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.

New element: clarification that the EMA assessment does not cover the interchangeability between the biosimilar and the reference medicinal product
One new element introduced in the draft revision of the Biosimilars Guideline is a reference to interchangeability between the biosimilar and its reference medicinal product. The draft revision states that the assessment of an application for marketing authorisation for a biosimilar conducted by the EMA does not include recommendations on whether a biosimilar should be used interchangeably with its reference medicinal product. This statement is not surprising as the EMA has no power to make such a determination as this is governed by the national laws of the EU Member States.

New element: use of comparator medicinal products that are not authorised in the EEA in certain studies
The requirement that the reference product for the biosimilar must be authorised in the European Economic Area (“EEA”) set out in the current version of the Biosimilar Guidelines is repeated in the draft revision. However, a new element is also introduced.

The draft revision provides that applicants for marketing authorisation for biosimilars may conduct “certain clinical studies and in vivo non-clinical studies” with a comparator medicinal product that is not authorised in the EEA.

The introduction of the possibility for applicants to use data generated in studies with comparator medicinal products that are not authorised in the EEA is intended to facilitate the global development of biosimilars and to avoid unnecessary repetition of clinical trials. This possibility is subject to a number of conditions:

• the comparator medicinal product that is not authorised in the EEA should be a version of the reference medicinal product authorised in the EEA. The term “version” is not defined in the draft revision of the Biosimilars Guideline; and
• the comparator medicinal product should be authorised by a regulatory authority on the basis of scientific and regulatory standards that are similar to the standards used by the EMA for the assessment of applications for marketing authorisation of biological medicinal products. The draft revision of the Biosimilars Guideline does not, however, define what the term “scientific and regulatory standards” means; and
• the applicant must establish that the comparator medicinal product is representative of the reference medicinal product. The draft revision of the Biosimilars Guideline does not include a definition of the term “representative” or a discussion concerning the criteria for the demonstration that the comparator medicinal product is representative of the reference medicinal product; and
• the applicant should provide data that scientifically justifies the relevance of the data generated in the studies conducted with the comparator medicinal product;
• the applicant should provide bridging data linking the comparator medicinal product, the reference medicinal product and the biosimilar.

The draft revision of the Biosimilars Guideline also provides that the acceptability of the data generated in studies conducted with a comparator medicinal product that is not authorised in the EEA would be assessed by the EMA on case-by-case basis as part of the assessment of the application for marketing authorisation for the biosimilar.

Next steps:
The public consultation concerning the proposed revision of the Biosimilars Guideline is open until 31 October 2013. After the end of the public consultation the EMA will discuss the feedback and will prepare the final draft of the revised Biosimilars Guideline.

Once adopted, this final draft will replace the current Biosimilars Guideline, which was adopted in October 2005.

“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).

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.

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.

What is the practical impact of this update?

In practice, this means that applicants for marketing authorisation for biosimilars in the EU could demonstrate the comparability of their biosimilars with reference biological medicinal products through pre-clinical and clinical studies using batches of the reference medicinal products manufactured and released outside the EEA. The EEA includes the EU Member States, Norway, Lichtenstein and Iceland. As a result, the batches of the reference medicinal product could be manufactured and released by a manufacturer other than the manufacturer referenced in the marketing authorisation for the reference medicinal product in the EU.

This is a departure from the current position of the EMA reflected in the EMA Biosimilars Guideline. The Guideline provides that it is mandatory that the batches of the reference medicinal product used in the comparability exercise for the biosimilar are sourced within the EEA.

The change in the EMA’s position reflects the intention of the European Commission to accept the use of batches of reference medicinal products sourced from outside the EEA in the comparability exercise conducted for the purposes of applications for marketing authorisation for biosimilars. The aim is to facilitate the global development of biosimilars and to avoid unnecessary repetition of clinical trials.

