Guidance for Industry
Pediatric Oncology Studies In Response to a Written Request
[PDF version of this document]
Draft Guidance
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 90 days of publication of the Federal Register notice announcing the availability of the draft guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
For questions on the content of the draft document contact Steven
Hirschfeld, 301-827-1532.
For additional copies contact the:
Drug Information Branch,
Division of Communications Management, HFD-210
Center for Drug Evaluation and Research (CDER)
5600 Fishers Lane, Rockville, MD 20857 (Tel) 301-827-4573
http://www.fda.gov/cder/guidance/index.htm
or
Office of Communication, Training and
Manufacturers Assistance, HFM-40
Center for Biologics Evaluation and Research
Food and Drug Administration
1401 Rockville Pike, Rockville, MD 20852-1448
Internet: http://www.fda.gov/cber/guidelines.htm
Fax: 1-888-CBERFAX or 301-827-3844
Mail: the Voice Information System at 800-835-4709 or 301-827-1800
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
June 2000
Clinical Medical
TABLE OF CONTENTS
- INTRODUCTION
- STATUTORY PROVISIONS FOR PEDIATRIC EXCLUSIVITY
- WHAT IS SPECIAL ABOUT STUDYING ONCOLOGY DRUGS IN CHILDREN?
- WHAT WILL A TYPICAL WRITTEN REQUEST ASK FOR?
- Phase 1 and 2 Studies
- Studies Using Unvalidated Surrogate Endpoints
- Study Rationale and Context
- WHAT WILL TYPICAL PROTOCOLS LOOK LIKE?
- HOW DOES AN APPLICANT QUALIFY FOR EXCLUSIVITY?
- What Requirements Must the Studies Meet?
- What If Pediatric Studies Were Discontinued After Phase 1?
Guidance for Industry1
Pediatric Oncology Studies In Response to a Written Request
Draft - Not for Implementation
This guidance represents the Agency's current thinking on the content and format of Written Requests for pediatric oncology studies. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both. |
- INTRODUCTION
This guidance is intended to assist applicants intending to respond
to a Written Request from the Food and Drug Administration (FDA) for
pediatric studies for a drug that may show potential health benefits
in children with cancer. The guidance will be of particular interest
to applicants planning pediatric studies for which no specific
oncology indication can be identified in advance (i.e., overall
pediatric development studies).2 The guidance discusses (1)
the kinds of information the FDA will be asking for in its Written
Requests for oncology studies, (2) the typical contents of a pediatric
oncology study protocol, and (3) general requirements for studies
submitted in response to a Written Request to qualify for pediatric
exclusivity.
This guidance is part of the Agency's initiative to generate new
knowledge to assist practitioners in the care of children with cancer
and help provide pediatric patients early access to emerging new
drugs.
Table of Contents
- STATUTORY PROVISIONS FOR PEDIATRIC EXCLUSIVITY
Section 111 of the Food and Drug Administration Modernization Act of
1997 (the Modernization Act), signed into law by President Clinton on
November 21, 1997, created section 505A of the Federal Food, Drug,
and Cosmetic Act (the Act) (21 U.S.C. 355a). Section 505A permits
certain marketing applications to obtain an additional 6 months of
marketing exclusivity if the applicant, in response to a Written
Request, files reports of investigations studying the use of the
drug in the pediatric population. The statute permits the Agency to
issue a Written Request for pediatric studies under section 505A(a)
or 505A(c) of the Act. A Written Request is a document in which the
Agency requests an applicant to submit certain studies. The studies
will be designed to provide information on the health benefits of a
drug in the pediatric population.
Table of Contents
- WHAT IS SPECIAL ABOUT STUDYING ONCOLOGY DRUGS IN CHILDREN?
The study of oncology drugs in children merits special consideration.
Compared to adult malignancies, pediatric cancers afflict small
numbers of patients. Because the majority of pediatric patients
receive cancer therapy as participants in clinical research protocols,
participation in oncology trials has become the standard of care in
pediatric oncology. Children with cancer are usually treated at
specialized centers by pediatric oncologists who are members of
national pediatric cooperative study groups. One of the important
goals of these groups is to develop improved novel therapies, and
encouraging early access to new drugs is one mechanism to achieve
this goal.
Unfortunately, known and potential differences in the biology of
pediatric and adult tumors make it difficult to extrapolate clinical
drug effects from adults to children. As a result, it is usually
impossible to rely on the pharmacokinetic and safety data gathered
from studies of a cancer drug in adults to guide the use of that
drug in children. Therefore, it is imperative to evaluate the
effectiveness and safety of new cancer drugs in pediatric populations.
