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PREA and 505(b)(2)

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement in waived, deferred, or inapplicable.  Given the time since the RLD was approved, many 505(b)(2) drug development projects are now subject to PREA.  We have been faced with several PREA-related issues with Premier Consulting clients since the Agency began enforcing the Act last fall.


There is a profound need for children’s products that have been tested and approved safe and effective for use by children.  In the period 1973 – 1997, the percentage of approved drugs that contained no labelling information for children remained fairly stable at 71 – 81%.[1] Of the 33 new molecular entities approved in 1997, 27 had potential for pediatric use, but only nine contained any pediatric labelling information.[2]  Two thirds[3]of the drugs that are prescribed to children have not been studied and labeled for pediatric use.  With so few medicines containing adequate labelling information to guide their use, off-label prescribing has become an accepted practice. Off-label prescribing includes the use of unapproved indications, or a different age group, dosage, frequency or route of administration. Off-label prescribing also includes the administration of extemporaneous formulations with untested bioavailability and stability.  Off-label use of medicines has become, unfortunately, a necessary and accepted part of pediatric medical practice.[4]  In recognition of the need to have a determination of pediatric applicability and adequate labeling instructions for children, Congress included incentives for conducting needed studies in the Food and Drug Administration Modernization Act of 1997 (FDAMA). Due to slow progress, Congress added additional incentives in the Best Pharmaceuticals for Children Act in January 2002.  In essence, this Act provided the innovator a 6 month extension to exclusivity if adequate studies were performed and allowed FDA to formally request such studies be performed.  Later, in 2003, Congress passed the Pediatric Research Equity Act which provided FDA with the authority to use bridging data from adult studies for the approval of pediatric medicines. The three Acts, together with continuing enabling legislation under the PDUFA renewals, are designed to encourage the development of pediatric drugs.  FDAAA of 2007 extended and amended BPCA and PREA.


[1]Wilson, JT, Kearns, GL, Murphy, D, and Jaffe, SJ. Clin Pharmacokinet. 1994;26:308-325.
[2]Rakhmanina, NY, van den Anker, JN. Adv Drug Del Rev. 2006;58:4-14.
[3] GAO, Pediatric Drug Research- Studies Conducted under Best Pharmaceuticals for Children Act, March 2007; GAO-07-557.
[4]Smyth, RL, and Edwards, AD. Arch Dis Child. 2006;91:212-213.

Key Concepts

A proposed 505(b)(2) drug product will require pediatric studies unless the drug clearly is not applicable to children under 18 year of age.  You must present a clear argument to FDA and FDA must agree that the drug is not applicable to pediatrics.  Remember, the FDA breaks down pediatrics into age groups, generally, neonates (0-1 month), infants (1 month to 2 years), children (2 years to 12 years) and adolescent (12 years to 16 years) but this can change based on physiological considerations.

If the drug is applicable to both adults and children, then there are a number of things to consider.  PREA provides for the possibility 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. A study may not be needed in each pediatric age group if data from one age group can be extrapolated to another age group.

Given that you might want to obtain approval for the adult market first, there is the possibility that you can defer or waive the requirements for pediatric studies.


A deferral means that the required studies may be completed, delayed or conducted after approval for the adult indication.  This in recognition that the Agency wants the efficacy and safety established in adults before conducting studies in pediatrics.  Progress on meeting the deferred studies is expected to be reported in the annual report which is also being made public on FDA’s web site.


You may be able to obtain a full or partial waiver.  Full corresponds to the entire pediatric age range, while partial refers to specific age groups.

Let’s look at a real example Agency comment (below, in blue) on a drug that is used lifetime from infancy. You will note that the Agency won’t waive the requirements for infants but may defer them.  The comments also give some insight into unacceptable reasons for waivers.


If you submit an NDA for a 550(b)(2) drug product, pediatric studies would be required under PREA for pediatric subpopulations for whom there are no or insufficient data included in the NDA. Since are impacted by this condition, it is unlikely that pediatric studies would be waived for this subpopulation, but we would consider deferring these studies, and requiring the performance of these pediatric studies as a condition of approval (i.e., post-marketing commitments). For infants,  PK/PD and safety studies would be required unless you provided a waiver justification consistent with the PREA requirements. The challenges of PK sampling and the severity of disease in infants are not justifications consistent with PREA waiver requirements. Under PREA, a partial waiver of pediatric studies in infants can be issued if the following criteria are met:

  • Necessary studies are impossible or highly impracticable (because, for example, the number of patients in that age group is so small or patients in that age group are geographically dispersed);
  • There is evidence strongly suggesting that the drug or biological product would be ineffective or unsafe in that age group;
  • The drug or biologic product 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; and the absence of adequate labeling could not pose significant risks to pediatric patients; or
  • The applicant can demonstrate that reasonable attempts to produce a pediatric formulation necessary for that age group have failed.

Of note, if a pediatric population is excluded from drug studies for safety reasons, this information must be included in the drug labeling.

If efficacy is demonstrated in children, adolescents, and/or adults, we may consider if it would be appropriate to extrapolate efficacy down to infants. However, if it is determined that extrapolation is inappropriate, efficacy studies in infants also would be required unless you provided a waiver justification consistent with the criteria listed above.

Please note that nonclinical juvenile studies are required prior to the initiation of any pediatric trial.