Conditions for the use of batches of reference medicinal products sourced from outside the EEA

The use of batches of reference medicinal products sourced from outside the EEA would, however, be subject to certain conditions. The applicant for marketing authorisation for a biosimilar will be required to provide an extensive analytical comparison in order to establish that the reference product batches sourced from outside the EEA are representative of the reference medicinal product authorised in the EEA. The suitability of the reference product batches sourced from outside the EEA will be ascertained on case-by-case basis by the EMA. The applicant for a marketing authorisation for a biosimilar may be required to provide comparative pharmacokinetic and pharmacodynamics data.

Moreover, the exclusive use of reference medicinal product batches sourced from outside the EEA should also be justified. The justification should be based on a comparability data for the biosimilar, the reference medicinal product manufactured in the EEA and the reference medicinal product sourced from outside the EEA.

Next steps

As a next step, the European Commission, the EMA’s Committee for Medicinal Products for Human Use (“CHMP”) and the CHMP Working Parties will discuss and establish the comparability data requirements and the conditions under which the use of batches of reference medicinal products sourced from outside the EEA would be permitted. This process will also involve a close cooperation with the United States Food and Drug Administration (“FDA”) in relation to the acceptance of batches of reference medicinal products sourced from the US.

Once established, the new conditions and requirements applicable to the use of batches of reference medicinal product sourced from outside the EEA will be reflected in the revisions of the EMA Biosimilars Guideline. As discussed above, the draft version of the revised Guideline will be released for public consultation in early 2013.

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.

Below is a summary of certain key provisions pertaining to innovator and, where specified, generic drugs and biosimilar biological products.

Review timeline changes: Title I, “Fees Related to Drugs,” contains the biggest changes sponsors will see in review timelines for New Drug Applications (NDAs) for New Molecular Entities (NMEs) and original Biologic License Applications (BLAs). FDA will get an additional 60 days for the review of these applications, whether the application is a priority application (six month review clock starting 60 days after receipt of the application) or a standard application (10 month review clock starting 60 days after receipt of the application). However, while the review cycle will be longer for these applicants, they will have additional opportunities to interact with FDA throughout the development and review process. The goal for the additional review time and increase in communications is to reduce the number of review cycles necessary to get to approval. Whether this will be of real benefit to the industry will unfold in the coming years, but the proof will be a reduction in total time from the first submission of the application to approval. Keep a close eye on a rise in the number of first cycle approvals to see if this bargain is showing benefits to the industry.

Generic drug user fees: Title III, the “Generic Drug User Fee Amendments of 2012” (GDUFA), establishes filing fees for Abbreviated New Drug Applications (ANDAs) and ANDA prior approval supplements, as well as: a one-time backlog fee for ANDAs pending on October 1, 2012 that have not received tentative approval; a one-time fee on owners of certain drug master files; and annual fees for facilities that manufacture generic drugs and active pharmaceutical ingredients (API) for generic drugs. The goal of the fee is to generate a total of US$299 million annually to be dedicated to human generic drug activities. Failure to pay the fees will subject the violators to various penalties, including some penalties that could affect third parties. For example, if the owner of a facility that makes even just one generic drug fails to pay the annual fee, all drugs and API manufactured in that facility, or containing an ingredient manufactured in that facility, shall be deemed misbranded. That penalty appears to apply to branded pharmaceuticals as well as all generics manufactured there. The law sunsets on October 1, 2017.

Biosimilar user fees: Title IV, the “Biosimilar User Fee Act of 2012” (BUFA), adopts the format and structure for prescription drug user fees to a large extent. Like PDUFA, it includes application, establishment, and product fees; virtually identical exclusions from the definition of biosimilar biological product application (such as in vitro biological products); and a waiver from the application fee for small businesses’ first application. A significant difference is that it also includes development program fees that apply to investigational biosimilars. The fees include an initial fee that is due either five days after the Secretary grants a request for a biosimilar development meeting or upon submission of an investigational new drug application (IND), whichever is earlier. In addition, an annual fee will be assessed for each year following the initial fee. Although there are generally no refunds, waivers, exemptions, or reductions for the development program fees, a sponsor who pays those fees prior to October 1, 2017 but submits a biosimilar biological product application for the product after that date is entitled to reduce its biosimilar biological product application fees by the cumulative amount of the development program fees it paid. These BUFA provisions sunset on October 1, 2017.

