Template for Written Request for Pediatric Studies for drugs used to treat chronic Hepatitis B Virus Infection
IND/NDA [INSERT APPLICATION NUMBER(S)]
[INSERT SPONSOR NAME]
[ATTN: CONTACT NAME]
[ADDRESS]
Dear [INSERT CONTACT NAME]:
Reference is made to your Proposed Pediatric Study Request submitted on [INSERT DATE], for [INSERT DRUG NAME] to IND [APPLICATION NUMBER(S)].
[Note: The sentence above should be left out if the Division is initiating the Written Request.]
To obtain needed pediatric information on [INSERT DRUG NAME], the Food and Drug Administration (FDA) is hereby making a formal Written Request, pursuant to Section 505A of the Federal Food, Drug, and Cosmetic Act (the Act), that you submit information from the following studies:
In the design of these studies, consideration must be given to the fact that chronic hepatitis B virus (HBV) infection in pediatric patients may ultimately lead to growth failure, renal toxicity, cirrhosis and/or hepatocellular carcinoma. There is a need to develop a long-term safety database to gather information regarding the development of these adverse conditions in relationship to treatment with [INSERT DRUG NAME]; specifically to understand whether treatment with [INSERT DRUG NAME] prevents, delays, increases or accelerates these events in pediatric patients.
Type of studies:
1. Study (or studies) to assess the single dose/multiple dose [as appropriate for the drug] pharmacokinetic (PK) profile of multiple dose levels of [INSERT DRUG NAME] in pediatric patients with chronic HBV infection
2. Randomized, controlled Phase 3 study of safety and efficacy of [INSERT DRUG NAME] in pediatric patients with chronic HBV infection treated for 48 to 96 weeks. Dose selection should be based on discussions between the sponsor and the Agency following review of the PK data. Study subjects should have evidence of chronic hepatitis B disease as documented by hepatitis B surface antigen (HBsAg) positivity, hepatitis B e antigen (HBeAg) positivity, measurable HBV DNA in the blood, and evidence of liver inflammation documented by abnormal liver transaminases or liver biopsy. Long-term follow-up to obtain safety data must be included in the study design.
Unless otherwise specified, both treatment-naïve and treatment-experienced patients should be evaluated and randomization in the Phase 3 study should be stratified according to prior treatment status.
Indication to be studied:
Treatment of chronic HBV infection in pediatric patients
The objective of these studies will be to determine the pharmacokinetic and safety profile of [INSERT DRUG NAME] across the age range studied, identify an appropriate dose (or doses) for use in HBV-infected pediatric patients, and evaluate the efficacy of this dose (or doses) in patients receiving treatment.
Age group in which studies will be performed:
Pediatric patients from 2 years through specific age not covered in adult labeling [eg., 13, 16, 18 years]
Study Endpoints:
Pharmacokinetics
Parameters including: Cmax, Cmin, Tmax, t1/2, AUC, and apparent oral clearance.
Safety and tolerability
Safety will be assessed in all studies including those designed primarily to assess PK profile. HBV-infected pediatric patients will be followed for safety for a minimum of 48 weeks at the recommended dose. Patients discontinuing treatment with [INSERT DRUG NAME] will be followed for at least 24 weeks.
Evaluation of long-term safety endpoints related to the use of [INSERT DRUG NAME] in pediatric patients including assessment of growth, renal function, and the potential for development of cirrhosis and/or hepatocellular carcinoma over a period of 5 years following treatment must be incorporated into study follow-up. The Division would expect that at least 50% of eligible patients will have data over 5 years of follow-up. Confirmation that patients are continuing in long-term follow-up will be required, however, submission of these data is not required for fulfillment of this written request.
Efficacy
Virologic efficacy will be determined for each subject after 48 to 96 weeks of treatment with [INSERT DRUG NAME] using virologic and serologic markers of chronic HBV infection. Efficacy may be measured using a composite endpoint that includes decline in serum HBV DNA (“undetectable” by PCR assay) plus normalization of ALT and/or the proportion of patients who become HBeAg negative during the study period. Any liver biopsy data obtained during the course of the study should be submitted for review.
Resistance
Collect and submit information regarding the resistance profile (genotypic and phenotypic) of clinical isolates at baseline and during treatment from pediatric patients receiving [INSERT DRUG NAME] who experience loss of virologic response. Data pertaining to the development of HBV mutants resistant to [INSERT DRUG NAME] should be analyzed for correlates to loss of efficacy, cross-resistance with other drugs, and hepatitis “flares”. Submit data in the HBV Resistance Format provided by the Division of Antiviral Products.