To encourage applicants to study new cancer drugs in the pediatric
population, the Agency is providing the following information and
recommendations for applicants who receive a Written Request from
the Agency for pediatric studies of oncology products.
- In most cases, in the absence of available therapies to treat
refractory stages of most pediatric cancers, the FDA expects
to use flexible regulatory approaches in approving drugs for
pediatric use. Approval could be based on an effect on the
size of a tumor or on another surrogate marker likely to predict
clinical benefit as provided for in Subpart H of 21 CFR 314
(for drugs) and 21 CFR 601 Subpart E (for biological products).
An acceptable level of safety might be demonstrated in studies
of smaller numbers of patients, which could be justified under
Subpart E of 21 CFR 312, which provides for flexibility in
applying statutory standards of safety and effectiveness.
- A Written Request for pediatric studies of a drug for pediatric
oncology will usually be issued in the context of an overall
development program for the drug. If appropriate, a specific
disease may be targeted; otherwise, several studies in a variety
of tumor types, such as brain tumors, solid tumors, or hematologic
tumors should be planned.
- Because pediatric oncology drugs are usually approved on the
basis of phase 2 studies3 and, therefore, phase 3 studies
for pediatric oncology drugs are generally initiated postapproval,
phase 3 studies usually will not be requested in a Written
Request as a prerequisite to a grant of pediatric exclusivity.
- When planning pediatric protocols, applicants should discuss
protocol designs with a pediatric cooperative study group.
These groups have experience, expertise, and resources that
can help applicants optimize their study designs and accrue
patients.
Table of Contents
- WHAT WILL A TYPICAL WRITTEN REQUEST ASK FOR?
To assist applicants planning to undertake pediatric oncology studies,
the Agency is providing the following information on a typical
Written Request for pediatric oncology studies. Applicants should
also consult the FDA's guidance for industry on Qualifying for
Pediatric Exclusivity Under Section 505A of the Federal Food, Drug,
and Cosmetic Act (September 1999), which discusses in detail the
contents of Written Requests, responses to those requests, and how
to qualify for pediatric exclusivity. A sample Written Request for
pediatric oncology studies is available on the Internet at
http://www.fda.gov/cder/pediatric/.
- Phase 1 and 2 Studies
Because of the high toxicity of many oncology drugs and the difficulty
in extrapolating efficacy and safety from adult experience to children,
it is particularly difficult to predict which drugs might prove too
toxic for use in pediatric patients and which warrant further study.
Typically, a Written Request for pediatric oncology studies will ask
for phase 1 and phase 2 studies, on the assumption that most products
will prove safe enough to progress through phase 2, and on the
assumption that most products for these indications would qualify for
approval based on surrogate markers (Subpart H, or Subpart E for
biological products) or under special conditions (Subpart E).
If the applicant submits phase 1 study reports that appear to demonstrate
an unacceptable toxicity such that phase 2 studies are no longer
indicated and FDA agrees with those findings, FDA will generally find
that the terms of the Written Request have been met and that no
further pediatric studies are required. In such cases, information on
the toxicity of the product in children would be incorporated into
any future labeling for the product (if the product were already
approved in adults or were it to be approved later for use in adults)
(see discussion under section VI). If phase 1 studies demonstrate an
acceptable level of safety, phase 2 studies will generally be required
to meet the terms of routine Written Requests for pediatric oncology
studies.
- Studies Using Unvalidated Surrogate Endpoints
A Written Request may ask for studies using presently unvalidated
surrogate endpoints. As with other such development programs, if the
data support the approval of a product for a specific indication, or
indications, based on unvalidated surrogate endpoints, the product
(and indications) would be approved under 21 CFR 314 Subpart H or
21 CFR 601 Subpart E. In such a case, the sponsor would have to
commit to further studies as required in those regulations. However,
completion of those further studies would not be required before
pediatric exclusivity could be granted.
- Study Rationale and Context
The FDA recommends that the rationale and context in an overall
pediatric oncology drug development program be included for each
study.
Table of Contents
- WHAT WILL TYPICAL PROTOCOLS LOOK LIKE?
The following lists illustrate what the Agency believes should be
included in a typical pediatric oncology study protocol. The lists
are organized by study phase.
- Phase 1 studies
A phase 1 pediatric oncology study protocol should contain the
following characteristics:
- A rationale for the starting dose based on either an adult dose
or preclinical data
- A targeted study population consisting of patients who have diseases
that would be likely candidates for further development. A phase 1
study in pediatric oncology usually would enroll between 18 and 25
patients.