Pediatric drugs and devices: Title V, “Pediatric Drugs and Devices,” makes permanent the Best Pharmaceutical for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). BPCA provides an additional six months of patent exclusivity as an incentive for manufacturers to test on-patent drugs for pediatric use. PREA grants FDA authority to require studies in children concerning certain medical products and under other specific circumstances. Until now, BPCA and PREA have been subject to reauthorization every five years as part of the PDUFA process.

Drug supply chain: Title VII, “Drug Supply Chain,” pertains to the drug supply chain and expands information and registration requirements around the manufacture, preparation, compounding, inspection, and importation of drugs from facilities. The drug supply chain provisions do not cover the concepts supported by some in Congress and several industries involved in the supply chain process. Those provisions were intended to create a uniform national standard to govern product traceability and pre-empt state law requirements. We understand that work on this issue continues, but prospects for the passage of drug supply chain provisions during this Congress remain unclear.

Antibiotic incentives: Title VIII, “Generating Antibiotic Incentives Now,” provides a battery of incentives to encourage companies to develop new antibacterial and antifungal drugs intended to treat serious and life-threatening infections, such as methicillin-resistant Staphylococcus aureus (MRSA). The incentives include: five-year extensions of exclusivity otherwise available to new drugs under the Hatch-Waxman and Orphan Drug Acts; Priority Review; Fast Track status; and the ability to request and receive written recommendations from FDA on the nonclinical and clinical investigations necessary for approval. The Secretary must adopt final regulations implementing Title VIII within two years, but in the interim must grant designations to drugs that qualify. Stakeholders should take advantage of the opportunity to comment on rulemaking to seek clarification of certain possible ambiguities. These include: whether a qualified infectious disease product may receive five-year extensions for more than one category of exclusivity; how FDA should interpret the exclusion of a “subsequent application filed with respect to a product” (including whether combination products containing a previously approved drug are excluded); and whether drugs intended to prevent, detect or identify qualifying pathogens qualify for the incentives, or whether only those that treat infections qualify.

Breakthrough therapies: Title IX, “Drug Approval and Patient Access,” provides for facilitated development and review of drugs designated as “breakthrough therapies.” The sponsor of a drug may request a breakthrough therapy designation from Secretary of HHS at the time of the submission of an application for the investigation of the drug under section 505(i) or section 351(a)(3) of the Public Health Service Act. To achieve the designation, a drug must be intended to treat a serious or life-threatening disease or condition, and preliminary clinical evidence must indicate that it may demonstrate substantial improvement over existing therapies. Drugs with breakthrough therapy designations are eligible for additional FDA interaction and guidance throughout the development process. Title IX also creates a demonstration project that provides priority review vouchers to companies that develop a drug for a pediatric rare disease. The voucher can be redeemed by the company for a subsequent application or transferred to another company.

Drug shortages: Title X, “Drug Shortages,” provides for the collection and reporting of information related to drug shortages. It does not include other provisions that were discussed in connection with drug shortages such as penalties or changes in Medicare drug reimbursement in response to shortage situations. Congress will almost certainly continue to consider and debate this issue post-FDASIA.

Hydrocodone: During floor debate of FDASIA, the Senate approved an amendment offered by Senator Manchin (D-WV) that would change the classification of hydrocodone-containing pain relief products from Schedule III to the more-restrictive Schedule II under the Controlled Substances Act. The provision was removed from FDASIA during conference. Title XI, “Other Provisions,” requires FDA to hold a public meeting on the scheduling of hydrocodone.

