The Biotechnology Industry Organization is asking FDA to initiate a public comment process on generic biologics before it moves forward in creating approval pathways for generic therapeutic proteins.

BIO's April 23 citizen petition requests that "FDA conduct a meaningful public participation process on the agency's policies on the issue of 'follow-on approval' of therapeutic proteins."

BIO said it is concerned by "recent indications by FDA that the agency might change its established requirements with regard to full data requirements" for therapeutic proteins that are regulated by CDER, namely insulin and human growth hormone.

FDA should publish a notice in the Federal Register explaining the legal, scientific and policy justifications for approval of follow-on therapeutic protein products, ¹ BIO's citizen petition states. The notice should create a public docket and propose a public meeting.

The petition cites several statements by FDA Commissioner McClellan about the inevitability of some mechanism for approval of follow-on biologics (² Also see "Generic Biologics Are Coming, Commissioner McClellan Tells MBC" - Pink Sheet, 24 February, 2003., p. 11).

BIO said it is "especially concerned" about comments made by McClellan at the recent Food & Drug Law Institute Educational Conference.

"I do have a vision that includes, in the long term, effective and safe biologic generics being potentially an important part of making low-cost treatments available to more people. That's a very long-term vision. It's going to require a lot more science and more legislation before we get close to this. So we're taking just some baby steps now," McClellan said during a question-and-answer session.

Those "baby steps" include efforts toward the approval of generic insulin and human growth hormone under existing law.

"There are two relatively non-complex - for biologics - agents that were approved as new drugs, that are not under BLA authorities, for human insulin and for human growth hormone," McClellan said. "I think there are opportunities for us to develop generic alternatives under current law for those approved as NDAs and we're in the process of that right now."

Novartis is one company that has indicated it is developing generic human growth hormone. The company told investors in January that it is in "a quite extensive discussion process" with FDA on approval requirements (³ Also see "Novartis Pursuing Generic Biologics; Says Brand And Generic Lines Co-Exist" - Pink Sheet, 3 February, 2003., p. 23).

BIO requested that until there is more public discussion, the agency stop work on any insulin or HGH guidances it has under development.

"Informal public statements by some FDA officials have indicated that the agency has drafted guidance documents describing in detail the amount and type of data it would require for approval of follow-on versions of recombinant human growth hormone and insulin," the petition states.

FDA is considering requiring human immunogenicity testing for approval of "interchangeable" human growth hormone (⁴ Also see "Generic Somatropin NDAs Would Require Human Immunogenicity Tests – FDA" - Pink Sheet, 22 April, 2002., p. 14).

BIO argued that "because FDA does not possess the authority to approve a product in this class through the section 505(b)(2) pathway, dissemination of such a guidance, even in draft form, would be contrary to law."

BIO is also requesting that, simultaneous with the Federal Register notice, FDA withdraw its 1999 draft guidance on 505(b)(2) applications.

The draft guidance "includes provisions that are at odds with the statute and long-standing agency interpretations of the [FD&C Act] forbidding reliance without permission by a 505(b)(2) applicant upon another sponsor's data, and requiring a full complement of data in applications for therapeutic protein products, especially recombinant versions," the petition maintains.

Under the draft guidance, an application submitted under Sec. 505(b)(2) may rely on FDA's findings of safety and effectiveness for an approved drug "to the extent such reliance would be permitted" under the generic drug approval provisions of Sec. 505(j).

BIO said that if FDA does not withdraw the draft guidance, it would consider filing for a "correction" under the Data Quality Act seeking withdrawal of the draft guidance due to the fact that it would allow FDA to approve therapeutic proteins based on data standards beneath those established by the law.

BIO objected that FDA appears to be moving toward the creation of an approval mechanism for therapeutic proteins through guidance alone.

"'Good guidance practices' do not offer a sufficiently robust procedure for the agency to consider the complex scientific, legal and policy issues at stake," the petition maintains.