Drug Information
Dosage form: Age appropriate formulation [INSERT ALL DOSAGE FORMS THAT MAY BE USED IN PEDIATRIC STUDIES, IE. LIQUIDS, TABLETS, CAPSULES ETC]
Route of administration: oral
Regimen: to be determined by development program
Use an age-appropriate formulation in the study(or studies) described above. If the studies you conduct in response to this Written Request demonstrate this drug will benefit children, then an age-appropriate dosage form must be made available for children. This requirement can be fulfilled by developing and testing a new dosage form for which you will seek approval for commercial marketing. If you demonstrate that reasonable attempts to develop a commercially marketable formulation have failed, you must develop and test an age-appropriate formulation.
Development of a commercially-marketable formulation is preferable. Any new commercially marketable formulation you develop for use in children must meet agency standards for marketing approval.
If you cannot develop a commercially marketable age-appropriate formulation, you must provide the Agency with documentation of your attempts to develop such a formulation and the reasons such attempts failed. If we agree that you have valid reasons for not developing a commercially marketable, age-appropriate formulation, then you must submit instructions for compounding an age-appropriate formulation from commercially available ingredients that are acceptable to the Agency. If you conduct the requested studies using a compounded formulation, the following information must be provided and will appear in the product label upon approval: active ingredients, diluents, suspending and sweetening agents; detailed step-by-step compounding instructions; packaging and storage requirements; and formulation stability information.
Bioavailability of any formulation used in the studies should be characterized, and as needed, a relative bioavailability study comparing the approved drug to the age appropriate formulation may be conducted in adults.
Drug specific safety concerns:
Based on available toxicity information with your product, please provide specific safety parameters that your pediatric program will address, including but not limited to:
1. Renal or hepatic toxicity arising during dosing
2. Possible hepatitis “flares” during or following therapy
3. Development of resistance mutations in HBV leading to loss of efficacy of [INSERT DRUG NAME] and/or other drugs or to a “flare” of disease
4. Long-term safety issues such as growth and development, progression of liver diseases, hepatocellular carcinoma
[Note: Other safety issues to be included based on available data for specific drug.]
Safety of [INSERT DRUG NAME] must be studied in an adequate number of pediatric patients to characterize adverse events across the age range. The safety database must include at least -- pediatric patients who have received [INSERT DRUG NAME] for at least 48 weeks.
[Note: The number of pediatric patients to be studied may be different for different products based on the known safety profile of the drug in adults. This number may range from 50-100 for drugs with no identified serious adult toxicity to > 100 for drugs with significant associated adverse events in adults and a need to characterize these events in pediatric patients. Each WR will provide a specific safety database size appropriate for the drug.]
Statistical information, including power of study and statistical assessments:
1. Descriptive analyses of pharmacokinetics at all doses, safety, and activity data in HBV-infected pediatric patients. A minimum number of pediatric patients (as stated below) should complete the pharmacokinetic study (or studies) conducted to characterize pharmacokinetics for dose selection. Final selection of sample size for each age group should take into account all potential sources of variability. As study data are evaluated, the sample size should be increased as necessary for characterization of pharmacokinetics across the intended age range.
2 years to < 6 years: 12
6 years to < 12 years: 8
12 years to 18 years: 8
Studies must include an adequate number of patients to characterize pharmacokinetics across the age ranges studied, taking into account inter-subject and intra-subject variability. The number of patients should be approximately evenly distributed across the age ranges studied.
2. A Phase 3 clinical study with a placebo control group should have sufficient power to detect clinically meaningful differences in efficacy between drug and placebo in patients completing 48 weeks of treatment. An active-controlled non-inferiority trial should have sufficient power to rule out significant difference(s) in virologic efficacy between the treatment arms. This number of pediatric patients should also provide an adequate sampling to assess safety of the drug as noted above.
[Note: Each WR should include the language appropriate to the type of study proposed, either placebo-controlled or active-controlled.]
Labeling that may result from the study (or studies):
Appropriate sections of the label may be changed to incorporate the findings of the study (or studies), including information regarding dosing, safety, and efficacy of [INSERT DRUG NAME] in pediatric patients with chronic HBV infection.
