By Kurt R. Karst –
Last Friday, BioMarin Pharmaceutical Inc. (“BioMarin”) and FDA announced (here and here) the approval of a BLA for a new biological product for patients with Mucopolysaccharidosis type IVA, also known a “Morquio A syndrome”: VIMIZIM (elosulfase alfa) Injection. The approval of VIMIZIM not only marks the first FDA-approved product for Morquio A syndrome, a rare, severely debilitating and progressive disease that previously had no standard accepted treatment other than supportive care, but also the first time a company has secured a Rare Pediatric Disease Priority Review Voucher (“Pediatric PRV”).
The Pediatric PRV was created by Section 908 of the 2012 FDA Safety and Innovation Act (“FDASIA”), which is codified at FDC Act § 529 (see our FDASIA summary at pages 54-56). The Pediatric PRV program is intended to encourage the development of treatments for rare pediatric diseases. The program was inspired by the existing Tropical Disease PRV (“TD-PRV”) program set forth at FDC Act § 524, as added by the 2007 FDA Amendments Act of 2007 (“FDAAA”) (see our FDAAA summary at page 45, and draft FDA TD-PRV guidance here), but differs from that PRV program in several respects.
A Pediatric PRV is a voucher issued to the sponsor of a “rare pediatric disease product application” that entitles the holder of such voucher to priority review (instead of a longer standard review) of a single NDA or BLA after the date of approval of the rare pediatric disease product application. A qualifying rare pediatric disease product application is an NDA or BLA for a drug or biologic intended to prevent or treat a rare pediatric disease. Such drug or biologic may not contain any active ingredient (including any ester or salt of the active ingredient) previously approved in any drug or biologic application. The application must also be deemed eligible for priority review and rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population. A sponsor cannot seek an adult indication as part of a rare pediatric disease application.
FDA defines a “rare pediatric disease” similar to that as a “rare disease,” but in pediatric patients. That is, a “rare pediatric disease” is a disease that affects fewer than 200,000 individuals primarily aged from birth to 18 years in the U.S. The definition also extends to diseases that affect more than 200,000 individuals primarily aged from birth to 18 years in the U.S. but for which no drug or biologic treatments are available because a company cannot reasonably expect to recover the costs of developing and marketing such products.
Upon the request of a sponsor, FDA may designate a new drug or biologic as a product for a rare pediatric disease, and the application for such drug or biologic as a rare pediatric disease product application. The request for designation must be made at the same time as a request for orphan drug designation or fast track designation; however, requesting orphan drug or fast track designation is not a prerequisite to receiving a PRV. Within 60 days of receiving a request for a determination, FDA must determine whether a product qualifies as a new drug or biologic for a rare pediatric disease and whether an application qualifies as a rare pediatric disease product application. PRVs are awarded upon approval. FDA will publish notice of the issuance of a Pediatric PRV or the approval of a drug that used a Pediatric PRV within 30 days of the issuance or approval, respectively.
FDA can revoke a Pediatric PRV if the product for which the voucher was awarded is not marketed within 1 year of approval. In addition, a sponsor of an approved rare pediatric disease product must submit a report within 5 years of approval that provides information on the estimated population in the U.S. suffering from the rare pediatric disease, the estimated demand in the U.S. for the sponsor’s product, and the actual amount of such product distributed in the U.S. for the past four years.
An important limitation on the Pediatric PRV program is its sunset clause. Under the statute, no further vouchers can be awarded “after the last day of the one-year period that begins on the date” that the third voucher is granted. Therefore, less than a handful of vouchers will be issued.
A sponsor must notify FDA of its intent to use a pediatric PRV no later than 90 days prior to submitting a drug or biologic application, and “[s]uch notification shall be a legally binding commitment to pay for the [Pediatric PRV] user fee,” in addition to other applicable user fees. Although FDA has not yet determined the Pediatric PRV user fee, the fee to use a TD-PRV, which is calculated using a similar formula, is substantial (see here and here).
In general, Pediatric PRVs may be sold or transferred, and there is no limit on the number of times a priority review voucher can be transferred. The transferee or purchaser must notify FDA of a change of ownership within 30 days after such transfer or purchase. A sponsor that provides notification of its intent to use a Pediatric PRV, while committed to pay the Pediatric PRV user fee, “may transfer the voucher after such notification is provided, if such sponsor had not yet submitted the human drug application described in the notification.”
The TD-PRV program is similar in many ways to the Pediatric PRV program, and, therefore, may provide a good example of how Pediatric PRVs might work. However, not a lot of TD-PRVs have been granted thus far.
When the TD-PRV program was introduced, many industry experts predicted that a market could be created for PRVs. At the time, PRVs were speculated to be worth between a whopping $50 million and $500 million! Despite their high valuation, only two drug sponsors have developed products that have received TD-PRVs: (1) Novartis’s COARTEM (artemether, lumefantrine), which was approved on April 7, 2009 for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least 5 kilograms; and (2) Janssen Therapeutics’ SIRTURO (bedaquiline), which was approved on December 28, 2012 for pulmonary multi-drug resistant tuberculosis. The COARTEM PRV was used by Novartis when in 2011 the company submitted a supplemental NDA for ILARIS (canakinumab) to add an indication for gouty arthritis. It is unclear whether Janssen has used its PRV. A third TD-PRV may be granted if FDA approves a pending application for IMPAVIDO (miltefosine) for the treatment of visceral, mucosal and cutaneous leishmaniasis (see here).
One takeaway from the TD-PRV program is that the value of PRVs is uncertain and has not encouraged large-scale development of new therapies for tropical diseases. It is important to note, however, that there are at some key differences between TD-PRVs and Pediatric PRVs that may make the latter more appealing. First, a sponsor using a TD-PRV is subject to a one-year notification requirement before submitting a human drug application for priority review, whereas a sponsor using a pediatric PRV is only subject to a 90-day notification requirement. Second, transfer of TD PRVs is limited to a single sale or transfer, whereas a Pediatric PRVs can be traded or sold multiple times. These differences, among others, may make the Pediatric PRV more appealing to companies.