While BIO disagrees that Sec. 505(b)(2) provides a legitimate approval pathway for therapeutic proteins, it said it appreciates FDA's informal reassurances "that follow-on applications are not contemplated for biological products licensed under" the Public Health Service Act. It asked that FDA confirm this view in its response to the petition.

The petition argues that FDA is singling out insulin and HGH for potential generics simply because of historical classifications at the agency.

The decisions to regulate certain products as drugs under the FD&C Act "were not based on any identifiable physical or chemical differences between these and similar therapeutic proteins approved under the PHSA," BIO maintained. "There was no express intent to establish a regulatory process distinct from the agency's general framework for approving biologically derived therapeutic proteins."

The petition points to Wyeth's conjugated estrogens product Premarin - which FDA has said is not adequately characterized to allow generics - as an example of the "challenge" of treating a biologically derived product as a drug.

"The agency explained that part of the difficulty in characterizing the active ingredients in Premarin stems from the fact that it is derived from natural sources," BIO said.

A recent citizen's petition submitted by Aventis argues that FDA should not approve any generic referencing its antithrombotic Lovenox (enoxaparin) because, like Premarin, it is not adequately characterized (⁵ Also see "Aventis Lovenox Petition Offers Premarin Defense To Hold Off Generics" - Pink Sheet, 21 April, 2003., p. 39).

BIO's petition maintains that Sec. 505(b)(2) was intended only to codify FDA's pre-Waxman/Hatch "paper NDA" policy, which allowed applicants to use published data as the main support for findings of safety and effectiveness.

"It cannot have been the intent of Congress for the carefully crafted ANDA provisions that were the centerpieces of the Hatch-Waxman Amendments of 1984 to be bypassed so easily, by a shift of agency decision-making to a separate statutory position," BIO declared.

"All 505(b)(2) was intended to cover was FDA's paper NDA policy for 'duplicates' of already-approved drugs where published scientific literature obviated additional safety and efficacy testing. There is no evidence that Congress intended for 505(b)(2) to function as a catch-all provision for FDA to approve products that do not meet the approval standards of either the full application requirement for 505(b)(1) or the sameness requirement for 505(j)."

The petition states that in its Federal Register notice, FDA should explain its interpretation of the scope of Sec. 505(b)(2) and whether it has broader applicability than the pre-Waxman/Hatch paper NDA. "If so, what are the other situations that it covers and how can FDA articulate in its regulation this additional coverage?"

The association maintained that a key element of the paper NDA policy "incorporated the doctrine that 'no data in the NDA can be utilized without express permission of the original NDA holder.'" The petition asks how FDA would justify basing an approval on another sponsor's unpublished proprietary data without consent, outside of the 505(j) ANDA process.

"What authority does FDA have to construe Sec. 505(b)(2) as enabling the agency to rely upon a prior agency finding of safety and effectiveness of another sponsor's drug, if the effect of this approach is to allow use of unpublished proprietary data, without permission?" the petition asks. "Are there any steps an innovative manufacturer can take to guard against such unintended reliance?"

Pfizer and Pharmacia, in a joint citizen's petition filed in July 2001, take a similar view that Sec. 505(b)(2) was meant only to codify FDA's pre-Waxman/Hatch "paper NDA" policy. The petition maintains that the draft guidance should be revised to state that only published data can be used in support of 505(b)(2) NDAs (⁶ Also see "Pfizer, Pharmacia Protest Inclusion Of Drug Innovator Data In "Paper NDAs"" - Pink Sheet, 20 August, 2001., p. 16).

BIO said it is submitting a copy of its citizen's petition to the Pfizer/Pharmacia petition docket.

Pfizer is fighting a pending 505(b)(2) application from Dr. Reddy's for a different salt formulation of Pfizer's Norvasc (amlodipine) (⁷ Also see "Pfizer Loses Norvasc Ruling: Rx Patent Extensions Are For Product, Not Use" - Pink Sheet, 23 December, 2002., p. 15).

BIO Petition Opposes Generic Insulin, HGH; Asks FDA To Open Public Debate

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