- A plan for gathering pharmacokinetic data
- Definitions of the maximally tolerated dose, dose limiting toxicity,
and biologically effective dose, if appropriate
- Appropriate stopping rules for toxicity
- A statistical plan based on the escalation scheme, cohort size, and
stopping rules.
- Phase 2 studies
A phase 2 pediatric oncology study protocol should contain the
following characteristics:
- Phase 3 studies
Because approval for oncology drugs will generally occur at the end
of phase 2 under subparts E or H, information from phase 3 studies
would generally not be included in a Written Request and would not
be required for a grant of pediatric exclusivity. However, because
phase 3 pediatric oncology studies are generally the postapproval
standard of care for children with various malignancies, we have
provided the general characteristics of phase 3 pediatric oncology
studies, which most likely are undertaken in conjunction with a
cooperative group as part of such standard of care.
- A targeted study population that is likely to have some clinical
benefit based on prior experience with the product.
- A study design that will demonstrate the contribution of a product,
even in combination with other products, to clinical benefit. One
example could be an add-on design where a product is added to a
standard regimen compared to the standard regimen alone.
- Appropriate stopping rules based on safety, lack of activity, or
definitive activity.
- A prospective statistical plan based on the population size,
response criteria, and stopping rules.
Table of Contents
- HOW DOES AN APPLICANT QUALIFY FOR EXCLUSIVITY?
Once an applicant has responded to a Written Request by carrying out
pediatric studies and submitting them to the Agency, the FDA must
decide if the product qualifies for 6 months of marketing exclusivity.
- What Requirements Must the Studies Meet?
Under section 505A, the Agency must determine that the pediatric
oncology studies:
- Were conducted in accordance with and are responsive to the
Written Request
- Were conducted in accordance with and are responsive to
either a written agreement if one existed, 4 or commonly
accepted scientific principles if no written agreement exists
- Were reported in accordance with FDA's requirements for filing
- What If Pediatric Studies Were Discontinued After Phase 1?
To obtain pediatric exclusivity under section 505A, an applicant must
file the pediatric study reports to a marketing application (either
approved or submitted for approval) that has either patent or other
marketing exclusivity (or other potential marketing exclusivity) that
can be extended by obtaining pediatric exclusivity.
In the case where a drug is found to be too toxic in phase 1 testing
to continue to phase 2 (or does not show sufficient evidence of
effectiveness at the end of phase 2 to warrant approval or phase 3
testing) and at the time pediatric testing is stopped no application
has been filed to which the pediatric studies can be submitted,
exclusivity may still be granted at the time the application for an
adult indication is filed. In such a case, prior to finishing the
study of the adult indication and submitting an application in
accordance with FDA's requirements for filing, the applicant may
want to request advice from FDA to determine if further work on the
pediatric studies is needed to meet the terms of the Written Request.
If an applicant requests such advice, it should submit its pediatric
study reports to the appropriate IND (investigational new drug
application) and submit a specific request for advice. FDA will
determine if the studies satisfy the terms of the Written Request
and were conducted in accordance with commonly accepted scientific
principles (or a written agreement) and will so inform the applicant.
However, this advice does not substitute for a pediatric exclusivity
determination.
Final determination of pediatric exclusivity can only occur when the
studies are submitted to an existing application or as a part of a
new marketing application in accordance with FDA's requirements for
filing. In all cases, pediatric exclusivity, if granted, will attach
to exclusivity and patent protection listed in the Orange Book for
any drug containing the same active moiety as the drug studied and
for which the party submitting the studies holds the approved new
drug application.5 For studies conducted on an unapproved
drug, pediatric exclusivity will attach to any exclusivity or patent
protection that is listed in the Approved Drug Products with
Therapeutic Equivalence Evaluations (Orange Book) upon approval of
that unapproved drug.6
Table of Contents
1 This guidance has been prepared by the Division of Oncology Drug
Products of the Center for Drug Evaluation and Research (CDER) at
the Food and Drug Administration.
2 For a more general discussion of qualifying for pediatric exclusivity,
see the FDA's guidance for industry Qualifying for Pediatric
Exclusivity Under Section 505A of the Federal Food, Drug, and
Cosmetic Act.
3 See 21 CFR 312.82(b).
4 Written agreements are discussed in detail in the Agency guidance
Qualifying for Pediatric Exclusivity Under Section 505A of the
Federal Food, Drug, and Cosmetic Act (September 1999).
5 See sections 505A(a) and (c) of the Act.
6 For a detailed discussion of applications to which pediatric
exclusivity will attach, see Qualifying for Pediatric Exclusivity
Under Section 505A of the Federal Food, Drug, and Cosmetic Act
(September 1999).
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