In April 2013, the US Food and Drug Administration (FDA) released the fourth in a series of draft guidance documents related to the emerging regulatory framework for biosimilar products, a product classification first passed into law in 2010. Now industry is weighing in on that guidance, saying it needs several major changes in addition to a host of minor clarifications.
Biosimilars were first identified as a unique regulatory classification under the 2010 Patient Protection and Affordable Care Act (PPACA), which directed FDA to regulate the products separately from innovative biologics applications. Biosimilars are in many ways similar to generic pharmaceutical drugs in that they are intended to rely on existing data to help accelerate their approval process. A key difference, however, is that unlike chemical drugs, biological drugs aren't exactly the same due to different production techniques that result in minor variations.
The difficulties associated with proving that a biosimilar drug is as safe and effective as the drug it references are myriad, and FDA has been left with the difficult task of setting up the biosimilar approval pathway, also known as the 351(k) pathway.
So far, that work has culminated in four guidance documents, with the fourth, Formal Meetings between the FDA and Biosimilar Biological Product Sponsors or Applicants, establishing the process by which industry and regulators should conduct pre-approval meetings.
FDA's draft guidance establishes five different types of meetings to be used at various junctures in the development cycle of a product.
Biosimilar initial advisory meetings are to be used to discuss general matters, most notably including whether the 351(k) biosimilar pathway is appropriate for a given product. Under FDASIA, these meetings should occur within 90 days of FDA receiving a request from a sponsor.
Biosimilar product development (BPD) meetings, meanwhile, are divided into four types, and constitute the remainder of the meeting types. BPD Type 1 meetings are used to discuss clinical hold, set protocols for evaluations under a special protocol assessment, discuss important safety issues or resolve disputes.
Type 2 meetings are meanwhile used to discuss a specific issue to allow FDA to dispense targeted advice; Type 3 is used to review data in depth; and Type 4 is used to discuss the format of a biosimilar application or supplement, as well as its content.
FDA is supposed to hold meetings within 30, 75, 120 and 60 days for BPD Type 1, 2, 3 and 4 requests, respectively.
All BPD meetings are subject to user fees, while the initial advisory meetings are exempt. There are three types of BPD fees: an initial fee, an annual fee and a reactivation fee if a product has since dropped out of the regulatory review process. Fees for the initial BPD meeting must be paid within five days of the meeting request being granted or else the meeting may be canceled.
The guidance also explains procedures for the content of meeting request submissions, the approval or denial of those submissions, conduct during the meetings and disputes regarding meeting minutes.
And, as they say, the devil is in the details. Industry comments submitted via FDA's Federal Docket reflect an appreciation for the general framework of meeting types, but consternation about some of the language and details associated with the draft guidance.
For example, comments submitted by the Pharmaceutical Research and Manufacturers of America (PhRMA) highlights Section XI of the guidance, which outlines the process by which regulators communicate with sponsors during pre-meetings and communications. PhRMA wrote that the current timeframe was too short, as FDA currently provides initial feedback on materials just a day or two in advance of the meeting, and sometimes during the day of the meeting.
"This timeframe can prevent a sponsor from being able to adequately prepare to respond to FDA at the meeting, which can lead to inefficient meetings," PhRMA wrote. More advanced communications can lead to the company being able to better-target appropriate staff to be at the meeting or conduct additional analyses to address questions raised by FDA.
PhRMA also argues that FDA uses some language that could potentially be misconstrued to blur the lines between an innovative biologic (351(a) application) and a biosimilar drug (351(k)), and requests that FDA clarify its intake and classification process for investigational new drug applications (INDs) submitted under both pathways. That process should be based on sponsor intent, and not FDA's own "determination," at the time of the IND's submission to FDA, PhRMA wrote.
Finally, PhRMA argues that the FDA staff members who worked on the biological product referenced in the 351(k) application should "generally not participate in biosimilar meetings or application reviews," saying that staff who conducted "significant work on the reference product" might inadvertently reveal trade secrets or confidential information to the generic competitor.
"Such disclosures may be subtle," PhRMA explained. "For example, if an FDA reviewer was intimately familiar with how the reference product sponsor overcame a particular problem in the product's development history, he or she could incorporate this information in responses to questions by a potential biosimilar sponsor about a similar developmental hurdle. The risk of disclosure of information from the BLA is perhaps at its highest in meetings with biosimilar sponsors, where FDA staff and the sponsor may engage in free-flowing discussion of critical development issues. In-person meetings may not allow sufficient time for review staff to think critically about the sources of knowledge that inform their responses."
Other groups and companies also weighed in on the guidance. The Generic Pharmaceutical Association (GPhA) noted that FDA should make clear that "Type" meetings need not be sequential, and called for FDA to specify which electronic Common Technical Document (eCTD) submission format it would accept, and what needed to be included on the eCTD. The sequence of meetings was also identified by Apotex as being a potential source of confusion.
Israeli pharmaceutical manufacturer Teva also weighed in, calling for the need for further guidance regarding FDA's processes for reviewing background packages for biosimilar products under development, greater clarity on the appropriate level of data required for initial advisory meeting briefing documents, and other various details.
AbbVie's comments, meanwhile, closely mirrored those made by PhRMA. All other comments, including those made by Pfizer and Boehringer Ingelheim, may be found here.
FDA Docket Page on the Biosimilar Guidance