Generic Biologics: European-Style Regulation Is The Answer, Big Pharma Says

The Senate Health Committee hearing on developing an approval pathway for generic biologics put the brand-name pharmaceutical industry in the unusual position of advocating that Congress adopt a European-style Rx oversight system.

The European health care system - where brands command much lower prices - has long been criticized by big pharma as stifling innovation, but at the March 8 hearing, Jay Siegel, Johnson & Johnson group president of research and development for biotechnology, immunology and oncology, argued that in the case of follow-on biologics, Europe should be the model.

"We are fortunate that the [European Union] has already made substantial progress in developing and implementing a policy based in good science and public health and consistent with their unique regulatory and healthcare framework," he said.

"We should be able to leverage that work to have a frank, transparent and scientific debate here in the United States, and thereby develop a model which will be compatible with our own regulatory and healthcare environment."

"The EU legislation clearly distinguished a 'biosimilar' from a 'generic' due to ... many scientific concerns," Siegel argued. "The EU also recognized the dangers of interchangeability."

Brand firms may find the European approach to follow-on biologics appealing because of the extended exclusivity, aversion to substitution, and extensive clinical data required for biosimilars to win approval.

Testifying at the hearing via satellite, European Commission Pharmaceuticals Unit Administrator Nicolas Rossignol said that biologics receive essentially 11 years of exclusivity in the EU. Interchangeability of products is not determined by the European Medicines Agency, but is left to the member states, he noted.

Europe's pathway has been used to approve two biosimilar human growth hormones - Sandoz's Omnitrope and BioPartners' Valtropin - but the EMEA gave a negative opinion to BioPartners' interferon alfa-2a Alpheon , which referenced Roche's Roferon-A . One of the main concerns was differences identified between the two products, including impurities, Rossignol said.

Republican senators praised the European model as one that needs to be carefully considered, suggesting that any measure hoping for broad bipartisan support would need to provide stronger exclusivity protections and study requirements than current proposals.

Sen. Sherrod Brown, D-Ohio, also addressed the European model in a statement issued at the hearing. Last year when he was in the House, Brown co-sponsored legislation introduced by Rep. Henry Waxman, D-Calif., which would give FDA authority to approve generic biologics on a case-by-case basis.

Waxman has reintroduced the bill this year, and it is being spearheaded in the Health Committee by Sen. Hillary Clinton, D-N.Y. (¹ (Also see "Generic Biologics Bill’s Key Battleground May Be Senate Health Committee" - Pink Sheet, 19 Feb, 2007.), p. 3).

Brown said, "The reason I am not yet a co-sponsor of S. 623 is that I wanted the opportunity to hear from those who have concerns about this bill, in case there are unintended gaps in safety that need to be addressed."

"I've heard a good deal about the European model for biologic follow-on access," Brown said. "I'd like to hear more. One thing to keep in mind, though. Most European countries negotiate the prices they pay for medicines. Price competition plays a less important role in affordability there then it does in our country, where we are passive price takers."

"Ultimately, the European timeframe for approval of follow-on biologics may be longer than ours for reasons other than safety," Brown said.

Former FDA Commissioner Mark McClellan has suggested that Europe's strict pathway is related in part to the adverse events linked to Johnson & Johnson's Eprex .

Any bill creating a pathway for generic biologics would need to require clinical trials from applicants, Sen. Orrin Hatch, R-Utah, suggested at the hearing.

Hatch admired Waxman's effort to create a pathway, but said, "I can't support it because I don't think it does provide the safety that we should have - frankly, the safety that we wrote into the original Hatch/Waxman bill. If a follow-on biologic is approved the way Henry's bill dictates ... patient safety, it seems to me, would be a problem because the legislation does not require any clinical trials as they move through the pipeline," he said.