Format of reports to be submitted:
You must submit full study reports not previously submitted to the Agency addressing the issues outlined in this request with full analysis, assessment, and interpretation. In addition, the reports are to include information on the representation of pediatric patients of ethnic and racial minorities. All pediatric patients enrolled in the study (or studies) should be categorized using one of the following designations for race: American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or other Pacific Islander or White. For ethnicity one of the following designations should be used: Hispanic/Latino or Not Hispanic/Latino. INCLUDE OTHER INFORMATION AS APPROPRIATE
Timeframe for submitting reports of the study(ies):
Reports of the above studies must be submitted to the Agency on or before [INSERT DATE]. Please keep in mind that pediatric exclusivity attaches only to existing patent protection or exclusivity that has not expired at the time you submit your reports of the studies in response to this Written Request.
Response to Written Request:
As per the Best Pharmaceuticals for Children Act, section 4(A), within 180 days of receipt of this Written Request you must notify the Agency as to your intention to act on the Written Request. If you agree to the request then you must indicate when the pediatric studies will be initiated.
Please submit protocols for the above studies to an investigational new drug application (IND) and clearly mark your submission "PEDIATRIC PROTOCOL SUBMITTED FOR PEDIATRIC EXCLUSIVITY STUDY" in large font, bolded type at the beginning of the cover letter of the submission. Please notify us as soon as possible if you wish to enter into a written agreement by submitting a proposed written agreement. Clearly mark your submission "PROPOSED WRITTEN AGREEMENT FOR PEDIATRIC STUDIES" in large font, bolded type at the beginning of the cover letter of the submission.
Reports of the studies should be submitted as a new drug application or as a supplement to your approved NDA with the proposed labeling changes you believe would be warranted based on the data derived from these studies. When submitting the reports, please clearly mark your submission "SUBMISSION OF PEDIATRIC STUDY REPORTS – PEDIATRIC EXCLUSIVITY DETERMINATION REQUESTED" in large font, bolded type at the beginning of the cover letter of the submission and include a copy of this letter. Please also send a copy of the cover letter of your submission, via fax (301-594-0183) or messenger to the Director, Office of Generic Drugs, HFD-600, Metro Park North II, 7500 Standish Place, Rockville, MD 20855-2773.
In accordance with section 9 of the Best Pharmaceuticals for Children Act, Dissemination of Pediatric Information, if a pediatric supplement is submitted in response to a Written Request and filed by FDA, FDA will make public a summary of the medical and clinical pharmacology reviews of pediatric studies conducted. This disclosure, which will occur within 180 days of supplement submission, will apply to all supplements submitted in response to a Written Request and filed by FDA, regardless of the following circumstances:
1. The type of response to the Written Request (complete or partial);
2. The status of the supplement (withdrawn after the supplement has been filed or pending);
3. The action taken (i.e. approval, approvable, not approvable); or
4. The exclusivity determination (i.e. granted or denied).
FDA will post the medical and clinical pharmacology review summaries on the FDA website at http://www.fda.gov/cder/pediatric/Summaryreview.htm and publish in the Federal Register a notification of availability.
If you wish to discuss any amendments to this Written Request, please submit proposed changes and the reasons for the proposed changes to your application. Submissions of proposed changes to this request should be clearly marked "PROPOSED CHANGES IN WRITTEN REQUEST FOR PEDIATRIC STUDIES" in large font, bolded type at the beginning of the cover letter of the submission. You will be notified in writing if any changes to this Written Request are agreed upon by the Agency.
As required by the Food and Drug Modernization Act and the Best Pharmaceuticals for Children Act, you are also responsible for registering certain clinical trials involving your drug product in the Clinical Trials Data Bank (http://clinicaltrials.gov & http://prsinfo.clinicaltrials.gov/). Since your drug is intended for the treatment of a serious or life-threatening disease or condition and you are conducting clinical trials to test its effectiveness, you must register these trials in the Data Bank. Additional information on registering your clinical trials, including the required and optional data elements and the FDA Draft Guidance for Industry, "Information Program on Clinical Trials for Serious or Life-Threatening Diseases and Conditions," is available at the Protocol Registration System (PRS) Information Site http://prsinfo.clinicaltrials.gov/.
If you have any questions, contact [insert project manager name and title], at 301-827-2335.
Sincerely yours,
Mark Goldberger, M.D.
Director
Office of AntimicrobialProducts
Center for Drug Evaluation and Research