FDA’s biosimilar stakeholder submission roundup – Part I

In March 2010, the Biologics Price Competition and Innovation Act of 2009 (BPCIA) became law and established a legal pathway for the approval of biosimilar protein products in the U.S. While the BPCIA provided the overall framework, many of the details of the pathway were not particularized and the FDA was provided with wide discretion in administering the new approval pathway.

In February 2012, the FDA published three biosimilar draft guidance documents for industry. The draft guidance documents provided a 60 day period for stakeholders to provide comments. The FDA opened a docket for the each of the three draft guidance documents, FDA-2011-D-0602 (Quality Considerations), FDA-2011-D-0605 (Scientific Considerations) and FDA-2011-D-0611 (Questions and Answers).

The FDA received 44 public submissions on the Q&A draft guidance document from a wide array of stakeholders. This is the first in a series of posts that will briefly summarize the public submissions received for the Q&A draft guidance document. Copies of the relevant public submissions may be found by clicking on the company’s name, below.

Biotechnology Industry Association (BIO)

Foreign Reference Product

• there is a statutory prohibition against using a foreign licenced reference product to establish biosimilarity
• if bridging data demonstrates that the foreign reference product is fully representative of the U.S. reference product, studies employing foreign reference products may be supportive of biosimilarity
• the use of foreign reference products would not generally be appropriate for “particularly complex biological products”

Trade Secrets / Confidential Information

• FDA must recognize that information of the reference product sponsor that provides the site of manufacturing is confidential
• where manufacturing site information is not publicly disclosed, the FDA cannot use or rely on such information in determining whether it is appropriate for a  biosimilar applicant to use an foreign reference product
• FDA’s Regulations should be amended to make it explicit that upon approval of a 351(a) biologics license application (BLA), only a summary of the safety and efficacy data is releasable to the public
• FDA should establish systems ensuring that the reference product sponsor’s information is not inadvertently disclosed to the biosimilar applicant, including by assuring that the primary reviewer of the 351(a) reference product does not participate in biosimilar product development meetings or a review of a biosimilar application that references the reference product

Pediatric Studies

• children are not “little adults”  biosimilar applicants should study pediatric indications under the Pediatric Research Equity Act

Reference Product Exclusivity

• there is a presumption that a 351(a) BLA is a “first licensure” and the FDA should not require 351(a) BLA applicant to supply an exclusivity justification for a product being licensed for the first time
• FDA should provide exclusivity decisions earlier than upon BLA approval

Patent Certifications

• FDA should require biosimilar applicants to certify compliance with section 351(l)(2) of the Public Health Services Act (PHSA) which requires the biosimilar applicant to timely provide the reference product sponsor with the 351(k) biosimilar application and such other information that describes the process or processes used to manufacture the biosimilar product
• Should a biosimilar applicant seek to opt out of the certification notice provisions by failing to provide the required information, the FDA should adopt a policy that it will refuse to file the biosimilar application

Indication Carve-Outs / Interchangeability

• necessary for biosimilar labels to clearly and prominently identify the differences in labelling between the biosimilar and the reference product
• no interchangeability designation where biosimilar does not contain all reference product indications
• interchangeability: the same efficacy and safety should be shown in clinical trials in each of the indications included in the reference product labelling

Immunogenicity

• biosimilar applications must include one adequate and well controlled trial comparing the immunogenicity profiles of the proposed biosimilar and the US-licensed reference products
• biosimilar applicant should generally be expected to evaluate the immunogenicity in patient populations sensitive to differences in immunogenicity, even if the biosimilar applicant is not seeking licensure for that indication

Extrapolation of Indications

• suggests a cautious approach that may be acceptable where
• the mechanisms and sites of action for both indications are very well understood;
• there are no significant differences between PK and bio-distribution in patient populations; and
• the study in the original indication is highly sensitive to differences in immunogenicity

351(a) vs. 351(k)

• FDA should maintain a distinction between the two pathways and not approve any 351(a) application that explicitly or implicitly seeks to reference an innovator product
• FDA should refuse applications filed under 351(a) that should have been filed under 351(k)

Definition of “protein (except any chemically synthesized polypeptide)”

• definition should be flexible and consider the presence of higher order structure
• definition should not be based on the FDA’s proposed 40 amino acid cut-off

Mylan

Generally

• uses the term “biogeneric” rather than “biosimilar”

Interchangeability

• is the cornerstone of an abbreviated pathway and a critical driver to achieving increases in access and affordability
• FDA should combine its biosimilarity and interchangeability determinations
• FDA should classify any product meeting the “highly similar” standard as interchangeable

Immunogenicity

• assertions that interchangeability will increase immunogenicity reactions in patients are unfounded – no report to this effect for any biosimilar marketed in Europe, Australia, Canada or any other jurisdiction that has approved “highly similar” biological products

“Highly Similar”

• biosimilar products should be treated using the same ICH Q5E comparability principles as applied to modified originator biologics

Foreign Reference Product:

• there is nothing in the law that requires any testing against the U.S. reference product
• FDA should amend the guidelines to eliminate any mandatory testing against a U.S.-licensed reference product

