Recently introduced follow-on biologics legislation has several characteristics that make it distinct from the current approval pathway for generic drugs

The "Access to Life-Saving Medicine Act," introduced by Rep. Henry Waxman (D-Calif.) (¹ HR 6257) and Sen. Charles Schumer (D-N.Y.) (S. 4016), grants FDA the authority to approve either comparable or interchangeable follow-on biologics based on clinical studies as determined necessary by FDA.

One of the bill's fundamental differences from the small molecule system is the treatment of exclusivity for follow-on proteins (see chart: " ² Follow-On Biologics Legislation' p. 6).

While still contingent upon litigation and commercial launch, exclusivity over any subsequent comparable product is awarded to the first follow-on applicant to receive approval for interchangeability, instead of the first applicant to file.

The legislation stipulates, however, that "a subsequent comparable biologics product application that has demonstrated interchangeability with the reference product may elect, at its option, to have the product approved as a non-interchangeable comparable biological product whose approval will not be delayed."

The bill encourages speedy approvals and multiple applicants since a second filer could receive approval first and be awarded exclusivity or approved second and not be completely blocked from the market. The drawback to this, however, is that the value of the exclusivity period could be diminished.

The bill appears to assume that interchangeable products have a significant advantage over comparable products. The generic industry, however, has yet to decide if substitutability is preferable; Barr CEO Bruce Downey recently suggested that non-interchangeable products could be preferable (³ Also see "AB Or Not AB? Barr & Sandoz Ponder The Biogeneric Substitution Question" - Pink Sheet, 25 September, 2006., p. 11).

While FDA is given two years to establish regulations for review of such products, the bill defines interchangeability as a biological product that "contains an active ingredient or ingredients with principle molecular structural features comparable to the reference product, and that the comparable biological product can be expected to produce the same clinical result...in any given patient."

On the other hand, the bill defines comparable as "the absence of clinically meaningful differences between the comparable biological product and the reference product in terms of safety, purity, and potency."

Comparability is based on data derived from chemical, physical and biological assays; other non-clinical laboratory studies; and data from "any necessary clinical study or studies sufficient to confirm safety, purity and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used."

An abbreviated comparable biological product application must include data demonstrating that the product contains "comparable principal molecular structural features as demonstrated by thorough characterization of the two products, notwithstanding minor differences in heterogeneity profile, impurities, or degradation patterns."

Commenting generally on the bill, the Biotechnology Industry Organization said that it has serious concerns over whether the legislation adequately addresses issues of patient safety and intellectual property.

The bill's proposed system for approval of follow-on biologics could avoid what some see as a problem with the current generic approval system, namely that first filers can postpone exclusivity without fear of forfeiture (⁴ Also see "Generic Exclusivity Forfeiture Provision Hits Snag In Courts; FTC Wants Fix" - Pink Sheet, 25 September, 2006., p. 15).

Under the bill, FDA may not approve additional interchangeable products until the earlier of 180 days after the first commercial marketing of an interchangeable product; one year after a final court decision in patent litigation against the sponsor of the first approved product or dismissal of such litigation; or 36 months after approval of the first agent if litigation is still ongoing at that point.

If there is no patent litigation, FDA can approve a second interchangeable product the earlier of either 180 days after the first product's launch or one year after the approval of the first follow-on. This condition effectively gives the initial sponsor six months to launch its product without losing at least some exclusivity.

The bill's approach to the listing and certification of patents differs significantly from the procedure followed for drugs.

As opposed to requiring that generic companies notify the brand company that their patent is either invalid or not infringed, the follow-on biologics bill leaves the decision to notify up to the discretion of the applicant.

Instead of creating an "Orange Book" for listing patents of biologics, the bill requires applicants to request from the brand company a list of patents related to the reference product. The applicant can then notify the owner of the brand product that it intends to challenge one or more of the patents.

If a patent is not disclosed in response to a request, that patent may not be enforced against the follow-on applicant.

The bill offers tax credits for studies performed to demonstrate interchangeability between a follow-on product and the reference product.

"Interchangeable biological products (those that could be substituted for the brand name product at the pharmacy) would generate the greatest cost savings, but because there currently is no equivalent of a simple 'bioequivalence' study for biologics as there is for traditional drugs, [they] would be significantly more costly and difficult to produce than comparable products," according to a ⁵ bill summary.

"To encourage the development of interchangeable products, the bill authorizes tax credits for the costs of studies establishing interchangeability," the summary explains.

The Generic Pharmaceutical Association described the proposed credits as being similar ones proposed for brand industry R&D, including in "BioShield II" legislation (⁶ Also see "Patent Extension “Wild Card” In Hatch/Lieberman Bill Depends On Five Factors" - Pink Sheet, 4 April, 2005., p. 27).

Despite the additional review burden of complex applications that could involve clinical studies, the bill makes no mention of user fees.

The current generic drug review situation has prompted the agency to suggest user fees for ANDAs, although it does not appear to be actively advancing the proposal (⁷ Also see "FDA Faces Pricing Pressure As Generic Drug User Fee Debate Begins" - Pink Sheet, 27 February, 2006., p. 8).

The bill seeks to prevent several problems for follow-on biologics that the generic industry perceives to be hampering the current system for approving generic drugs.

The bill would prohibit brand firms from introducing an "authorized" generic during an interchangeable follow-on biologic's exclusivity period.

"No holder of a biologic product license...shall manufacture, market, sell, or distribute a rebranded interchangeable biologic, directly or indirectly, or authorize any other person to manufacture, market, sell, or distribute a rebranded interchangeable biologic," the bill states.

The legislation also attempts to prohibit the use of citizen petitions from delaying follow-on biologics.

"The Secretary shall not fail or refuse to take a final action on a comparable biological product application by the final action date on the basis that a person...has requested (in a petition or otherwise) that the Secretary refuse to take or otherwise defer such final action."

However, a court can issue a permanent injunction preventing the approval of a follow-on product if the petitioner has prevailed on the merits of the complaint, proves he or she will suffer more than irrecoverable economic losses that also threaten the business, and proves his or her interest outweighs the public need for the follow-on product.

The citizen petition language is similar to a provision in Waxman's version of the Lower PRICED Drugs Act (HR 6022), which sought to correct perceived abuses of exclusivity provisions by brand companies.

Both the House and Senate version (S. 2300) of the Lower PRICED Drugs Act would require the petitioner to sign a verification that includes the date that the relevant information became known (⁸ 'The Pink Sheet' Feb. 27, 2006, p. 28).

- John Rancourt

Biogenerics Bill Differs From ANDA System In Exclusivity, Patent Listing

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