaningful therapeutic benefit over existing therapies for pediatric patients or is likely to be used in a substantial number of pediatric patients.

• Under PREA, a drug or biological product is considered to represent a meaningful therapeutic benefit over existing therapies if FDA estimates that (1) "if approved, the drug or biological product would represent a significant improvement in the treatment, diagnosis, or prevention of a disease, compared with marketed products adequately labeled for that use in the relevant pediatric population," or (2) "the drug or biological product is in a class of products or for an indication for which there is a need for additional options"

• Improvement over marketed products might be demonstrated by showing (1) evidence of increased effectiveness in treatment, prevention, or diagnosis of disease; (2) elimination or substantial reduction of a treatment-limiting drug reaction; (3) enhancement of compliance; or (4) safety and effectiveness in a new subpopulation for which marketed products are not currently labeled

• The appropriate age ranges to be studied may vary, depending on the pharmacology of the drug or biological product, the manifestations of the disease in various age groups, and the ability to measure the response to therapy.  In general, the pediatric population includes patients age "birth to 16 years, including age groups often called neonates, infants, children, and adolescents"

• The complex medical state of neonates and infants makes it critical to evaluate drugs specifically for their use.  FDA generally will require studies in neonates and infants under PREA if the drug represents an important advancement and use in these age groups for the approved indication is anticipated.  partial waivers for these specific age groups might be appropriate under certain circumstances  with partial waivers when "necessary studies are impossible or highly impracticable," or when "there is evidence strongly suggesting that the drug or biologic product would be ineffective or unsafe in that age group"

C.  Must the Sponsor Develop a Pediatric Formulation?

• PREA requires pediatric assessments to be gathered "using appropriate formulations for each age group for which the assessment is required". Applicants must submit requests for approval of the pediatric formulation used in their pediatric studies, and failure to submit such a request may render the product misbranded

• FDA interprets the language "request for approval of a pediatric formulation" to mean that applicants must apply or supplemental application for any not previously approved formulation(s) used to conduct their pediatric studies.  Where appropriate, applicants may need to begin the development of a pediatric formulation before initiation of pediatric clinical trials

D.  When to Initiate Pediatric Studies

• Applicants may initiate pediatric studies of drugs and biologics for life-threatening diseases for which adequate treatment is not available earlier in development than might occur for less serious diseases.

• In some cases, pediatric studies of a drug or biological product for a life-threatening disease may begin as early as phase 1 or phase 2, when the initial safety data in adults become available

• In certain cases scientific and ethical considerations will dictate that pediatric studies should not begin until after approval of the drug or biological product for use by adults

• The Agency recommends that for products with a narrow therapeutic index, the nature of the disease in the pediatric population to be studied and the context in which the drug will be used should factor into the decision on when to initiate the studies in the affected pediatric patient population

B.  How to Apply for a Waiver

1. Criteria for Full Waiver

On FDA’s initiative or at the request of an applicant, FDA will grant a full waiver of the requirement to submit pediatric assessments if the applicant certifies and FDA finds one or more of the following:

a When necessary studies are impossible or highly impracticable because the number of patients is so small, or the patients are geographically dispersed

b When a drug or biological product for an indication that has extremely limited applicability to pediatric patients because the pathophysiology of these diseases occur for the most part in the adult population

c When here is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in all pediatric age groups

d When the drug or biological product (1) does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients, and (2) is not likely to be used in a substantial number of pediatric patients

2. Criteria for Partial Waiver

On its own initiative or at the request of an applicant, FDA will grant a partial waiver of the requirement to submit pediatric assessments for a drug or biological product with respect to a specific pediatric age group, if the applicant certifies and FDA finds evidence of one or more of the following:

a Necessary studies are impossible or highly impracticable

b There is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in that age group

c The drug or biological product (1) does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in that age group and (2) is not likely to be used by a substantial number of pediatric patients in that age group

d The applicant can demonstrate that reasonable attempts to produce a pediatric formulation for that age group have failed

3. Information in a Waiver Request

Discussions with FDA on developing pediatric plans and initiating pediatric studies should occur early in the drug development process.  If an applicant believes a full or partial waiver of the pediatric studies requirement is warranted, FDA strongly encourages the applicant to request the waiver at the earliest appropriate time. However, the information necessary to support any particular waiver will be determined on a case-by-case basis

