As biosimilar applications begin rolling in, FDA has issued two of its 2014 “promised” guidances, addressing important issues of how the agency is implementing the BPCIA: (1) what information FDA will consider to determine “first licensure” for a biologic licensed under 351(a), which is essentially a decision on eligibility for the 12-year exclusivity period provided to new biologics; and (2) regulatory expectations for clinical pharmacology in support of a biosimilar application.
Reference Biologic Exclusivity
The BPCIA provides an abbreviated pathway to FDA licensure for “biosimilar” versions of existing biological products with approved BLAs. As a trade-off for allowing biosimilars to rely on a previously licensed biologic as the “reference product,” the BPCIA provides exclusivity to the reference product. A biosimilar application cannot be submitted to FDA until four years after the date of licensure of the reference product, and the biosimilar cannot be licensed until 12 years after the reference product was. Thus, a decision by FDA regarding the date of first licensure of a reference product is, in effect, a decision on that product’s eligibility for exclusivity and on the date on which such exclusivity begins to run. Continue Reading
Including biosimilars in the release of expected 2014 CDER draft guidance documents has sparked the public interest as industry, physicians, patients and others await additional cues on FDA’s implementation of the BPCIA. The Center for Drug Evaluation and Research’s 2014 agenda for new and revised draft guidances includes the following for Biosimilars:
- Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Considerations in Demonstrating Interchangeability to a Reference Product
- Labeling for Biosimilar Biological Products
- Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act
Except for the “Additional Questions and Answers” guidance, these are not updates to the previously released draft guidances from March 2012. These are entirely new topics not yet addressed for implementation of the biosimilars pathway. With their publication will come additional opportunities for public input.
Not surprising after the European Medicines Agency (EMA) positive opinion for two biosimilars to Remicade (infliximab) in June, the first of these was authorized in September. Authorization of Remsima represents the first monoclonal antibody biosimilar, and the thirteenth biosimilar, authorized in the European Union.
In the United States, the Food and Drug Administration is into its third year of implementing its own biosimilars pathway. At a recent meeting of the Regulatory Affairs Professional Society (RAPS), FDA Officials announced that they are working with biosimilar sponsors on a total of 17 Investigational New Drug applications (INDs) but have not yet received any biosimilar Biologics License Applications (BLA) under the 351(k) pathway. FDA is also working diligently on the draft biosimilars guidances and plans to have final versions released within a year.
The EMA also posts its general and product class specific biosimilar guidelines, including concept papers, drafts and final versions.
The U.S. Food and Drug Administration staff will continue User Fee supported activities and vital consumer protection activities during the government shutdown. FDA staff, including review divisions and chief counsel’s office, will continue work on regulatory activities covered by user fees under the Prescription Drug User Fee Act (PDUFA), Generic Drug User Fee Amendments (GDUFA), Medical Device User Fee Amendments (MDUFA), Animal Drug User Fee Act (ADUFA), Animal Generic Drug User Fee Act (AGDUFA), and Family Smoking Prevention and Tobacco Control Act.
It appears from the HHS Contingency Plan that because of the user-fee funded activities, FDA drug review will be less interrupted during the shutdown than other FDA work. FDA will be unable to support the majority of its food safety, nutrition, and cosmetics activities. HHS reports that outside of the user-fee funded work, FDA will only “continue select vital activities including maintaining critical consumer protection to handle emergencies, high-risk recalls, civil and criminal investigations, import entry review, and other critical public health issues.”
Specifically with respect to the approval and regulation of drugs approved under 505(b) of the Food, Drug, and Cosmetic Act (FDCA) and biologic products, user fee funded activities are defined under FDCA Section 735(6), which covers all aspects of drug review and approval, including the review itself, issuing action letters, conducting approval related inspections, monitoring certain research, postmarket safety activities, adverse event collection, and enforcement activities. Section 736(7) describes the resources that are covered under the user fees, which includes staff, facilities, and information management.
However, according to an Agency announcement, FDA will not accept any new applications or supplements that require user fee submissions. Thus, new drug applications (NDAs) and biologics license applications (BLAs) and supplements to NDAs and BLAs that require a user fee will not be accepted during the government shutdown.
It is less clear whether the Agency will continue work on citizen petitions, even those subject to the 505(q) 150-day deadline for FDA response.
The Generic Pharmaceutical Association requests that the U.S. Food and Drug Administration assign the same non-proprietary name to a biosimilar as the one held by its reference biologic. FDA has not articulated a policy for naming of biologics, biosimilars and interchangeable biosimilars, although they asked for input on the topic in the Public Meetings and Dockets surrounding the issuance of the Draft Biosimilar Guidances.
At the heart of the discussion is whether it is in the best interest of public health and the individual patient for one biologic product to be distinguishable from another based upon the non-proprietary name (often called the “generic” name). The BPCIA is silent on naming, but FDA retains naming authority under the Food Drug and Cosmetic Act [502(e); 21 CFR Part 299]. The arguments for and against unique names for biologics, including biosimilars, have been articulated through the FDA public process. The September 17, 2013 GPhA Citizen Petition does not raise anything new. However, the petition does create a forum for public input and sets the stage for an FDA response on a biologics naming policy. Docket FDA-2013-P-1153 is open for public comment.