Hatch had been more upbeat about the prospects for the creation of a pathway when he addressed the Generic Pharmaceutical Association's annual meeting March 2, stating, "This year, I predict we will get it done" (see ² (Also see "What’s In A Name? Hatch And Waxman Stake Claims To Generic Biologics Bill" - Pink Sheet, 12 Mar, 2007.)).

Hatch's discomfort with Waxman's bill was evident from his decision not to sign onto it initially, but emphasizing his concerns along safety and data lines, as opposed to intellectual property issues, will likely complicate the job of the legislation's advocates.

In response to Hatch's concerns about the lack of data requirements, Clinton said the agency could request any studies it felt were appropriate. "Our legislation provides FDA with the authority to require clinical testing," she said.

Siegel acknowledged that "there's not any question that this bill authorizes the agency to require testing," but he contrasted it with the authorizing legislation for the approval of new drugs and biologics, which "doesn't simply authorize the agency to require clinical testing. It states there needs to be adequate and well controlled tests. It sets a floor."

Clinton used the discussion of biogenerics to make a case for FDA safety reform. "What the testimony today highlights is the need for greater FDA postmarket authority across the board," she said. The generic biologics bill "was written to reflect the current reality."

"There are no postmarket studies on the brand side because the FDA does not have the authority. So if the reality does not provide great enough safety assurances, then we should raise the standard across the board, and provide FDA with an enforceable authority to require postmarket studies on both brand and follow-on biologics."

Health Committee Chairman Ted Kennedy, D-Mass., and Ranking Member Michael Enzi, R-Wyo., have sponsored legislation which will allow FDA to require postmarketing studies (³ , p. 3). The bill is seen as a likely candidate for inclusion with the renewal of the user fee act, and the Health Committee has scheduled a hearing on user fees and drug safety for March 14.

The follow-on biologics hearing also provided another airing of scientific disputes between FDAers brought out on Capitol Hill (⁴ , p. 8). At the hearing, Siegel, the former director of CBER's Office of Therapeutics Review & Research, squared off against Ajaz Hussain, the former deputy director of CDER's Office of Pharmaceutical Science who is now Sandoz's VP for biopharma development.

Hussain said, "The science is here, and has been for at least at decade," to create a follow-on pathway. Manufacturing changes and batch-to-batch variability of brand products show that two biologics could be considered the same even if made slightly differently, he argued.

Siegel declared, "There is no realistic potential for a scientifically valid determination of interchangeability."

"Although clinical testing can place limitations on the possible extent of differences, for most products, only extremely extensive comparison studies [perhaps as large as 50,000 patients] could rule out clinically significant differences."

In addition to other rhetoric, the various sides of the generic biologics debate have exchanged declarations related to Sen. Kennedy. Following the hearing, the Massachusetts Biotechnology Council issued a statement headlined "Mass Biotech Joins Sen. Kennedy in Opposing Federal Biologics Bill."

In contrast, Waxman told the Generic Pharmaceutical Association on March 2 that Kennedy was "very strongly supportive of this legislation."

For his part, Kennedy gave little direct indication of his opinion at the hearing, although his decision to hold the meeting must be seen as a sign that a generic biologics pathway stands a strong chance of being folded in the legislation renewing the user fee program.

Kennedy asked each of the panelists what their key criteria for a pathway were, and followed up with Siegel to see if he felt that FDA had the "know how" at the present time to regulate follow-on biologics. Siegel replied that he thought it did, but the agency's ability to request data should not be limited by legislation.

Kennedy also asked Rossignol if, given that firms make about half the profit in Europe than they do in the U.S., products should receive less exclusivity in the U.S. than they do in Europe. Rossignol replied that exclusivity should be considered in the context of pricing and reimbursement.

Kennedy noted that he had met recently with biotechnology firms in his state. "I was interested in the coming together, after a good deal of debate and discussion, around the idea that there was a pathway to move on this, as long as it was basically driven by the science, protected safety, and also promoted innovation," he said.

- M. Nielsen Hobbs ([email protected])