安渡分享 | FDA《儿科研究计划：提交初步儿科研究计划和修订初步研究计划的内容和流程》摘要

The purpose of this guidance, issued July 2020, is to provide recommendations to sponsors regarding the submission of an initial pediatric study plan (iPSP) and any amendments to the iPSP.  Specifically, this guidance provides the current thinking of the Food and Drug Administration (FDA) regarding implementation of the requirement for sponsors to submit an iPSP.

This guidance addresses the following:

• Applications for which an iPSP is required

• Timing of an iPSP submission

• Content of an iPSP

• Content and timing of a requested amendment to an agreed iPSP

   

• A template that is recommend being used for an iPSP submission

• The pediatric rule aims at achieving the adequate labeling of drugs for its use in pediatric patients.

• Sponsors should submit, at least 1 month in advance of the end of-phase 2 meeting, certain background information, including a proposed timeline for protocol finalization, enrollment, completion, and data analysis, or, in the alternative, information to support a planned request for waiver or deferral.

• The intent of the iPSP is for a sponsor to identify needed pediatric studies early in development and begin planning for these studies resulting in a more efficient pediatric drug development program.

• A sponsor who is planning to submit a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an iPSP unless the drug is for an indication for which orphan designation has been granted.

• In addition, a sponsor who is planning to submit, on or after August 18, 2020, an original application for a new active ingredient that is subject to the molecularly targeted cancer drug provision of PREA (i.e., the drug that is the subject of the application is intended for the treatment of an adult cancer and is directed at a molecular target that the FDA determines to be substantially relevant to the growth or progression of a pediatric cancer) is also required to submit an iPSP, regardless of whether the drug is for an indication for which orphan designation has been granted.

• By statute, a biosimilar product that has not been determined to be interchangeable with the reference product is considered to have a new active ingredient for purposes of PREA.

• The sponsor must submit an iPSP for any new application or supplement that is subject to PREA, regardless of whether the FDA has previously granted waivers or deferrals under PREA for the same drug. Additionally, for drugs that are being developed specifically for use in pediatric populations, the sponsor should submit an iPSP

• A sponsor must submit an iPSP, if required under PREA, before the date on which the sponsor submits the required assessments or investigation and no later than either 60 calendar days after the date of the end-of-phase 2 meeting or such other time as agreed upon between FDA and the sponsor.

• In the absence of an end-of-phase 2 meeting, the sponsor should submit the iPSP as early as practicable but before the initiation of any phase 3 studies, or any combined phase 2 and phase 3 studies, of the drug that is the subject of the iPSP.

• If a phase 3 study, or a combined phase 2 and phase 3 study, will not be conducted or will be conducted but not under IND, the sponsor should submit the iPSP no later than 210 calendar days before it submits a marketing application or supplement.

• The sponsor should submit the iPSP to the relevant drug’s IND for review by the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research as appropriate.

• In cases where the sponsor has no active IND for the drug but the sponsor expects to open the IND with an initial phase 3 study, the sponsor should submit the iPSP as a pre-IND submission.  In this situation, the FDA encourages the sponsor to schedule a pre-IND meeting before submission of the iPSP, and such submission should precede initiation of any phase 3 studies or combined phase 2 and phase 3 studies.

• After the sponsor submits an iPSP, the FDA has 90 days to review the iPSP and provide a written response to the iPSP, or meet with the sponsor to discuss the iPSP, as appropriate. This review process includes consultation with FDA’s internal Pediatric Review Committee (PeRC).

• The sponsor then has a second 90-day period during which it may review FDA comments and initiate any needed negotiations to discuss the iPSP.  By the end of this second 90-day review period, the sponsor must submit an agreed iPSP.

• The FDA then has 30 days after receipt of the agreed iPSP to review and issue correspondence confirming agreement or issue correspondence stating disagreement. If the FDA does not agree, the iPSP is considered a non-agreed iPSP.

• The total length of time for review of an iPSP should not exceed 210 days.  A sponsor should not submit a marketing application or supplement until the FDA confirms agreement on the iPSP.

• An iPSP should include “(i) an outline of the pediatric study or studies that the sponsor plans to conduct (including, to the extent practicable, study objectives and design, age groups, relevant endpoints, and statistical approach); (ii) any request for a deferral, partial waiver, or waiver, if applicable, along with any supporting information; and (iii) other information specified in the regulations” issued by the FDA.

