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FDA Readies New Guidance and User Fee Program for Biosimilars

Biotechnology Healthcare...Summer 2012

     Hospira, Inc. started Phase III clinical trials for generic erythropoietin (EPO) in late 2011. When the Lake Forest, Ill. company submits an application to the Food and Drug Administration (FDA) for its biosimilar EPO--and that won't be until at least 2015--it could be the first U.S. company to take advantage of the new expedited approval pathway for biosimilars established by the Biologics Price Competition and Innovation Act of 2009 (BPCIA), which was an amendment to the health care reform bill called the Affordable Care Act. Hospira's generic EPO would be an alternative to Amgen's Epogen®. 

      But with the FDA set to issue final guidance on requirements for what are called 351(k) expedited biosimilar applications and inaugurate a new biosimilars user fee program to help pay for examination of those applications, there will be a number of entrants in the race to be the first biopharma company into the 351(k) pipeline. Momenta Pharmaceuticals signed a collaborative agreement last December with Baxter Healthcare with the intention of developing biosimilar and potentially interchangeable biologic products.  James Roach, M.D., Chief Medical Officer, Momenta, says the draft FDA guidelines published in February allow for the possibility the FDA could approve a biosimilar without the company necessarily having to go through time-consuming, costly clinical trials, as Hospira is doing. Those draft guidelines will be finalized, possibly with alterations, probably by summer 2012. "However, we understand the burden will be on the sponsor to provide a data package that scientifically justifies  a reduction in requirements for preclinical or clinical studies," Roach adds. "And we think that bar should be high for achieving biosimilarity at one level and interchangeability at another level."

          "Interchangeability" is a higher designation than "biosimilarity" and would allow a pharmacist to substitute a biosimilar for the brand-name reference drug prescribed by the physician without the physician's prior approval. Health insurers and employers particularly are anxious for the FDA to set the interchangeability bar as low as possible, so that their prescription drug costs are reduced to the maximum extent possible.

     Roach hopes to obtain reduced FDA testing requirements for biosimilars, including interchangeable products. He believes the approach the company took to develop a generic version of enoxaparin (Lovenox), a low molecular weight heparin the company developed with Sandoz, conceptually applies to biosimilars. While Lovenox is not technically a biosimilar, it is a complex drug derived from pig intestines. Biosimilars are derived from cell cultures and other living organisms. "We did a small, normal volunteer study for enoxaparin but in accordance with generic drug requirements were not required to perform clinical trials to independently establish safety and efficacy," Roach states.

     Avoiding a full complement of clinical studies might lead not only to earlier product entry, but also to lower cost entry for the developer. Hospira's U.S. clinical trials for biosmilar EPO will cost in the neighborhood of $100 million - $200 million, according to Sumant Ramachandra, Senior Vice President, Research & Development and Medical Affairs, and Chief Scientific Officer, Hospira.
     Once it opens the door to 351(k) applications, the FDA will have to walk a fine line between imposing onerous testing requirements and speeding approval of biosimilars which will save consumers and payors, federal and private, billions of dollars a year. Roach estimates that generic enoxaparin--again, technically not a biosimilar--has saved health insurers, employers and consumers somewhere between $750 million to $1 billion since it was introduced.  The Pharmaceutical Care Management Association commissioned a 2007 report that projected Medicare Part B savings from biosimilars at $3 billion by FY2016.
       Those savings are already being felt in Europe where the European Medicines Agency has approved a number of big-molecule biosimilars such as  Hospira's Retacrit  and Nivestim, a biosimilar version of filgrastim. Sandoz is selling two biosimilars in Europe, its anemia medicine Binocrit® (epoetin alfa) and oncology medicine Zarzio® (filgrastim). They are generally priced 15-30 percent below the reference drug. But "take up" has been slow because of the lack of interchangeability designations.
       However, U.S. companies generally have been hesitant to jump into the FDA biosimilar pipeline without some formal clarification of what the FDA will expect to see data-wise in applications. In order to avail themselves of this new section 351 (k) of the Public Health Service Act,  companies have to show that their biosimilar "is highly similar to the reference product notwithstanding minor differences in clinically inactive components'' and that "there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.''
     Companies such as Hospira and Momenta have generally applauded the FDA draft 351(k) guidelines issued in February. "The guidance is pretty solid, although we have caveats," states Hospira's Ramachandra. "When you read draft guidance it is very broad. It gives the FDA to adjudicate. We believe in that approach. It is hard to legislate or regulate this type of field when tools still being built it."
      The most controversial and important issue surrounding the draft (and final) guidance is the FDA's "take" on interchangeability. The FDA says in the draft that companies can apply for an interchangeability designation. However, it goes on to say that it would be "difficult" for applicants "as a scientific matter to establish interchangeability in an original 351(k) application."

