The following questions and answers have been prepared by Pediatric Implementation Team (PdIT) in the Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration. This guidance represents the Agency's current thinking on pediatric exclusivity (505A), the Rule and their interaction. 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 statute, regulations or both.
Section 505(A) of The Modernization Act enabled FDA to:
- Issue Written Requests for pediatric studies prior to approval of a new drug application if FDA has determined that information related to the use of the drugs in the pediatric population may produce health benefits.
- Issue Written Requests to holders of approved applications for pediatric studies if it has determined that information related to the use of the drug in the pediatric population may produce health benefits.
Section 505(A) also required FDA to develop, prioritize, and publish a list of approved drugs for which additional pediatric information may produce health benefits in the pediatric populations and update it annually.
As an incentive to industry to conduct studies requested by the Agency, Section 505(A) provides for a 6-month period of marketing exclusivity (pediatric exclusivity).
Q1. How does a sponsor or applicant qualify for pediatric exclusivity?
A1. Three essential elements must be in place before an applicant is eligible for pediatric exclusivity. To qualify for pediatric exclusivity, the applicant must meet all of the following conditions:
- Be in receipt of a written request from FDA. On June 30, 1998, FDA issued a Guidance for Industry, Qualifying for Pediatric Exclusivity Under Section 505(A) if the Federal Food, Drug, and Cosmetic Act (June 1998) [PDF]. The guidance describes what constitutes a Written Request and what it must address. Prior correspondence with applicants regarding clinical trials, agreements at meetings, correspondence describing phase 4 commitments, and other communications with sponsors DO NOT CONSTITUTE a Written Request. The Written Request describes in detail the studies needed and the time frame for their completion; the guidance describes ways in which the Written Request can be amended to revise the study requirements or the specified time frame. The Written Request is the key to whether submitted study reports qualify the applicant for pediatric exclusivity.
- Submit study reports after receipt of the written request. Firms are to submit reports of studies conducted in pediatric populations to the FDA after FDA has issued a Written Request. Under the terms of the statute, FDA must determine whether the studies submitted meet the terms of the Written Request. Submissions of reports should generally be in the form of a new drug application, a supplement to an approved application, or an amendment to a pending application. A firm should, but is not required to, obtain approval of pediatric labeling to qualify for pediatric exclusivity.
Meet the conditions of the written request. Whether an applicant qualifies for exclusivity for a product after conducting the studies and submitting the reports depends on whether:
- The submission meets the time frame described in the Written Request, and
- The studies performed meet the terms specified in the Written Request.
Q2. Can an applicant ask FDA to issue a Written Request for pediatric studies?
A2. Yes. The guidance to industry describes a process in which a sponsor of a new drug or the holder of an application for a product on the list may make a submission to FDA in which it makes a detailed proposal for a Written Request. Where an applicant has more than one product containing the active moiety, the proposal should address each indication that has applicability to pediatric patients and should propose studies in all appropriate age groups. FDA encourages applicants to make such proposals. FDA will review the submitted proposal and MAY issue a Written Request to the applicant based on the applicant's proposal.
Q3. Where should proposals for Written Requests from applicants be sent?
A3. Proposals for Written Requests should be sent to each of the review divisions with regulatory responsibility for any of the applicant's products that contains the same active moiety cited in the Written Request.
Q4. Does a sponsor HAVE to conduct pediatric studies if it receives a Written Request from FDA?
A4. No. A company is not required to do the studies requested by FDA in a Written Request if it chooses not to do so. If, however, the applicant decides to conduct studies that differ from those described in the Written Request, the applicant will not qualify for pediatric exclusivity upon submission of the reports thereof. Applicants who choose to deviate from the studies described in the Written Request and who are interested in obtaining pediatric exclusivity should contact the review division and seek to amend the Written Request prior to the conduct of the studies. The applicant must receive an amended Written Request prior to submission of the study reports to NDA.
Q5. Can an applicant obtain exclusivity by submitting an analysis of the literature in response to a Written Request?
A5. Simply compiling the literature on pediatric use of a drug in a given indication will not qualify an applicant for pediatric exclusivity. The generous incentives were made available to stimulate performance of studies necessary to provide useful information on drug use in children.
Q6. Can the applicant for any approved product qualify for pediatric exclusivity?