REMS: While the change to the FDA’s authority over Risk Evaluation and Mitigation Strategies (REMS) in Title XI, “Other Provisions,” makes no real substantive changes to the agency’s authority to require a REMS, it does allow FDA to designate certain minor modifications to a REMS that can be made through a less burdensome administrative process.

While the merits of the Biologics and Price Competition Act were not in play during the Supreme Court’s evaluation of the constitutionality of PPACA, few changes to the approval and regulations of medicines in this country have had the potential for such a large effect on what medicines will be available to patients.  Prior to enactment, there was no abbreviated pathway for approval of biologic medicines under the Public Health Service Act. BPCIA, buried within PPACA, created that pathway in the U.S.

With Thursday’s (June 28, 2012) Supreme Court decision, any remaining legal debris has been cleared from the path and it looks like biosimilars in the U.S. will march ahead.

Neal Katyal, former Acting Solicitor General of the United States and Appellate practice Co-Director, Cate Stetson, Co-Director of our Appellate practice; and Chris Handman, a seasoned Appellate partner, will conduct a 30-minute webcast on the ramifications of decisions handed down by the high court this term, which may include the Affordable Care Act, and how the three key cases challenging aspects of President Obama’s healthcare plan will be resolved.  As previously posted, the outcome of the decisions on the Affordable Care Act could have direct implications for the U. S. biosimilars pathway.

The half-hour program, which begins at 1 p.m. on June 26, will also provide essential background on the Supreme Court, including the composition, recent personnel changes, and background on the Justices, and explain the impact of these structures on the decisions.

Register online for the free webcast.

Stakeholders lined up for their turns at the podium at the Public Hearing held on May 11, 2012.  To be sure, there were the predictable disagreements among stakeholders on issues such as naming and interchangeability, in addition to the now-familiar (and sometimes conflicting) views on the need to protect patient safety, encourage product innovation, and create meaningful cost-savings.  However, the strong consensus that FDA should implement an education and communication plan about biosimilars was noteworthy.  For example, a speaker from the American Pharmacists Association said pharmacists don’t know what to expect or do when they start seeing prescriptions for biosimilar products. Patient advocates and physician groups also said their constituents will need additional educational materials and are interested in interactive presentations from FDA on the appropriate use of these new products. 

It’s not clear what steps FDA will take to articulate clear policy and provide guidance in these areas.  At the hearing, however, the agency asked speakers for details and supporting data, and encouraged everyone to submit these and other concrete suggestions on implementation to the docket (FDA-2011-D-0618), which is open until May 25^th.

The Supreme Court recently concluded three days of oral argument challenging the constitutionality of several provisions of PPACA. There was general agreement amongst the petitioners, defendants and the Justices that the biosimilars provisions are “peripheral” to the challenges under review by the Court.  Nevertheless, it remains possible that if the Court decides any one provision (such as the so-called “individual mandate”) is unconstitutional, rather than parsing out the constitutional bits, even those recognized to be peripheral to the provisions at issue, the Court could strike down the entire Act to let Congress sort it out.  So even though “the biosimilar thing,” as described by Justice Breyer, would seem to stand on its own without the other parts of the Act, the BPCIA could be swept into a sweeping decision that would invalidate the biosimilars pathway along with the rest of the Act.

The BPCIA was the result of significant bipartisan effort and support in both the House and Senate.  FDA reports (PDF) at least 35 requests for biosimilar pre-IND meetings as of February 15 and is holding a public meeting on the three issued draft biosimilar guidances in May.  If the Supreme Court throws out the BPCIA with the bath water, it is reasonable to expect that the law would be re-enacted as a stand-alone.  However, as we head into the presidential election season, the ability or will of Congress to enact any laws may come to a halt.  There is little profit here in speculation, but in terms of setting expectations, it is possible that the BPCIA would come off the books temporarily, leaving many interesting questions about the legal significance of the gap period if the law were re-enacted in, say, early 2013.