• In certain situations, it may be premature to include a detailed outline of a planned pediatric study because additional data are needed. In such cases, the outline of the pediatric studies should include a brief explanation for the lack of more detailed information.

• The sponsor will receive feedback at the time of the review of the iPSP on the planned request for waivers and/or deferrals, however the FDA does not make a formal decision about granting a waiver and/or deferral of required pediatric assessments, or reports on the molecularly targeted pediatric cancer investigation, until the time of the approval of the marketing application.

• The FDA acknowledges that the development program for a drug, including the design of the pediatric studies, may change as the sponsor collects new data from nonclinical studies, clinical trials, and/or other clinical development programs.

• The iPSP should include a well-constructed pediatric plan based upon current knowledge of the drug and disease epidemiology; sponsors can submit amendments to an agreed iPSP at any time, including changes to the pediatric plan that need to be considered based on additional data.

A. Materially Incomplete iPSPs

• Failure to include required information may result in an iPSP that the FDA considers materially incomplete. Additionally, if a sponsor fails to provide justification for any planned waivers or deferrals, the FDA may consider the iPSP to be materially incomplete.

• If the iPSP is considered materially incomplete, the FDA intends to contact the sponsor, and the sponsor should submit a complete iPSP within 30 days to address the identified deficiencies.  A new 210-day review period will start when the sponsor submits a complete iPSP.

• However, if the sponsor includes sufficient information for the FDA to evaluate the plan, even if the FDA disagrees with the proposed plan, the FDA in general considers the iPSP to be sufficient for initial review.

B. Recommendations for the Contents of Each Section of the iPSP

This section provides specific recommendations for the content of each section of the iPSP.

• TITLE PAGE

Sponsors should include relevant administrative information on the title page such as drug name, IND number, indication or indications that apply.

1. Overview of the Disease/Condition in the Pediatric Population

This section should briefly summarize (1 to 3 pages) available information on the pathophysiology of the disease, methods of diagnosis, and currently available treatments and/or prevention strategies in the pediatric population, including neonates.

The sponsor should also include available information on the incidence and prevalence of the disease in both the overall population and the pediatric population, including in specific age subgroups when appropriate.

2. Overview of the Drug or Biological Product

• This section should briefly summarize (1 to 3 pages) the proposed mechanism of action of the drug, the intended pediatric population that will be studied, and the indications that the sponsor is seeking.

• Based on the indications included in an iPSP, the sponsor should consider any possible therapeutic uses of the drug in children beyond the disease or indication being sought in adults.

• The FDA encourages sponsors to discuss the potential therapeutic benefits and/or fulfillment of therapeutic needs in the pediatric population, including neonates, beyond any indication(s) for which pediatric assessments will be required under PREA.

• Any changes to this discussion of the use of the drug, including any clinical studies that the sponsor may propose other than those required under PREA, will not require an amendment to an agreed iPSP.

3. Overview of Planned Extrapolation to Specific Pediatric Populations

• The iPSP should address whether extrapolation of effectiveness to pediatric populations is planned for the proposed product (1 to 3 pages).

• Extrapolation of effectiveness from adult populations to pediatric populations may be appropriate if the course of the disease and the effects of the drug are sufficiently similar in adult and pediatric patients.

• Extrapolation of effectiveness assumes that an appropriate pediatric dose can be established either through achieving a similar exposure in children as in adults or by using an appropriate pharmacodynamic or clinical endpoint to achieve the targeted effect.

• Extrapolation of effectiveness from one pediatric age group to another pediatric age group also may be appropriate. The sponsor should consider all age ranges of pediatric patients, including neonates, when applicable.
  

• The sponsor should provide justification for the extrapolation, including any available supporting data for all age groups for which the sponsor intends to extrapolate effectiveness.  This justification should include supportive data from all available sources: sponsor data, published literature, expert panels, workshops and other.

• Extrapolation of effectiveness for other drugs in the same class, if previously accepted by the FDA, also may be considered supportive information. If more information becomes available to support extrapolation to a pediatric population, the sponsor can then submit a proposed amendment to the agreed iPSP to address plans for extrapolation in the marketing application or supplement.

• If appropriate, the sponsor should include discussion on similarity in exposure-response relationship for effectiveness between adults and pediatrics based on experience with drugs in the same class or other drugs approved for use in the same disease/disorder. When applicable the sponsor also should discuss use of modeling and simulation to optimize studies to support extrapolation.
  