A6. No. Pediatric exclusivity is an ADD-ON to existing marketing exclusivity or patent protection. In general, products with no patent life or exclusivity remaining cannot qualify. Under certain conditions, however, pediatric exclusivity may be granted to a product without remaining exclusivity IF the supplemental application itself qualifies for a new exclusivity period under the Drug Price Competition and Patent Term Restoration Act (Waxman-Hatch Amendments). For example, an application to extend an approved adult indication to the pediatric population for a product with no patent life or exclusivity remaining could obtain pediatric exclusivity IF new clinical studies of safety and efficacy are required for approval. In that case, the pediatric supplement would earn 3 years of marketing exclusivity under the 1984 amendments, to which the additional 6 month pediatric exclusivity would be added. A somewhat different situation would be where dosing information was needed in children under 6 years of age that could be based on PK studies. An oral solution dosage form exists but has no marketing exclusivity remaining. However, the firm has a controlled release product containing the same active moiety that is still protected by a 3 year exclusivity period. The controlled release product would not be appropriate for this age group because of the dose delivered. In this situation, PK studies conducted to label the oral solution could be the basis of a 6 month extension of the exclusivity for the controlled release product, provided the terms of the Written Request are met.
Q7. Does Section 505(A) apply to OTC drugs?
A7. Yes. It applies to those OTC drugs that are the subject of approved NDAs.
Q8. For approved drugs, must FDA approve a supplemental application before pediatric exclusivity is granted?
A8. No. The granting of exclusivity is not connected to approval; the pivotal factor is whether the applicant complied with the terms of the Written Request.
Q9. How is pediatric exclusivity different from other exclusivity available under the Waxman-Hatch amendments or the Orphan Drug Act?
A9. Pediatric exclusivity differs from other exclusivity in the following important ways:
Pediatric exclusivity does not accrue only to the product that was studied in the pediatric population. It attaches to all the applicant's formulations, dosage forms, and indications for products with existing marketing exclusivity or patent life that contain the same active moiety. For example, if a firm markets an oral formulation, a topical cream, and an ophthalmic containing the same active moiety and all the products have remaining marketing exclusivity or patent life, and if the firm conducts studies regarding the active moiety in accordance with a Written Request, 6 months additional exclusivity will be granted to ALL DOSAGE FORMS AND ALL INDICATIONS with the same active moiety as the drug studied.
- Pediatric exclusivity attaches to the END of all existing marketing exclusivity and patent periods. Waxman-Hatch exclusivity, orphan exclusivity, and patent periods run concurrently.
- Pediatric exclusivity is not tied to approval of labeling containing information on pediatric use based on the studies conducted. It may be granted upon acceptance of the study reports. Acceptance in this context means the Agency has determined that the studies were conducted in accordance with the terms of the Written Request and were reported in accordance with FDA's requirements for filing. Waxman-Hatch and orphan exclusivity are not granted until approval of the application.
Q10. What is the list?
A10. The Modernization Act required the Secretary to "develop, prioritize, and publish a list of approved drugs for which additional pediatric information may produce health benefits." As a practical matter, the list consists of those approved drugs for which there is a pediatric manifestation of any of the adult indications for which the product is approved. The list that was made available by notice in the Federal Register on May 20, 1998 is the priority section of the list. The list will be updated periodically - at least annually. FDA plans to issue Written Requests for products that appear on the priority section of the list first. Persons seeking to add a particular drug to the priority section of the list or to have a drug removed from the priority section of the list may submit to the agency a citizen petition that complies with the requirements of 21 CFR 10.30. Inclusion of a drug on the list does not necessarily mean that the drug is entitled to pediatric exclusivity.
Q11. Should a Written Request be issued to the IND or NDA holder?
A11. If an NDA for the drug product exists, the Written Request should be issued to the applicant of the NDA. If no NDA exists for the product, the Written Request should be issued to the IND holder.
Q12. For over-the-counter (OTC) products that are the subject of an NDA, which Office Director should sign Written Requests for pediatric studies?
A12. Consistent with CDER policy for decision making responsibilities on certain other regulatory documents that require Office level sign-off pertaining to OTC drug products subject to NDAs, both the Director of ODE V and the Director of the Office responsible for the specific subject matter review division should sign Written Requests for OTC products.
Q13. If a sponsor submits a pediatric study that meets the terms of a Written Request but the study is not adequate for inclusion in the labeling, will the sponsor get pediatric exclusivity?
A13. Yes. Pediatric exclusivity is not dependent on whether information from the requested study is included in the labeling.