Extrapolation of Indications

• scientific justification for extrapolation should be the exception rather than the norm
• requirements for repetitive studies across multiple indications is inappropriate and the BPCIA imposes no such requirement

Pediatric Studies

• scientifically and ethically inappropriate to mandate pediatric testing of a “highly similar” product

Off-Label Routes of Administration

• no scientific or public policy rationale for conducting additional studies for off-label routes of administration

Labeling

• biogeneric applicant should not be required to include in its label a statement indicating that the product is biosimilar to a reference product and that the product has not been determined to be interchangeable with the reference product

Naming

• deeply concerned that guidance documents did not address naming
• biogenerics must have same USAN/INN name as brand counterparts

Amgen

“Highly Similar”

• FDA should require identity of primary amino acid sequence, notwithstanding minor differences in the extent of N-terminal or C-terminal processing

Immunogenicity

• clinical evaluation of immunogenicity will always be essential
• the effect of anti-drug antibodies should be evaluated in a sufficiently powered preapproval study
• comparative immunogenicity studies should be run at the same time using the same assays
• subjects positive for anti-drug antibodies should be followed for at least one year after the last administration of the biosimilar product

Naming

• requiring biosimilars to bear distinguishable non-proprietary names is an efficient means of facilitating pharmacovigilance

Foreign Reference Product

• urges the FDA to take a highly cautious approach
• appropriate when the foreign-sourced product is fully representative of the US licensed product
• applicant must bear the burden of establishing a scientific basis for relying on comparative data with the foreign reference product and
• the foreign reference product must have the same formulation as the US-licensed product

Clinical Studies

• applicants should be expected to provide comparative PK data, comparative PD data, comparative immunogenicity data, and comparative efficacy and safety data in one or more conditions of use for which the reference product is licensed
• at least one clinical study evaluating safety and efficacy will be needed in every case
• clinical studies should be designed to show equivalent efficacy

Extrapolation of Indications

• clinical data may be extrapolated to support other indications only if the data were sufficient to demonstrate the safety, purity, and potency of the biosimilar in the clinically studied indication

Product Drift

• recommends that the final guidance indicate that there is no statutory requirement to maintain biosimilarity post-approval

Labeling

• should include reference product and biosimilar data, presented on an indication-by-indication basis
• labeling should identify whether the product is a biosimilar and/or is interchangeable with its reference product
• the indications and clinical use section of the biosimilar should not contain any reference to indications that have not been approved or evaluated for approval

Naming / Appearance

• FDA should require biosimilars to bear distinguishable non-proprietary names
• FDA should require biosimilars to have unique, distinctive packaging and presentations

351(a) vs. 351(k)

• FDA should require consistency and parity in what is included in the two types of applications

Interchangeability

• is a higher standard than biosimilarity
• should only be available where the biosimilar applicant seeks approval for all of the reference product indications

Reference Product Exclusivity

• 12 year exclusivity for 351(a) BLA should be presumed – applicant should not have to provide supporting data and information
• decisions on reference product exclusivity should be made much earlier than upon reference product licensure
• any difference in the structure of the product resulting in a change in safety, purity or potency is entitled to its own 12 year exclusivity

Novartis

Generally

• scientific basis behind a determination of “highly similar” should be the same as that which the FDA applies in the comparability exercise for manufacturing changes for already licensed biologic products

Foreign Reference Product

• endorses a scientific stepwise approach for bridging data obtained from a foreign licensed product to the US-licensed product in any analytical characterization, animal or clinical efficacy and safety trials
• foreign sourced reference product should generally be available only from ICH compliant jurisdictions

Extrapolation of Indications

• extrapolation is one of the leading reasons why a sponsor would choose the 351(k) biosimilar pathway
• it is inconceivable that a biosimilar could be shown to be “highly similar” to the reference product, but not share the same mechanism of action

Immunogenicity

• is an issue that all biologic manufacturers must consider – not unique to biosimilars
• biosimilars need to be reviewed and approved to the same consistent standards as their originator reference products
• studies should focus on the potential clinical consequences of anti-drug antibodies
• it should not be assumed that anti-drug antibodies will be induced after long-term exposure to a biosimilar
• no evidence that switching between products confers any additional immunogenicity risk over and above the multiple use of a single product
• it is virtually impossible to power a study solely on the basis of immunogenicity

Biosimilar Development

• FDA’s “consult early and often” policy for biosimilars is undermined by waiting times for FDA meetings, currently approaching six months
• development should be allowed to proceed in parallel and not as a strictly linear process – linear process will delay biosimilar development to the point that the 351(k) pathway will be untenable

Pediatric Studies

• it is scientifically implausible that a “highly similar” product would not produce the same expected clinical outcome in children
• pediatric studies may not be feasible or ethical to conduct and the FDA should clarify whether such studies may be waived

Naming

• recognizes the need for good record-keeping in all circumstances but such systems should not be specific to biosimilar products
• unique INN/USAN naming will not fix otherwise poor record-keeping
• is counterintuitive to impose different INNs on products which have been shown to be “highly similar” and are expected to have the same clinical effect when separate non-comparable products currently share the same INN (c.f. alglucosidase alpha)