Biosimilar Guidance Comments Reveal Small Window Of Agreement On Foreign Data

In comments on FDA’s three biosimilar draft guidances, PhRMA and BIO seek a more limited role in biosimilar approval decisions for clinical data involving foreign reference products than does GPhA, but all the trade associations believe that the foreign product needs to be made by the same company in the same facility as the U.S.-licensed reference product.

Use of foreign comparator data to demonstrate biosimilarity should only be allowed if the foreign product is made by the same company and/or in the same facility as the U.S.-licensed reference product, the three major pharmaceutical and biotechnology trade groups say in comments on FDA’s biosimilar draft guidances.

The source of foreign reference products seems to be a rare area of agreement among the innovator industry groups – the Pharmaceutical Research and Manufacturers of America and Biotechnology Industry Organization – and the Generic Pharmaceutical Association in their views on three recently released draft guidances.

PhRMA and BIO seek a more limited role for foreign comparator data than does GPhA.

Not unexpectedly, PhRMA and BIO seek more stringent limits on use of foreign comparator data than does GPhA. The divide between the innovator and generic sectors also can be seen in the groups’ views about the amount of clinical data needed to support a biosimilar’s approval and the extent to which such data can be extrapolated across indications.

Caution Urged On Foreign Comparator Data

In February, FDA released three draft guidances on the development and approval of biosimilars under the Section 351(k) pathway created by the Biologics Price Competition and Innovation Act. The guidances addressed scientific considerations, quality considerations and general questions (Also see "FDA Biosimilars Guidances Address Immunogenicity Studies, European Bridge Data, Analytics" - Pink Sheet, 13 Feb, 2012.). The comment deadline for the guidances was April 16; FDA will hold a public meeting May 11 to gather further input.

At the time the guidances were released, representatives of the branded and generic drug industries offered generally positive reviews (Also see "FDA’s Biosimilar Guidances Win Praise For High Hurdles, Flexibility" - Pink Sheet, 13 Feb, 2012.). However, as stakeholders had time to sort through the documents, it became clear that some provisions would be considered controversial (Also see "Biosimilars With Foreign Comparator Data Could Open FDA To Criticism" - Pink Sheet, 2 Apr, 2012.).

Among these potentially controversial areas was FDA’s willingness to consider comparative animal or clinical data referencing a product approved outside the U.S., albeit with the requirement that a biosimilar sponsor provide adequate bridging data to the U.S.-licensed product. The provisions reflected the agency’s desire to leverage data generated from global development programs (Also see "Biosimilar User Fee Agreement Allows For Reliance On Foreign Clinical Data, FDAer Says" - Pink Sheet, 14 Dec, 2011.).

However, PhRMA and BIO point to concerns about the potential extent of use and importance placed on data involving foreign comparator products.

Foreign comparator data should play, at most, only a supportive or corroborating role in a biosimilar’s approval, the innovator groups said.

In PhRMA’s comments, the group said a foreign-approved version of a U.S.-licensed biological product, no matter how similar, is not likely to comply with all aspects of the corresponding FDA approval with regard to manufacturing location, formulation, source and specifications of active ingredients, processing methods, manufacturing controls, container/closer systems and appearance.

The group wants the final guidance to clearly state that foreign comparator data may be used only to corroborate the pivotal data comparing the biosimilar to the U.S. reference product. The guidance should recommend that the foreign product have the same drug substance, dose, dosage form and route of administration as the U.S. reference product, and that it be produced by the same company that manufactures the U.S. reference product, in the same plant and using the same cell line, PhRMA said.

“Although a bridging exercise (three-arm study comparing the proposed biosimilar, statutory reference product and foreign product) might close some of the gaps, PhRMA believes that given the strong likelihood of product drifts and FDA’s lack of access to the foreign product application, use of a foreign product that was not identical as just described would present an unwarranted risk to patients.”

BIO’s comments also take the position that foreign comparator data may only be used to support an application when both the foreign and U.S. reference product are released by the same license holder/manufacturer. Furthermore, use of foreign comparator data generally would not be appropriate “for particularly complex biological products,” BIO said.

The biotech group requested additional clarity from FDA on the types of bridging studies that would be needed to support approval. “FDA should address scenarios where comparator data and bridging studies would not be sufficient to support licensure of a biosimilar, or where additional bridging information would presumptively be required, e.g., where the non-U.S. comparator product has a different strength, dosage form or route of administration.”

Sponsors of biosimilar products approved in the EU should be able access the U.S. market without having to repeat “extremely expensive clinical studies for purely confirmatory study results,” GPhA said.

The foreign comparator provisions drew more positive reviews from GPhA, which said sponsors of biosimilar products approved in the EU should be able access the U.S. market without having to repeat “extremely expensive clinical studies for purely confirmatory study results.”

GPHA said it supports use of data generated in head-to-head studies with foreign comparator products as long as it is scientifically justified.

“Public information that a single facility produces the product, and appropriate characterization data confirming the match, should suffice for bridging studies with the foreign-sourced reference product to a U.S. biosimilar application,” GPhA’s comments state. “Three-arm clinical trials of EU reference, U.S. reference and a potential biosimilar are clearly scientifically unnecessary and therefore clinically inappropriate, and inevitably unethical.”

GPhA Wary Of FDA Heavy-Handedness On Clinical Data

The generic and innovator industry groups also differ on the role of clinical trials envisioned in FDA’s draft guidances.

FDA currently expects that a biosimilar sponsor will have to submit at least one clinical study comparing the immunogenicity of its product with that of the reference biologic, and that a clinical study will be required to support an interchangeability determination.