The European Medicines Agency (“EMA”) initiated a public consultation on a proposed revision of its Guideline on “Similar Biological Medicinal Products” (the “Biosimilars Guideline”), available at the EMA website . The 2 April 2013 proposed revision would ultimately result in a new guideline replacing the current Biosimilars Guideline adopted in October 2005.
The draft revision of the Biosimilars Guideline
The draft revision of the Biosimilars Guideline reflects the main principles set out in the current version of the Guideline. It describes the concept of biosimilar and provides the general principles to be applied in the assessment of applications for marketing authorisation of biosimilars. This includes the choice of a reference biological medicinal product and the principles for establishing biosimilarity between the reference product and the biosimilar. Continue Reading
A collection of associations for higher education wrote to FDA Commissioner Margaret Hamburg urging a requirement for biosimilar applicants to certify that they have complied with the information exchange and patent dispute resolution provisions of the BPCIA. The concern raised is that:
“biosmilar sponsors can effectively circumvent every patent litigation provision of the statute simply by failing to provide timely requirement for notice and access to the reference product sponsor without meaningful consequences, despite the requirement for such notification.”
As stakeholders in the patent dispute resolution process, the higher education associations urge the Food and Drug Administration that:
“A mandatory yet simple requirement that biosimilar applicants certify their compliance with the notice and access provisions of the statute is warranted.”
This is another instance where manufacturers and trade associations believe FDA must play a role in refereeing potential disputes between pioneer companies and biosimilar applicants. Other close watchers, including the Biotechnology Industry Organization (BIO) and Pharmaceutical Manufacturers of America (PhRMA), have made similar comments in responses to the FDA draft guidances on biosimilars released earlier this year.
The November 5, 2012 letter was signed by:
- The American Council on Education (ACE)
- The Association of American Medical Colleges (AAMC)
- The Association of American Universities (AAU)
- The Association of Public and Land-grant Universities (APLU)
- The Association of University Technology Managers (AUTM) and
- The Council on Governmental Relations (COGR).
I recently participated in the American Conference Institute panel discussion “Maximizing Patent Life Cycles,” which was moderated by Pfizer Associate General Counsel Geoffrey Levitt. In case you missed it, “The Pink Sheet” covered the event in its article “FDA Denies Veramyst NCE Exclusivity, Revokes Torisel Exclusivity,” which expands upon several recent decisions from FDA on whether certain types of chemical compounds, known as “stable esters,” are eligible for non-patent exclusivity from FDA.
It also published the article “ANDA Changes May Require Paragraph IV Recertification, New 30-Month Stay,” which includes my comments from the event on the trend in the amending of generic drug applications to adjust to developments in ongoing patent litigation.
Applicants for marketing authorisation for biosimilars in the European Union (“EU”), under certain conditions, will be able in the near future to use batches of reference biological medicinal products sourced from outside the European Economic Area (“EEA”) in pre-clinical and clinical studies that are part of the comparability exercise preceding authorisation of biosimilars. On 28 September 2012, the European Medicines Agency (“EMA”) announced that it has updated its procedural advice document for applicants for marketing authorisation for biosimilars to reflect this change.
As a result, pharmaceutical companies developing biosimilars in multiple jurisdictions both within and outside the EU would be permitted to conduct related comparability studies with batches of the reference medicinal product sourced from outside the EEA without the need to repeat the studies with EU-sourced reference product batches. This would simplify the global development of biosimilars and would avoid the duplication of studies. The requirement that the reference biological medicinal product is authorised to be placed on the market in the EU is, however, maintained. Applications for marketing authorisation in the EU for biosimilars relying on a reference medicinal product which is not authorised in the EU would not be permitted.
The new regime will apply after the adoption of the revised EMA Guideline on similar biological medicinal products (CHMP/437/04) (“EMA Biosimilars Guideline”). The draft of the revised Guideline is expected to be published and released for public consultation in the beginning of 2013. The expected date for the adoption of the revised EMA Biosimilars Guideline is not yet announced. Continue Reading
The biosimilar biological product development (BPD) fee has been set at $195,880 (10% of the full application fee). This is the amount due when a sponsor submits an investigational new drug (IND) application for a biosimilar (or within 5 days of FDA granting a BDP meeting request – whichever occurs first).
When a sponsor is ready to submit a fully-developed biosimilar marketing application, the application fee for FY 2013 is $1,958,800 ($979,400 if the application does not include clinical data).
Notably, President Obama’s budget for FY 2013 projected approximately $20 million to be collected by the federal government in biosimilar user fees. Based on the just-announced user-fee rates, therefore, a maximum of 10 biosimilar marketing applications have been anticipated, and probably somewhat fewer depending on whether (and how many) INDs are anticipated. However, even if we see half that many applications in FY 2013, it will still be enough to trigger a host of novel issues, including the sharing of each application with the corresponding pioneer and the initiation of the biosimilar patent exchange procedures.
FDA published details of the user fees in an August 1, 2012 federal register notice.