4. Planned Request for Drug-Specific Waiver(s)

• Under PREA, sponsors may request a waiver of pediatric assessments, or reports on the molecularly targeted pediatric cancer investigation, at the time of the submission of the new drug application (NDA), biologics license application (BLA), or supplement.

• FDA does not formally grant or deny a request for a waiver in response to the iPSP.  The FDA formally grants a waiver(s) when it issues an approval letter for an NDA, BLA, or supplement.

• PREA authorizes the FDA to grant a full waiver of required pediatric assessments or reports on the molecularly targeted pediatric cancer investigation if it finds that:

    (1) Necessary studies are impossible or highly impracticable.

    (2) There is evidence strongly suggesting that the drug would be ineffective or unsafe in all pediatric age groups.

    (3) The drug does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients and is not likely to be used in a substantial number of pediatric patients.

• In addition, PREA authorizes the FDA to grant a partial waiver of required pediatric assessments or reports on the molecularly targeted pediatric cancer investigation if it finds that:

    (1) Necessary studies are impossible or highly impracticable

    (2) There is evidence strongly suggesting that the drug would be ineffective or unsafe in that age group

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

    (4) The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed

• The sponsor should provide justification with a summary of supporting data, for all age groups for which the waiver will be sought.  This justification should include supportive data from all available sources: sponsor data, published literature, expert panels, workshops, or other. Full or partial waivers previously granted for other drugs in the same class can be considered supportive information.

• For indications that have extremely limited applicability to the pediatric population because the pathophysiology of the relevant disease occurs for the most part only in adults, the FDA generally does not intend to require sponsors to provide additional evidence that studies are impossible or highly impracticable.

• The FDA anticipates that the partial waiver provision based on failure to produce a pediatric formulation may, for example, apply to situations where the sponsor can demonstrate that unusually difficult technological problems prevented the development of a pediatric formulation for a particular pediatric age group.

• If, early in the preapproval development period (e.g., end-of-phase 1 or end-of-phase 2 meeting), the FDA agrees that a plan for a waiver is reasonable, such agreement would reflect the FDA’s best judgment at that time.  However, the FDA does not formally grant a waiver until it issues an approval letter for an NDA, BLA, or supplement.

• If, before approval of an application, the sponsor becomes aware of new or additional information that affects the plan for a waiver of pediatric assessments or reports on the molecularly targeted pediatric cancer investigation, the sponsor should submit at the earliest possible time an amended iPSP with an updated plan.

• If the FDA becomes aware of new information, it intends to notify the sponsor at the earliest possible time and request that the sponsor amend the iPSP to reflect the new information (see section VI., Relationship of Agreed Initial PSP to the Requirement to Submit a Pediatric Study Plan with an Application).  Such a requested amendment could include a plan for deferral of pediatric studies if appropriate.

• Sponsors submitting a plan for a full waiver of pediatric studies should complete the Initial Pediatric Study Plan Template.

• For sponsors submitting a plan for a full waiver of pediatric studies, based on an indication that appears on the list of adult-related conditions that rarely or never occur in children, the iPSP should be limited to a one-page plan that specifies that the drug product is intended for the treatment of such an adult-related condition.  This one-page plan should also include a sentence that the sponsor plans to request a full waiver of pediatric studies.

• If pediatric studies will be waived because evidence exists that the drug would be ineffective or unsafe in any pediatric age group, this information must be included in the product labeling.  Generally, this information would be included in the Pediatric Use subsection of labeling and also may be included in the CONTRAINDICATIONS or WARNINGS AND PRECAUTIONS sections.

5. Planned Request for Deferral(s) of Pediatric Studies

• Under PREA, sponsors may request deferral of pediatric assessments or reports on the molecularly targeted pediatric cancer investigation at the time of the submission of the NDA, BLA, or supplement.

• It is important to include in the iPSP any plan to submit a request for a deferral for any study required under PREA that will not be submitted as part of a planned application (i.e., NDA, BLA, efficacy supplement).  Because the sponsor must submit with the NDA/BLA an agreed iPSP when there are plans for requests for deferral of pediatric assessments or reports on the molecularly targeted pediatric cancer investigation, the information in this section should be as complete as possible and updated as needed.

