Everything Old is New Again: FDA Revises its 2014 Rare Pediatric Disease Priority Review Voucher Guidance for Industry

August 2, 2019By James E. Valentine & Larry J. Bauer, Senior Regulatory Drug Expert

Developing drugs for kids with rare diseases is important work. If you would like to hear from one of these kids, check out this video: “My Philosophy for a Happy Life,” by the late Sam Berns.

Offering priority review vouchers to sponsors that develop new drugs for children with rare diseases is an important incentive program that has wide support.  This week, FDA published a revised draft guidance of the original November 2014 draft guidance titled, “Rare Pediatric Disease Priority Review Vouchers, Guidance for Industry” (hereinafter “revised guidance”).  This revision was primarily intended to reflect more recent legislative changes from the Advancing Hope Act of 2016, as well as clarify several other aspects of the program.

New Requirements and Changes

The revised guidance is updated to reflect a number of post-2014 statutory updates.  First, the Advancing Hope Act created a requirement for sponsors seeking a rare pediatric disease priority review voucher (RPD PRV) to request the voucher upon submission of the rare pediatric disease product application.  This change clarifies that the voucher must actually be requested in the original NDA or BLA application.  Prior to this, even if the sponsor had not requested it, the FDA felt obligated to review an application and award an RPD PRV if it appeared to meet the requirements of the program.  This shifted the burden and responsibility from the Agency to the sponsor.

A second change from the Advancing Hope Act was the clarification that no sponsor of a rare pediatric disease product application may receive more than one priority review voucher issued under any section of the Federal Food, Drug, and Cosmetic Act for the same drug. This prevents a product for a rare disease that also happens to be a neglected tropical disease or medical countermeasure from getting two priority review vouchers for the same application.

The revised guidance also reflects that the 21st Century Cures Act of 2016 provides a sunset for the RPD PRV program so that FDA may not award any RPD PRVs after September 30, 2020, unless the rare pediatric disease product was designated by September 30, 2020 and subsequently approved by September 30, 2022.  After September 30, 2022, FDA may not award any RPD PRVs.  The program could possibly be extended in the future but that will require legislative action.

Re-Defining a “Rare Pediatric Disease”

Perhaps the greatest change in this revision is its incorporation of the new statutory definition of a “rare pediatric disease.”  The original definition stated that the disease had to “primarily affect individuals from birth to 18 years of age.”  FDA interpreted this to mean that sponsors were required to submit substantiating data that greater than 50% of the affected U.S. population with the disease were aged 0-18 years.  This original definition, not only being challenging to demonstrate, had unintended consequences.  The standard of care for certain rare diseases, e.g., sickle cell disease, has gradually improved the life expectancy of people with the disease. Currently, for some rare diseases, more than 50% of the people living with the disease are surviving into adulthood.  Children with the disease continue to be seriously affected but are living longer.  Under the old definition, these diseases would be excluded from being eligible for a voucher, contrary to the intent of legislators.  The new definition corrected this problem by stating that a rare pediatric disease is one where “the serious or life-threatening manifestations (of the disease) primarily affect individuals from birth to 18 years of age.”  Under this definition, a larger range of rare diseases that would not have qualified previously may now be eligible for vouchers.

What are Serious or Life-Threatening Manifestations?

This new statutory definition of rare pediatric disease hinges on the interpretation of the word “manifestations.”  The revised guidance states that manifestations are “expressions” or “symptoms” that are serious or life-threatening that occur during childhood (i.e., 0-18 years old) given current standard of care for pediatric patients.  Importantly, the guidance states that onset of a symptom is not enough, but it must progress to be serious or life-threatening while patients are children.  Then, to determine whether these manifestations “primarily affect children,” the guidance provides the following factors:

  1. Timing and rate of disease progression (e.g., end-stage organ disease occurs in childhood);
  2. Manifestations of abnormal growth or development; and
  3. Whether the proportion of children is greater than the proportion of adults with the given manifestation.

These factors are consistent with our experience with qualifying rare pediatric diseases as such under this new statutory definition.

Needing to Show A Drug Is “For” Prevention or Treatment of a Rare Pediatric Disease

Given that rare pediatric diseases are now defined by their manifestations, FDA included a new section on what it means for a drug to be “for” the treatment or prevention of the disease.  The revised guidance does not require a drug to be studied in or approved for treatment of the manifestations that “primarily affect children,” but instead merely requires the drug to be approved for an indication that is clinically meaningful to pediatric patients with the disease (e.g., for treatment of some other serious or life-threatening manifestation, or if it treats the underlying cause of the disease generally).  Importantly, the guidance states that applications should include in their priority review voucher requests scientific justification for how the approved indication will be clinically meaningful to pediatric patients.

Clarifying the Requirement to Rely on Clinical Data from Studies in the Pediatric Population

The revised guidance also interprets and clarifies the requirement that the application “relies on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population.”  It shifts in its language, from saying that the application “must” have certain information, to stating that it “should” have it:

  1. It should have been studied in a clinically meaningful pediatric population with the rare disease (although the studies may include adults in appropriate circumstances)
  2. The pediatric data should have been critical to obtaining adequate labeling for the pediatric population in terms of safety, effectiveness, and dosage information (although data from studies including adults may also have supported the pediatric labeling in appropriate circumstances).

In addition, the revised guidance walks back in requiring labeling of the drug be for use by the full range of affected pediatric patients in all cases, now acknowledging there are reasonable exceptions.  For example, the guidance states that there may be instances where it is not reasonable to include all pediatric age ranges affected by the disease without causing undue delays in completing the studies and submitting the application.  FDA appears to be most interested in preventing sponsors from submitting data from a “token pediatric population” to try and justify meeting the requirements for a voucher.

The revised guidance also added the statement reminding sponsors that after getting an RPD PRV, they may still further develop the same drug for additional indications, including different adult indications, without losing the voucher.

Providing FDA Comments on the Revised Guidance

FDA is accepting comments on the revised draft guidance by September 30, 2019 here.