To request a waiver, we recommend an applicant provide:

• Product name, applicant name, and indication

• Age group(s) included in waiver request

• Statutory reason(s) for requesting a waiver, including reference to the applicable statutory authority

• Evidence that the request meets the statutory reason(s) for waiver of pediatric assessment requirements

• Applicant Certification

4. Waiver Decision

• The Agency will grant a waiver request if FDA determines that any of the criteria for a waiver enumerated in the statute have been met

• Decisions to waive the requirement for submission of pediatric assessments that are made early in the pre-approval development period (end-of-phase 1 or end-of-phase 2 meetings) reflect the Agency’s best judgment at that time

• A waiver decision becomes final once issued in the approval letter for an NDA, BLA, or supplement

C.  What Is a Deferral?

A deferral acknowledges that a pediatric assessment is required but permits the applicant to submit the pediatric assessment after the submission of an NDA, BLA, or supplemental NDA or BLA. On its own initiative or at the request of an applicant, FDA may defer the submission of some or all of the pediatric studies until a specified date after approval of the drug or issuance of the license for a biological product for adult use

D.  How to Apply for a Deferral

1. Criteria for Deferral (Section 505B(a)(3) of the Act)

FDA may defer the timing of submission of some or all required pediatric studies if it finds one or more of the following:

• The drug or biological product is ready for approval for use in adults before pediatric studies are complete

• Pediatric studies should be delayed until additional safety or effectiveness data have been collected

OR

• There is another appropriate reason for deferral

In addition, to obtain a deferral the applicant must submit certification of the reason(s) for deferring the assessments, a description of the planned or ongoing studies, and evidence that the studies are being conducted or will be conducted with due diligence and at the earliest possible time

2. Information in a Deferral Request

FDA provides a sample Deferral Request checklist to assist applicants in providing sufficient information for FDA to determine whether to grant a deferral request

To request a deferral an applicant should provide:

• Product name, applicant name, and indication

• Age group(s) included in deferral request

• Where deferral is only requested for certain age groups, reason(s) for not including entire pediatric population in deferral request (e.g., studies have already been completed in other age groups and need not be deferred)

• Reason(s) for requesting a deferral

• Evidence justifying that the proposed product meets the criteria for deferral of the pediatric assessment requirement

• Description of planned or ongoing studies

• Evidence that planned or ongoing studies are proceeding

• Projected date for the submission of the pediatric assessment (deferral date)

• Applicant certification

3. Deferral Decision

The decision to defer and the deferral date will be determined on a case-by-case basis.  Considerations used in determining whether and how long to defer submission of the pediatric assessment may include:

• The need for the drug or biologic in pediatric patients

• Availability of sufficient safety data to initiate pediatric trials

• The nature and extent of pediatric data needed to support pediatric labeling

• The existence of substantiated difficulties in enrolling patients

• Evidence of technical problems in developing pediatric formulations

For a deferral granted during the pre-approval development period, it is possible that FDA may reevaluate the length of the deferral closer to the time of approval, taking into account any new information obtained while the product was in development and information reviewed in the NDA or BLA

• If a pediatric assessment or a request for approval of a pediatric formulation is not submitted by an applicant in accordance with the statutory requirements, the drug or biological product may be considered misbranded solely because of that failure and subject to relevant enforcement action

• The failure to submit a pediatric assessment or request for waiver or deferral will not be the basis for withdrawing approval of a drug, however, the Agency could bring injunction or seizure proceedings if a product is found to be misbranded under these provisions

It is the Agency’s policy to offer applicants the opportunity to qualify for pediatric exclusivity for studies required and conducted under PREA.  Under that policy, however, FDA will not issue a Written Request for or grant pediatric exclusivity for studies that have been submitted to the Agency before the Written Request is issued

An applicant seeking to qualify for pediatric exclusivity should obtain a Written Request for studies from FDA before submitting the pediatric studies to satisfy PREA

To qualify for pediatric exclusivity, the pediatric studies conducted to satisfy the requirements of PREA must satisfy all of the requirements for pediatric exclusivity

General information about complying with PREA can be obtained from the Division of Pediatric Drug Development (DPDD)

Additional pediatric information is available at http://www.fda.gov/cder/pediatric.

Specific information about the types of pediatric studies that must be conducted and requirements for submission of assessments for your drug product can be obtained from the appropriate review division