Q14. Where can I get answers to questions that come up regarding our implementation of the pediatric exclusivity provisions?
A14. Send questions via E-mail to email@example.com. It is an E-mail account that has been set up by the Pediatric Implementation Team.
The "Rule," effective April 1, 1999, modified 21 CFR Parts 201, 312,314, and 601. It specifies "Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients."
The "Rule," effective April 1, 1999, modified 21 CFR Parts 201, 312,314, and 601. It specifies "Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients."
Q15. What pediatric studies can FDA require a company to conduct under "the Rule" for each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration?
A15. Under the pediatric rule, FDA can require an applicant to conduct a pediatric assessment of the product for the indication(s), dosage form, dosing regimen, or route of administration that is the subject of the application or supplement. This means that FDA can require an applicant to assess the safety and effectiveness of the drug product in the application under review in all relevant pediatric subpopulations. If FDA deems it necessary, it may require an applicant to develop a new formulation if it is needed for use in the targeted pediatric population.
Q16. What pediatric studies can FDA require a company to conduct for an approved drug product?
A16. Under the rule, FDA has the authority to require pediatric studies on a drug product for the product's approved indications IF there is SUBSTANTIAL USE in the pediatric population OR the product would provide a MEANINGFUL THERAPEUTIC BENEFIT - AND the absence of adequate labeling could pose significant risk (see 21 CFR 201.23(a)). At this time, however, FDA will not require studies of approved drugs except if approved by the Center Director. Instead, FDA will seek to have manufacturers voluntarily submit studies for marketed drugs under the incentives provided by FDAMA (see 63 FR 66634 Sec II). For those drugs in which voluntary measures fail to obtain necessary pediatric studies, FDA will consider requiring studies.
Q17. Does FDA ask for the same scope of studies to qualify for pediatric exclusivity as it does to fulfill the requirements of the pediatric rule?
A17. No. For pediatric exclusivity, FDA will issue a Written Request for necessary studies on all of the indications that occur in pediatric populations for which an active moiety is used. A sponsor does not have to respond to a Written Request. However, a sponsor must supply all the information asked for in the Written Request to obtain pediatric exclusivity.
At present, under the pediatric rule, FDA is requiring applicants to conduct a pediatric assessment only for drug products and indications contained in applications submitted for review. The application could be for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration. The Agency reserves the right to require studies on approved indications of a marketed drug as discussed above at Q17.
Q18. Under the pediatric rule, does FDA have authority to set a clock for needed studies to be submitted?
A18. Yes. Under 21 CFR 314.55(a), each application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration must contain adequate pediatric data unless the requirement is DEFERRED (314.55(b)), WAIVED (314.55(c)), or EXEMPTED (314.55(d) - Orphans). Therefore, under the rule, for new applications and supplements, the "clock" is the time of submission of the application. FDA cannot require the submission of pediatric study reports prior to December 2nd, 2000, the "compliance date" published in the Federal Register. Thereafter, necessary pediatric information is required in applications and supplements for approval. Deferrals of the requirement for pediatric data will provide a date by which data submissions are required.
Under 314.55(b) - Deferral - the rule states that FDA may approve an application for use in adults SUBJECT TO THE REQUIREMENT that the applicant submits the required assessments WITHIN A SPECIFIED TIME. However FDA cannot require manufacturers to submit information before December 2, 2000 (63 FR 66632, "Compliance dates"). Waiver and exemption remove the requirement to conduct pediatric studies (and the "clock") with respect to the particular supplement or application. A waiver may also be granted only for studies in a particular age group.
Q19. What if a sponsor does not comply with an FDA requirement to perform a pediatric assessment within the set time?
A19. If an applicant does not conduct a required pediatric assessment within the set time, the reviewing division should first notify and meet with the applicant to discuss the reasons for non submission of the studies within the agreed timeframe. If the applicant cannot provide a reasonable explanation for the delay and obtain a deferral from the division, the reviewing division should pursue appropriate regulatory actions in
Q20. What if the study submitted is not adequate (not a good study)?
A20. If the study submitted with an application is not adequate, the sponsor will not have satisfied the pediatric study requirements. Further study would be necessary unless the requirement is waived. Presumably, if the adult indications were ready for approval, the Division could approve the application for adults with a deferral of the pediatric data until a specified time for completion of the pediatric requirement.
Please note that an inadequate study that meets the terms of a Written Request (FDAMA) may still earn pediatric exclusivity, even if the study is not adequate for approval.
