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. The submission must be done according to the Pediatric investigation plan guidance from FDA 2020. 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. The FDA expects to agree to time frames other than those described in this guidance only if there are exceptional circumstances. 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. Sponsors should contact the appropriate component of the Center for Drug Evaluation and Research or the Center for Biologics Evaluation and Research if they believe exceptional circumstances exist. 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. In cases where the drug development program includes the possibility of using expedited programs,23 the FDA encourages the sponsor to have discussions about the pediatric development plans with the review division as early as possible. 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 (see section VIII., Non-Agreed Initial PSPs)
FDA has worked to address the problem of inadequate testing of drugs in pediatric populations and inadequate pediatric use information in drug labeling. In 1994, the FDA published a final rule that required manufacturers of marketed drugs to survey existing data and determine whether those data were sufficient to support adding pediatric use information to the drug’s labeling.
However, the 1994 rule did not impose a general requirement that manufacturers carry out studies when existing information was not sufficient to support adding pediatric use information. This initial attempt to encourage sponsors to submit pediatric studies and plans to sufficiently inform use of drugs in pediatric patients was not successful in achieving adequate labeling for most drugs regarding use in the pediatric subpopulation, and product labeling frequently failed to provide directions for safe and effective use in pediatric patients.
To address this continuing problem, the Food and Drug Administration Modernization Act of 1997 was signed into law and contained provisions that established incentives for conducting pediatric studies on drugs for which exclusivity or patent protection exists.
On December 2, 1998, the FDA published a regulation known as the pediatric rule.
This rule partially addressed the lack of pediatric use information by requiring manufacturers of certain new and marketed drugs to conduct studies to provide sufficient data and information to support
directions for pediatric use for the claimed indications. This pediatric rule also stated that the
FDA would provide sponsors with its best judgment on whether pediatric studies would be
required and whether their submission would be deferred until after approval
The pediatric rule also stated that sponsors should submit, at least 1 month in advance of the endof-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. However, on October 17, 2002, the U.S. District Court for the District of Columbia held that the FDA had exceeded its statutory authority when issuing the pediatric rule and the court enjoined the rule’s enforcement.nCongress subsequently passed PREA, which was signed into law on December 3, 2003.
Many of the provisions described under the pediatric rule were adopted under PREA. Under PREA as originally enacted and under its reauthorization under the Food and Drug Administration Amendments Act of 2007, a sponsor was not required to submit a proposed timeline and plan for the submission of pediatric studies during the investigational new drug application (IND) phase of drug development.
Under the Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on July 9, 2012, for the first time PREA includes a provision that requires a sponsor planning to submit an application for a drug subject to PREA to submit an iPSP early in the development process. The intent of the iPSP is for a sponsor to identify needed pediatric studies early in development and begin planning for these studies. Early dialogue with the FDA on a comprehensive pediatric development plan, including both required pediatric studies under PREA and potential pediatric uses under the BPCA, is intended to result in a more efficient pediatric drug development program. The timing and content of the submission of an iPSP are described below. The FD&C Act, as amended by FDASIA, requires the FDA to issue regulations and guidance to implement these and other provisions.