• If new information, such as data from ongoing or planned studies, indicates that a criterion for a waiver (or partial waiver) is met, the sponsor can change planned requests for deferral of pediatric assessments or reports on the molecularly targeted pediatric cancer investigation in the iPSP to planned requests for waiver (or partial waiver).  The sponsor should submit these changes as an amendment to an agreed or amended iPSP.

• At the time of approval of an application, the FDA may grant a deferral of required pediatric assessments or reports on the molecularly targeted pediatric cancer investigation if it finds that:

    (1) The drug is ready for approval for use in adults before pediatric studies are complete

    (2) Pediatric studies should be delayed until additional safety or effectiveness data have been collected

    (3) There is another appropriate reason for deferral

• The planned request for a deferral should include adequate justification and any currently available evidence supporting the justification for a deferral (1 to 2 pages).

• If the sponsor becomes aware of new or additional information that affects the decision to plan for any deferral of pediatric assessments or reports on the molecularly targeted pediatric cancer investigation, the sponsor should reconsider the agreed iPSP and should submit an amended iPSP at the earliest possible time.

• The FDA may also request that the sponsor amend the iPSP to reflect any new information.

6. Tabular Summary of Planned Nonclinical and Clinical Development

• This section should include a summary in tabular form of all planned sections: nonclinical

• development to be conducted in support of the proposed pediatric clinical trials clinical pediatric development categorized by age

• The table should include a column to identify whether the sponsor plans to request a deferral of the study

• The table should also include any age groups for which the sponsor plans to request waivers

7. Age-Appropriate Formulation Development

• If the current formulation is not suitable for all pediatric age groups, sponsors should provide specific plans for the development of an age-appropriate formulation for all pediatric age groups that will be studied

• In this section (1 to 3 pages), sponsors should include information regarding planned excipients, to the extent practicable, which will be contained in any pediatric formulation being developed with details of measures taken to ensure appropriate design of a drug formulation, including the design of delivery systems to be used in pediatric studies

8. Nonclinical Studies

• This section should provide a brief summary (1 to 3 pages) of the data from relevant nonclinical studies that support the use of the drug in all pediatric age groups the sponsor will study in the proposed clinical trials.

• The sponsor should include information that supports the maximum dose and duration of treatment to be used in pediatric studies.  If the sponsor has determined that the nonclinical data are sufficient to support the proposed clinical trials and additional nonclinical studies are not planned, this summary should include such a statement and justification for this conclusion.

• If a sponsor plans to conduct a juvenile animal study, we recommend sponsors contact the review division for feedback before initiating this study.

• If the existing nonclinical data are not sufficient to support the proposed clinical trials, sponsors should provide a brief description for each of the nonclinical studies they will conduct, including, at a minimum the following:

• The species to be studied

• The age of animals at the start of dosing

• The duration of dosing

• The route of administration

• The target organ systems with key developmental endpoints to be evaluated

9. Clinical Data to Support Design and/or Initiation of Studies in Pediatric Patients

• This section should provide a brief summary (1 to 5 pages) of any clinical data that support the design or initiation of pediatric studies
  

• This section also should include a summary of available data in adult or pediatric patients who have received treatment with the drug (or related drugs) for the proposed indication, for other conditions, or in earlier studies.

• This section is intended to provide an overview of information already available to support design or initiation of pediatric studies; therefore, a detailed review of available data is not needed in this section.

10. Planned Pediatric Clinical Studies

10.1 Pediatric Pharmacokinetic or Pharmacokinetic/Pharmacodynamic Studies

This section (1 to 10 pages) should provide an outline of each of the pediatric PK/PD studies planned, if applicable. Sponsors should discuss the studies in the order they are presented in the table in section 6.  For each study, to the extent practicable, the sponsor should address the following:

• The type of study/study design

• The objectives of the study

• The age group and population in which the study will be conducted

• The pediatric formulation(s) to be used in the study

• The dose ranges to be used in the PK studies

• The endpoints and justification (PK parameters; PD biomarkers)

• The existing or planned modeling and simulation for planned pediatric studies

• Any planned pharmacogenomic analyses

• Sample size justification

10.2 Clinical Effectiveness and Safety Studies

This section should provide a brief outline of each pediatric study planned, discussed in the order each is presented in the table in section 6 (1 to 10 pages).  For each study, to the extent practicable, the sponsor should address the following:

• The type of study/study design

• The objectives of the study

• The age group and population in which the study will be conducted

• The key inclusion and exclusion criteria for the study

• The endpoints (primary and key secondary) to be used

• The timing of endpoint assessments

• The safety assessments including timing and length of follow-up

• The statistical approach

• The modeling and simulation to be used

Sponsors should be aware that agreement with the outline of planned clinical studies does not constitute agreement with the protocol.  Sponsors must submit full protocols separately to their INDs for FDA review and should obtain FDA agreement regarding all full protocols before initiation of pediatric studies outlined in this section.  Sponsors should also submit statistical analysis plans separately to their INDs for FDA review and agreement.

