FDA issued a draft guidance on March 14, 2016 explaining how the agency proposes to implement the provisions under the Biologics Price Competition and Innovation Act of 2009 (BPCIA) for moving protein products currently approved under the drug statute (section 505 of the Food, Drug and Cosmetic Act) to the biologics system (section 351 of the Public Health Service Act). Essentially, the BPCIA requires that as of March 23, 2020, all new drug applications (NDAs) and abbreviated new drug applications (ANDAs) for protein products will be “deemed to be a license” under section 351 of the Public Health Service Act (PHS Act). The draft guidance is the first time FDA has issued an interpretation of the “deemed to be a license” provision. Continue Reading
In a Federal Register notice, FDA announced its draft guidance, “Nonproprietary Naming of Biological Products,” in which the agency articulates the need “for biological products licensed under the Public Health Service Act (PHS Act) to bear a nonproprietary name that includes an FDA-designated suffix.” Described in an accompanying proposed rule, the Agency proposes that the proper name of all biologics includes a core name and a designated suffix. For originator products, the core name would be the name adopted by the United States Adopted Name (USAN) Council for the drug substance when available. Related, biosimilar or interchangeable products would include the core name of the relevant, previously licensed product and a designated, 4-letter suffix attached by a hyphen.
Essentially, FDA is proposing a unique nonproprietary naming policy for all biologics approved under PHSA 351(a) or 351(k). While ending some speculation on FDA’s policy toward naming of biosimilars, the guidance seeks extensive input from stakeholders regarding the application of a four-letter suffix to distinguish all biologics and biosimilars from one another and whether interchangeable biologics should similarly have unique suffixes or share the same four-letter suffix. FDA summarized its intention with this policy:
“By differentiating biological products from one another that have not been determined by the FDA to be interchangeable, this naming convention is intended to help minimize inadvertent substitution. Inadvertent substitution may lead to unintended alternating or switching of biological products that have not been determined by FDA to be interchangeable. A naming convention that differentiates among biological products also could help facilitate pharmacovigilance for all biological products. By applying this naming convention to all biological products, this approach is intended to: (1) Encourage routine use of designated suffixes in ordering, prescribing, dispensing, and recordkeeping practices and (2) avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathways.”
In the accompanying proposed rule, FDA provides additional details on its proposed naming policy and the application of this policy to six products. Each of the six products is either a reference product for an approved or publicly disclosed biosimilar product application or a biological product that is either biosimilar to or related to one of these reference products.
Comments on the guidance, which has been assigned Docket No. FDA-2013-D-1543, are open through October 27, 2015. (Although, per FDA regulation, comments on a guidance may be received at any time.) Comments on the proposed rule, including the assignment of proper names, should be sent to Docket No. FDA-2015-N-0648, which is open through November 12, 2015.
In a citizen petition, AbbVie has challenged the Food and Drug Administration’s (FDA’s) approach to biosimilar labeling, as implemented in the agency’s recent approval for Zarxio (filgrastim-sndz) as a biosimilar to Neupoen (filgrastim). As we previously blogged, the prescribing information FDA approved for Zarxio seems to follow a “generic drug” model; the Zarxio labeling is essentially the same as Neupogen’s, except for details regarding the administration of the product, which differ. The labeling contains none of the substantial clinical or preclinical data submitted in the Zarxio application (see here), and which FDA presumably relied on in finding the product to be biosimilar and safe and effective; only Neupogen data are found in the Zarxio labeling.
The AbbVie petition requests that FDA require that the approved prescription drug labeling for biological products licensed under section 351(k) of the PHSA contain:
- A clear statement that the product is a biosimilar, that the biosimilar is licensed for fewer than all the reference product’s conditions of use (if applicable), and that the biosimilar’s licensed conditions of use were based on extrapolation (if applicable);
- A clear statement that FDA has not determined that the biosimilar product is interchangeable with the reference product (if applicable); and
- A concise description of the pertinent data developed to support licensure of the biosimilar, along with information adequate to enable prescribers to distinguish data derived from studies of the biosimilar from data derived from studies of the reference product.
There is an open docket, FDA-2015-P-2000, while FDA considers the petition submitted June 2, 2015.
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.
- Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product. Final 4/28/15.
- Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. Final 4/28/15.
- Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. Draft 5/12/15.
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.