GPhA believes FDA should only require clinical trials “if and when the totality of the other evidence is insufficient to establish that the proposed biological product is highly similar to the reference product.”

The group points out that when a BLA holder makes a manufacturing change to a currently approved biologic using comparability protocols, animal and clinical studies frequently are avoided. Similar regulatory tools should be available for biosimilar applicants, GPhA said, arguing for “regulatory consistency” in the treatment of biosimilars and novel biologics – a theme that runs throughout the group’s comments.

FDA may not need to require clinical immunogenicity studies because it can be argued that an immunological response with a biosimilar is no more likely, and may be less likely, than with the reference product, GPhA asserted.

“Given the progress made over the last few decades with biomanufacturing there is a likelihood that biosimilars can be made more consistently and with higher purity than was possible for their originator counterparts, but the concern is that they show no greater immunogenicity – not that they show less immunogenicity,” GPhA said. “That this will be possible through analytics and the demonstration of ‘high similarity,’ plus the lack of feasibility (ethically, through patient availability, and economically) of the massive clinical studies, will be important to recognize and discuss amongst all stakeholders.”

BIO said the guidances suggest clinical data are a “residual requirement,” rather than a key element needed for approval.

In contrast, BIO believes clinical studies get short shrift in the guidance.

“As written, it appears as though the requirements for clinical data are a ‘residual requirement,’ and triggered only if there are gaps or insufficiencies in the analytical, pharmacokinetic/pharmacodynamic (PK/PD) data, and safety package,” BIO said. “In contrast, the statute is set up such that clinical trials are required, and it takes an affirmative finding by the FDA in order to determine they are not necessary.”

The guidance leaves open the possibility of establishing biosimilarity based on human PK/PD and immunogenicity data. However, such data may be inadequate to predict clinical safety and efficacy, BIO said. “We believe that, in general, clinical trials evaluating safety and effectiveness will be necessary, and equivalent efficacy between the biosimilar and the reference product likely will need to be demonstrated in a minimum of one adequately powered, randomized, and controlled confirmatory trial.”

Similarly, PhRMA believes the final guidance should recommend that a biosimilar sponsor conduct at least one comparative, equivalence design clinical trial, as well as clinical immunogenicity testing, for approval. “Moreover, in the absence of strong scientific justification, clinical data would be necessary to support each indication for which the biosimilar seeks approval.”

Limits Sought On Extrapolating Across Indications

Guidance provisions allowing extrapolation of clinical data from one indication to support licensure in another also raise concerns with BIO and PhRMA.

Both groups said more emphasis should be placed on first ensuring that the mechanisms of action for both indications are well understood and identical before allowing extrapolation across indications. FDA’s draft guidance lists mechanism of action as one of several considerations to be addressed in demonstrating scientific justification to support extrapolation.

BIO also believes that extrapolation may be acceptable only if there are no significant differences between the PK and bio-distribution of the product in the indication and patient populations studied clinically and for the new use. The studies in the original indication also should be highly sensitive to potential differences that might emerge in the new indication.

PhRMA distinguishes between extrapolating from one population to another within the same, or closely related, indication and extrapolating across completely different indications. “We urge caution in permitting extrapolation with respect to either efficacy or safety (particularly immunogenicity) in the latter case – because of potential differences in pathophysiology and in (tissue) site of action, as well as potential differences in comorbidities and concurrent therapies in the patient population.” Biosimilar labeling should reflect when indications are based on extrapolation as opposed to original clinical data, the group said.

GPhA believes FDA should be lenient in allowing extrapolation across indications without a showing that the mechanisms of action are the same.

“With appropriate scientific data developed in a stepwise manner, an applicant should able to show … that the product is a highly similar, interchangeable biologic,” GPhA said. “That such extrapolation is appropriate without clinical studies is well established through the nearly two decades of use of the ‘highly similar’ analytic standard in support of manufacturing changes, where [mechanism of action] has never been an issue, including on the very same products that will be the reference products for biosimilars.”

Interchangeability …

GPhA believes FDA is taking an overly conservative approach to interchangeability.

FDA said it can make a determination of interchangeability in either an original biosimilar application or supplement. Currently, however, it would be difficult as a scientific matter for an applicant to establish interchangeability in an original application given the statutory standard for interchangeability and the sequential nature of the assessment, the guidance states.

“One reservation that we want to express is about the FDA’s suggestion that interchangeability is difficult, and the agency’s tendency to talk about higher standards for interchangeability,” GPhA said. “Any agency suggestion of a ‘higher standard’ for interchangeability will be misconstrued and misinterpreted to mean that any other biological product without such a formal designation is made to a ‘lower standard.’” GPHA said sponsors should have the option of an interchangeability designation at the time of initial approval.

… And Intentional Changes

PhRMA and BIO said intentional changes in the primary structure or formulation of a biosimilar, compared to that of a reference product, should not be permitted if reasonably avoidable because they increase the risk of undetected, clinically significant differences between a proposed biosimilar and the reference product.

While focusing on the scientific and clinical implications of such changes, the groups’ argument also could reflect intellectual property concerns, as biosimilar sponsors may seek to design around certain patented elements in the reference products.

The groups’ comments also addressed several issues that were not discussed in the three guidances (see sidebar).

In addition to substantive differences with GPhA’s comments, BIO and PhRMA’s comments also had considerable tonal departures from the generic association. While GPhA largely stuck to general principles for FDA to consider, BIO and PhRMA also offered line-by-line critiques of many parts of the guidances. Indeed, while GPhA submitted one comment to the main docket, there were threeseparatecomments from PhRMA and threefromBIO submitted to each of the three dockets FDA opened for the draft guidances.