     That general wording has led some companies such as Sandoz, a leading biosimilar marketer in Europe, to express disappointment in a lack of specifics with regard to interchangeability requirements. "The FDA is the only regulatory body that has been provided with the legal authority to allow interchangeability of substitution," explains Sreejit Mohan, Head Biopharma, Oncology & Financ. Communications, Sandoz International GmbH. "In particular in the recently released draft guidances, FDA has not clearly outlined how interchangeability could be supported."

      Momenta's Roach thinks the hurdle should be high for the FDA to grant interchangeability.   "However nothing in draft guidance leads us to believe that achieving a designation of interchangeability is an impossibility if we are able to present a compelling and scientifically robust data package," he states. "But we don't underestimate the complexity."

       To insure it has the staff to make timely decisions on biosimilarity and interchangeability, the FDA has asked the Congress to authorize it to collect user fees from biopharma companies who submit 351(k) applications. This Biosimilar User Fee Act (BsUFA) program would impose fees in different categories, but they essentially would add up to the fee a drug company pays the FDA when it submits a new drug application for a conventional, chemically synthesized drug under the Prescription Drug Users Fee Act (PDUFA) program. In return for biosimilar fees, the FDA would commit to approving 351(k) applications in a certain timeframe. The biosimilar user fee program will probably be approved as part of congressional passage of the fifth iteration of PDUFA. Its current authorization expires by the end of September. So Congress, theoretically, must renew it by then, and establishment of the BsUFA would ostensibly be attached as an amendment. 

     While biopharma companies do not question the need for a biosimilar user fee, they have question the structure the FDA has proposed. Nikhil Mehta, Vice President, Biologics Worldwide Regulatory Affairs, Merck, has raised questions about the proposed $150,000 per IND application "development fee." That money would be used to support FDA biosimilar programs generally. Then, the company would get some sort of "credit" against that fee when it submitted a marketing (IND) application. However, the FDA has not explained what would happen if the biosimilar did not get beyond the IND phase. That would, according to Mehta, leave drug companies "with no way to recoup the additional cost burdens associated with this unique development fee if the product was discontinued." Another issue is what happens if the FDA deems a product "not biosimilar." Failure to resolve these issues, Mehta says, "will serve as disincentives to utilizing the biosimilar pathway."

     But both innovator and generic drug companies are in basic support of a BsUFA as long as Congress does not make the 351(k) program dependent on those user fees only. David Wheadon, M.D., Senior Vice President, Scientific and Regulatory Affairs, Pharmaceutical Research and Manufacturers of America, says user fees should supplement, rather than replace, congressional appropriations. Sara Radcliffe , Executive Vice President, Health, Biotechnology Industry Organization, Washington, DC, says whatever user fees that are collected annually should be in addition to $20 million a year Congress appropriates for the program. .

     It is too early to bestow industry blessings on both the final guidance and the BsUFA program. Neither will be in place for a few months, probably. But regardless how the bricks are laid on the new 351(k) pathway, biopharma companies will eventually be skipping down it like Dorothy and company down the Yellow Brick Road. They won't be off to see The Wizard, of course. But they will hope to be successful with some biological wizardry of their own.