Q21. Does the firm have to initiate a request for a waiver or can FDA grant a waiver in the absence of a request from the company?
A21. FDA could waive the requirement without such a request from the company.
Q22. Can FDA ask for a new formulation under the pediatric rule?
A22. Under the rule FDA not only can ask but can require a new formulation if it is needed in a pediatric age group that will use the drug.
Can FDA ask for a new formulation in a Written Request for pediatric exclusivity?
FDA can request a sponsor to conduct studies in all relevant pediatric populations. A sponsor will not be able to satisfy such a Written Request unless it completes studies in all relevant populations. To complete such studies, a sponsor may need to develop a new formulation.
Q23. For the pediatric rule, does the sponsor have to address each of the pediatric age groups?
A23. A sponsor must address all of the pediatric age groups in which the drug is appropriate for use. FDA considers pediatric patients to be those aged birth up to the 16th birthday. Age categories are set as: neonates (0-1 month), infants (1 month to 2 years); children (2 years to 12 years); adolescents (12 years to 16 years). Sponsors must address the entire age range but need not necessarily use these specific age categories. If a sponsor bases its studies on characteristics other than ages, such as physiological development, the sponsor should support its categories with scientific, developmental, compliance, or ethical reasons.
Q24. When are only pharmacokinetics (PK) needed?
A24. Regulations state that where the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, FDA 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. Studies may not be needed in each pediatric age group, if data from one age group can be extrapolated.
It should be noted, however, that PK/Safety studies in pediatric population alone would more likely be sufficient if a drug’s effect is well characterized with regard to the important PK parameters. Where PK parameters have not been correlated well with activity in adults (topicals for example), a clinical study would more likely be required. The study requirements will be decided on a case by case basis.
Q25. Can FDA require a sponsor to conduct pediatric studies if the disease only occurs in certain pediatric subpopulations?
A25. Yes. FDA can require a sponsor to conduct pediatric studies even if only a small number of children are affected if the information would provide a meaningful therapeutic benefit in pediatric patients. FDA should issue a partial waiver for the age groups in which the disease does not occur. In addition, if the sponsor tries to conduct a study in the affected population but cannot complete the study, perhaps due to a very small number of patients in which the disease occurs, FDA may issue a waiver.
Q26. Can FDA require a sponsor to conduct preclinical (animal pharmacology/toxicology) studies in young animals?
A26. Yes. The rule requires each application to contain data adequate to assess the safety and effectiveness of a drug product in pediatric patients for its claimed use(s) (314.55(a)). If animal studies are necessary to provide "adequate data" they are required under the rule. However, each case must be considered on a case by case basis. There is no standard number or type of "pediatric preclinical studies" that would be requested. Divisions should consult with pharmacology/toxicology reviewing staff regarding the need for any juvenile animal data.
Q27. FDA receives an application containing a new adult indication that does not occur in the pediatric population. The agency knows that the active moiety in the application is also used off-label for a pediatric indication. Can FDA require the applicant to conduct pediatric studies on the off-label indication?
A27. No. FDA cannot require an applicant to conduct a pediatric assessment for off-label indications. However, FDA can issue a Written Request to the applicant seeking the off-label studies. If the applicant completed the Written Request, they could qualify for pediatric exclusivity.
Q28. If a sponsor submits an application on a drug for which there are multiple NDAs held by multiple sponsors, who is responsible for conducting the pediatric assessment?
A28. The applicant who submitted the application is responsible for conducting a pediatric assessment. However, at present FDA would only require the applicant of the application to conduct the assessment for the drug product and indication included in the application.
Q29. Does each Division make its own decision as to what products, etc. will be granted waivers?
A29. Each Division will make the decisions. The decisions will be tracked and consistency across divisions will be evaluated.
Q30. Will lack of an acceptable pediatric development plan for a drug in development be an acceptable reason for FDA to refuse to file an application?
A30. Not at this point. However, sponsors are required to include a pediatric drug development plan as part of the background package for the end-of-phase 1 meeting with the division for drugs used for serious and life threatening diseases or the end-of-phase 2 (EOP2) meeting with the division for other drugs. If this is not included in the background package, the Division need not grant the meeting until the background package is complete.
Q31. Where can I get answers to questions that come up regarding FDA's implementation of the pediatric "Rule" provisions?
A31. Send questions via E-mail to firstname.lastname@example.org
It is an E-mail account that has been set up by the Pediatric Implementation Team.