By Kurt R. Karst –
Since 2008, FDA’s annual guidance document agendas (here, here, and here) have noted FDA’s plans to issue guidance on the Agency’s so-called Pre-Launch Activities Importation Request (“PLAIR”) program. Although FDA officials have discussed PLAIRs in presentations, the Agency has not yet provided any formal guidance, and the PLAIR program remains largely shrouded in mystery. Despite the lack of guidance to industry, FDA has been implementing its PLAIR program and simultaneously refining its policies. As such, we think it’s high time to pull back the shroud and demystify FDA’s PLAIR program.
FDC Act § 505(a) prohibits the introduction or delivery for introduction into interstate commerce of a new drug “unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug.” While there are several regulations that permit the transport of unfinished bulk product for further manufacture in anticipation of marketing (see e.g., 21 C.F.R. § 314.410(a)(2) and § 201.122(c)), there is no regulation excepting the domestic transport of finished product in anticipation of marketing approval. Instead, FDA has historically exercised enforcement discretion to permit these shipments, and has traditionally cited to its authority under FDC Act § 309 as the legal basis for its use of enforcement discretion when the belief is that the public health is best served.
FDA developed the PLAIR program with an eye towards the increasing globalization of the drug industry, and presumably as a means to both formalize the Agency’s historical use of enforcement discretion and to extend to finished products manufactured overseas the same courtesy FDA extends to unfinished bulk product. FDA’s PLAIR program allows, on a case-by-case basis, the importation and warehousing of finished drugs where an application for drug approval (i.e., an NDA or ANDA) is pending and where the import and warehousing will expedite the commercial launch of the drug once FDA approves an application. Specifically, FDA’s Center for Drug Evaluation and Research (“CDER”) and the Division of Import Operations and Policy (“DIOP”) exercise enforcement discretion to permit certain interstate shipments of unapproved products in finished dosage form by the domestic drug industry to prepare these products for market launch in anticipation of approval. Such shipments are allowed under certain controls and restrictions. For example, the drug products may only be shipped to facilities identified in a pending NDA or ANDA or to facilities owned and controlled by the applicant.
When pressed, FDA has provided informal guidance on PLAIRs. In the interest of transparency, that guidance is provided below:
Please provide us with the following information on an electronic compatible file by email. If you have more than one application, please submit these separately.
a. Drug product name (trade and established) and complete product description (color, shape, etc);
b. Name of CDER Project Manager assigned to pending application;
c. Finished bulk drug NDC #, if assigned;
d. Name & address of foreign manufacturer (includes building # and street name) of finished drug product;
e. Name & address of U.S. consignee;
f. Pending application number (and supplement number, if appropriate) and date applicant expects its approval;
g. The name and address of the warehouse or distribution warehouse controlled by or under contract by the applicant where finished dosage form product in final packaged form will be stored pending approval;
h. When finished dosage form drug product in bulk is imported for further processing, the name and address of the facility where further processing activities will occur;
Include description of further processing activities;
If processed product will be transferred, provide information on the location where the product will be stored until the application is approved and effective; and,
i. Letter signed by senior management stating that neither they nor their consignee or distributor in the U.S. will sell, offer for sale, or distribute in domestic commerce this drug product until FDA approval is effective.
After receipt of this information, we will decide on a case-by-case basis, whether to exercise enforcement discretion to permit entry of the unapproved, finished dosage form drugs and notify you if the importation request is acceptable (normally within two weeks or less). Please that the firm must register and the drugs must be listed once the application is approved. Although drug listing is not required until the drug product is ready for commercial distribution, it is recommended to list your drug product electronically as this will expedite the listing process once the application is approved. If changes need to be made, the information can later be updated. We will also provide an email confirmation to the Division of Import Operations and Policy (DIOP) in the Office of Regulatory Affairs (ORA) that the importation request is acceptable. You should then provide to DIOP (contacts: Steven Branch and Stella Notzon) the Customs Entry number in advance (at least one month before the expected arrival) your company is importing under the PLAIR enforcement discretion letter. Also, please note that one shipment meaning one entry regardless of the quantity, batches or lot numbers offered for imports will be acceptable for the initial market launching. Keep in mind that the amount of product imported into the US must match with what you stated in the PLAIR. Otherwise, an amended PLAIR must be submitted to CDER-OC-PLAIR@fda.hhs.gov for approval. You can make the changes on the existing PLAIR request, however, identify your request as an “amendment.”
FDA is reportedly still working through some of the kinks in the implementation of its PLAIR program, and policy changes are expected as the Agency gains greater experience with PLAIRs. Our experience with FDA’s current PLAIR program, however, has revealed one problem in particular that should be fixed.
The informal PLAIR guidance provided by FDA notes that “one shipment meaning one entry regardless of the quantity, batches or lot numbers offered for imports will be acceptable for the initial market launching.” Thus, regardless of the amount of drug product FDA authorizes under a PLAIR, if a company’s carrier is unable to ship that full amount because of space limitations and the shipment must be broken up into multiple shipments, we understand that the Agency’s current policy is not to allow a second shipment, absent a public health issue or a shortage. A similar problem could arise if, for example, there are changed circumstances, such as a decision from FDA concerning 180-day exclusivity eligibility. If a company has already used up its PLAIR and circumstances change such that additional product will be needed in anticipation of approval, we understand that FDA does not currently allow a company to amend its PLAIR or to obtain a second PLAIR to account for the changed circumstance.
These limitations to FDA’s current PLAIR program are likely related the Agency’s funding and personnel limitations and concern about losing control of product imported into the U.S. Hopefully, with time and experience, FDA will be better able to address them, if not universally, then on a case-by-case basis. (For example, perhaps FDA can integrate an initial PLAIR approval into the Agency’s new PREDICT system for imports, thereby allowing for automated approvals of subsequent shipments.)