Five years after enactment of the BPCIA and following its first biosimilar approval, the U.S. Food and Drug Administration finalized its initial guidances describing the scientific and regulatory expectations for biosimilar approval under the 351(k) pathway.
A list of current versions of all biosimilars guidances is readily accessible on FDA’s web site.
Last month, the Food and Drug Administration (FDA) approved the first U.S. biosimilar, Zarxio (filgrastim-sndz). Since the positive vote of FDA’s Oncologic’s Drugs Advisory Committee at its January meeting, approval of Sandoz’s biosimilar to Amgen’s Neupogen for all 5 Neupogen indications was anticipated. This landmark event comes almost exactly 5 years after passage of the Biologics Price Competition and Innovation Act and demonstrates that the pathway created by Congress can be used to get biosimilars to the U.S. market and to patients with FDA’s full confidence in the underlying science for the safety and efficacy of biosimilars.
However, the Zarxio approval leaves key FDA regulatory questions about the pathway unanswered.
- Although Zarxio was approved with the non-proprietary name, filgrastim-sndz, FDA was quick to point out this was a “placeholder” name and that the agency has not yet decided on its policy for naming of biologics and biosimilars, though it plans to issue guidance “in the near future.”
- Contrary to FDA’s own draft biosimilars guidance, there is no statement in the Zarxio labeling that identifies the product as a biosimilar , a biosimilar to Neupogen or not interchangeable with Neupogen. Further, Zarxio’s labeling follows a “generic drug” model; the labeling includes ONLY data derived from studies with Neupogen and NONE of the data generated with Zarxio in support of its approval. Because FDA has not yet issued detailed labeling guidance any policy reasons behind the Zarxio labeling have not been articulated.
- Extrapolation of indications. FDA had earlier suggested that extrapolation could be acceptable; the Zarxio approval provides the sense that the “scientific justification” for extrapolation requires a relatively low threshold when there is a common molecular mechanism of action even across different disease states. Sandoz provided clinical non-inferiority data to Neupogen in treatment of neutropenia in breast cancer patients receiving chemotherapy; Zarxio was approved for 4 indications related to neutropenia and one indication related to mobilization of cd34 cells. In the ODAC meeting materials, FDA discussed the common mechanism of action at the cellular level.
- Reference product. FDA appears flexible in its use of a non-U.S. reference product with the appropriate “scientific bridge” between the three products—biosimilar, U.S. reference product and non-U.S. reference product. The bulk of the non-clinical and clinical data were generated in comparison to the European version of Neupogen; only 2 of the 12 referenced studies compared Zarxio to the U.S.-approved Neupogen.
- Sandoz did not request an interchangeability designation for Zarxio, and so this first biosimilar does not provide any additional insight on expectations for interchangeability of biologics and biosimilars.
Interestingly, the Center for Medicare and Medicaid Services appeared to have been ready for the event, issuing three policy statements on reimbursement for biosimilars on the heels of the approval. Although not the final word on biosimilar reimbursement, these releases on Medicaid, Medicare Part B and Part D establish the initial CMS policies.
The Dutch Medicines Evaluation Board (MEB) published a new position on biosimilars, in which it accepts substitution or interchangeability of biosimilars under certain conditions.
The MEB’s revised position on biosimilars was published on 31 March 2015 and replaces its previous position of 2010. The 2010 position provided that patients should be kept at the same biological medicinal product if the patient responded well to such biological medicinal product. The MEB now considers that substitution of one biological medicinal product for the other – both for originator biological and biosimilar medicinal products – is possible, provided that the substitution is adequately clinically monitored and that the patient is well informed.
This results in the following new position of the MEB:
- New patients can be prescribed with a biosimilar medicinal product without further ado.
- Uncontrolled substitution between biological medicinal products – irrespective of whether it concerns an originator biological medicinal product or a biosimilar – should be avoided. This means that a patient should be informed about the substitution and that substitution should be adequately clinically monitored.
- The patient file of a patient that is treated with a biological medicinal product should contain information regarding the biological medicinal product, including the batch number of such product in order to ensure that the product can be traced if problems should occur.
The MEB further informs that it is necessary that both the treating physician and the pharmacist are involved when one biological medicinal product is substituted for another in order to ensure that such decision is taken with due care. The MEB stresses that collaboration regarding pharmacovigilance is essential in this respect.
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).