Hospira started phase 3 clinical trials for generic erythropoietin (EPO) in late 2011. When the Lake Forest, Ill., company submits an application to the U.S. Food and Drug Administration for its biosimilar EPO — which won’t be until at least 2015 — it could be the first U.S. biopharmaceutical company to take advantage of the expedited approval pathway for biosimilars established by the Biologics Price Competition and Innovation Act of 2009 (BPCIA). 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 to inaugurate a new user fee program to pay for the examination of those applications, there will be many entrants in the race to be first in the 351(k) pipeline.
Momenta Pharmaceuticals signed a collaborative agreement with Baxter Healthcare last December to develop biosimilar products. James Roach, MD, chief medical officer at Momenta, in Cambridge, Mass., says the draft FDA guidelines published in February allow for the possibility that the agency could approve a biosimilar without the company having to go through time-consuming and costly clinical trials, as Hospira is doing. Those draft guidelines may be finalized this summer.
“We understand the burden will be on the sponsor to provide a data package that scientifically justifies a reduction in requirements for pre-clinical or clinical studies,” Roach says. “We think that bar should be high for achieving biosimilarity at one level and interchangeability at another.”
Interchangeability dilemma
Interchangeability — a higher designation than biosimilarity — would allow a pharmacist to substitute a biosimilar for the brand-name reference drug prescribed by the physician without that physician’s prior approval. Health insurers and employers, in particular, want the FDA to set the interchangeability bar as low as possible so that their prescription drug costs are reduced to the maximum extent.
Roach hopes the FDA will reduce testing requirements for biosimilars and interchangeable products. He believes the approach Momenta took to develop a generic version of enoxaparin (Lovenox), a low-molecular-weight heparin, conceptually applies to biosimilars. While Lovenox is not technically a biosimilar, it is a complex drug derived from pig intestines. Biosimilars (like their reference biologics) 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, we were not required to perform clinical trials to establish safety and efficacy,” Roach says.
Stephen Barlas
Avoiding a full complement of clinical studies might lead not only to earlier product entry but also to lower-cost entry. Hospira’s U.S. clinical trials for biosmilar EPO will cost $100 million to $200 million, according to Sumant Ramachandra, MD, PhD, Hospira’s chief scientific officer and senior vice president for research and development and medical affairs.
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. Roach estimates that generic enoxaparin 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 $3 billion in Medicare Part B savings from biosimilars by federal fiscal year 2016.
Those savings are already being seen in Europe, where the European Medicines Agency has approved a number of large-molecule biosimilars such as Hospira’s Retacrit and Nivestim, a biosimilar version of filgrastim. Sandoz is selling two biosimilars in Europe — Binocrit (epoetin alfa) and Zarzio (filgrastim) — which are generally priced 15 percent to 30 percent below the reference drugs. Take-up has been slow, however, because of the lack of interchangeability designations.
U.S. companies, however, have been hesitant to jump into the FDA biosimilar pipeline without some formal clarification of what data the FDA will expect to see in applications. To avail themselves of the section 351(k) provisions 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 the draft guidance, it is very broad. It gives the FDA the ability to adjudicate. We believe in that approach. It is hard to legislate or regulate this type of field when tools are still being built.”
The most controversial and important issue surrounding the draft and final guidances is the FDA’s take on interchangeability. The FDA says companies can apply for an interchangeability designation. But 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, to express disappointment in the 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 of biopharma communications at Sandoz. “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 the 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. But we don’t underestimate the complexity.”
The user fee issue
To ensure it has the staff to make timely decisions on biosimilarity and interchangeability, the FDA has asked Congress for authorization to collect user fees from biopharma companies who submit 351(k) applications. The Biosimilar User Fee Act (BsUFA) would impose fees in different categories, which would essentially equal the fee a 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). 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 next iteration of PDUFA.
Although biopharma companies do not question the need for a biosimilar user fee, they have questioned the FDA’s proposed structure. Nikhil Mehta, Merck’s vice president for biologics worldwide regulatory affairs, has raised questions about the proposed $150,000 “development fee” for each investigational new drug (IND) application. That money would be used to support the FDA’s biosimilar programs. The company would get some sort of credit against that fee when it submits an IND application.
The FDA has not explained what would happen if a 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.” Failures to resolve these issues, Mehta says, are “disincentives to utilizing the biosimilar pathway.”
David Wheadon, MD, senior vice president for scientific and regulatory affairs at Pharmaceutical Research and Manufacturers of America, says user fees should supplement rather than replace congressional appropriations. But Sara Radcliffe, executive vice president for health at the Biotechnology Industry Organization, says that whatever fees are collected annually should be in addition to the $20 million a year Congress appropriates for the program.
Still too early
Neither the final guidance nor the BsUFA program will be in place for at least a few months. Regardless of how the bricks are laid on the new 351(k) pathway, biopharma companies will eventually be skipping down it like Dorothy down the yellow brick road. They won’t be off to see the wizard, of course, but they hope to be successful with some biological wizardry of their own.