11. Timeline of the Pediatric Development Plan

• For each study a general timeline for completion should be included.

• The sponsor should estimate these dates based on current projections for the drug development program.

• The target date of application submission should be based on clinical, scientific, and operational considerations and should be made independent of an anticipated submission date of an application or approval date of a drug.

12. Agreements for Pediatric Studies With Other Regulatory Authorities

• It is recommended that sponsors include, if available, a summary (1 to 3 pages) of the most recent agreed pediatric investigation plan with other regulatory authorities (e.g., European Medicines Agency).

• If negotiations with a regulatory authority are in progress or previous plans are under modification, a sponsor should include a summary of the most recent draft plan.

• A sponsor should highlight and comment on any differences between the most recent plan with other regulatory authorities and the plan submitted to the FDA.  The purpose of including a summary of agreements with other regulatory authorities is to encourage global alignment in pediatric development plans across regulatory authorities when possible

• For NDAs, BLAs, or supplemental applications subject to PREA, sponsors must include an agreed iPSP in the application when a deferral of pediatric studies is requested.

• Failure to fulfill the requirement to submit a pediatric study plan with the application may be grounds for refusal to file an application.

• Any planned requests for waivers and/or deferrals included in the iPSP serve as the official request with the application submission.  The PeRC will review any requests for waivers and/or deferrals and make recommendations as needed to the review division.

• A final decision about granting or denying such requests is made by the review division at the time of approval of the marketing application

Sponsors can request an amendment to an agreed iPSP at any time if emerging safety data from nonclinical juvenile animal studies and/or adult human clinical trials may support converting a planned request for a deferral to a planned request for a waiver for reasons of safety.

The need for additional safety data from adult human clinical trials may support a delay in the initiation of pediatric clinical trials

A request for an amendment to an agreed iPSP should include the following:

• The requested change(s) supported with a justification.

• A copy of the agreed iPSP with the requested change(s) tracked and clearly identified.

• A clean copy of the proposed amended iPSP.

• Once the FDA accepts for filing an application or supplemental application, it is not necessary to submit amendments to the iPSP because changes to the plan for pediatric development can be negotiated during the review cycle as appropriate.

• If the FDA does not agree to the amended iPSP, the original agreed iPSP remains in force.

• If the sponsor submits an amendment to an agreed iPSP within 210 days of the planned submission of an NDA, BLA, or supplement, the amendment may not be considered agreed absent sufficient time for the FDA review.

• The sponsor may submit the NDA, BLA, or supplement with the previously agreed iPSP since the FDA intends to, as appropriate, consider changes to the plan for pediatric development during the application review cycle.

• The failure of the sponsor to complete the agreed iPSP included nonclinical and/or pediatric clinical studies that were expected to have been completed before submission of the NDA, BLA, or supplement may result in a refusal to file.

• In this situation, a sponsor should submit a request for an amendment to the agreed iPSP that includes an updated timeline for the studies and justification for the delay in completing one or more of the agreed pediatric studies.

• If the FDA considers the justification for the delay to be inadequate and does not agree with the proposed iPSP amendment, the agreed iPSP would remain in force until the FDA and sponsor agree on an amended iPSP.

• If the FDA and the sponsor are unable to reach agreement on an iPSP at the end of the 210-day review period, the FDA intends to issue a letter stating that the iPSP is considered a non-agreed iPSP.

• Reaching Agreement on the Non-Agreed Initial PSP, there is no established timeline for the review and agreement of a non-agreed iPSP.  Therefore, sponsors are encouraged to work with FDA to reach agreement during the initial 210-day review period.

• If the FDA and the sponsor are unable to reach agreement on the proposed amendments to an agreed iPSP, the FDA intends to issue a letter stating that the amended iPSP is considered a nonagreed amended iPSP.  Under this circumstance, the agreed iPSP would be considered to be in force until the FDA and sponsor agree on an amended iPSP.