Follow-on Biologics Base Camp: Senate Has Four Rival Proposals

Brand biologics fare well in the amendments prepared for the HELP Committee mark-up, as even Sen. Brown offers at least seven years of exclusivity.

Sen. Edward Kennedy's, D-Mass., revised proposal for a follow-on biologics pathway offers brand products the opportunity for even more exclusivity than the fixed 12 years in last session's bill (S 1695). This year's version offers a base period-plus-plus design that offers brands up to 13.5 years.

That change is perhaps the clearest sign that brands are in a strong position as health care reform enters a crucial month in which Democratic leaders hope to pass initial bills on the floors of each chamber.

Kennedy's new FOB legislation could be offered soon as an amendment to the health care reform legislation as part of the ongoing markup in the Health, Education, Labor and Pensions Committee.

How The Kennedy Bill Adds Up

The Kennedy bill would create separate base periods of exclusivity for different types of reference products.

Under the first base exclusivity period, FDA could not approve an FOB for nine years so long as:

1) No major substance, nor highly similar major substance in the reference product has been approved in any other BLA;

2) The reference product's application is approved after enactment of the law; and

3) The BLA for the reference product did not rely on clinical safety, purity or potency studies submitted in other BLAs or applications approved under section 505 of FDCA.

The base period may be extended for another three years if a supplemental BLA for the reference product is approved based on new clinical studies (other than pharmacokinetics or pharmacodynamics) that are essential to approval, and the product provides a significant therapeutic advance, such as demonstration of safety, purity and potency for a significant new indication or subpopulation (other than pediatrics).

An additional one-year extension would be allowed for a second significant innovation under the same conditions as the three-year extension.

The second base exclusivity period would be two years. This would be available for reference products that contain a major substance or any highly similar major substance that has been approved in another BLA.

The same three-year and one-year exclusivity extensions would be allowed as for the first base period.

Six months of exclusivity also could be added under either scenario if FDA requests and receives acceptable pediatric studies.

Many Bills To Come

Three other follow-on biologics proposals have been prepared as amendments for the HELP mark-up and more are possible. Each of the other amendments would offer less exclusivity, but even the lowest - the proposal from Sen. Sherrod Brown, D-Ohio, for a maximum of eight years - shows that brand firms will be comfortably positioned in the Senate if the legislation reaches a House/Senate conference.

Brown is a Senate co-sponsor of legislation from Rep. Henry Waxman, D-Calif., which would offer a maximum of only six years of exclusivity (HR 1427). Brown's amendment, however, starts with a base of seven years of exclusivity.

Waxman seems unable to get his bill even out of his committee because of the support behind brand-friendly legislation from Rep. Anna Eshoo, D-Calif., and the House health reform bill seems likely to be silent on the issue of follow-on biologics (Also see "FOBs Must Follow The Senate’s Health Reform Pathway; Placeholder Is Key" - Pink Sheet, 15 Jun, 2009.).

For generic firms and their allies, these facts paint a gray picture for conference negotiations.

Despite Waxman's influence and the desire of leadership to reduce healthcare spending as much as practicable, strong parts of the Democratic caucus in both chambers have gone on record, either through co-sponsorship or by voting, in support of a brand friendly approach to follow-on biologics.

President Obama has endorsed seven years of exclusivity, but it remains to be seen how much twisting strength he can reserve for the follow-on biologics arm of the bill (Also see "FOBs: White House Says 7 Years Of Exclusivity Is "Generous Compromise"" - Pink Sheet, 29 Jun, 2009.).

Brown's exclusivity approach differs from Kennedy's largely in the numbers, not the criteria. Brown proposes seven instead of nine years exclusivity for unique products, For reference products containing a major substance or highly similar major substance approved in a previous BLA, Brown would provide three years of exclusivity.

For both types of products, there would be only a single six-month extension for significant innovation, and this would be cut by 90 days if the innovator sponsor has $1 billion in sales for all products containing the major substance in the reference product. Products could also receive six months of pediatric exclusivity.

Exclusivity language from Sen. John McCain, R-Ariz., is simpler. FDA could not approve a follow-on until 10 years after the reference product is first licensed. Approval of a supplemental or subsequent application for a new indication, route of administration, dosage form or strength would not be considered a first license.

Exclusivity could be extended for two years if there are "significant therapeutic advancements" in the reference product. The amendment does not explain what constitutes a significant advance.

Like McCain, Sen. Barbara Mikulski, D-Md., would allow 10 years of data exclusivity for the reference product.

Her amendment would specifically prohibit "evergreening," going so far as to use the term - which generic firms say is the practice of brand firms making minor tweaks to gain major exclusivity - in the legislative language. Her bill states that the 10-year exclusivity period is allowed only for "a new biological product that meaningfully differs from a previously-licensed biological product in molecular structure, starting materials, or manufacturing process."

So-called evergreening was a major sticking point in the reintroduction of the Senate bill.

Kennedy's amendment specifically prohibits nine-year exclusivity for reference products that have minor differences from other biologics, such as proteins that differ in structure solely due to minor post-translational changes or amino acid sequence; polysaccharides with similar saccharide repeating units; glycosylated protein products that differ in structure solely due to minor changes in structure or number of saccharide moieties; and polynucleotide biological products with identical sequence of purine and pyrimidine bases bound to an identical sugar backbone (Also see "Kennedy's Follow-On Biologics Revisions Add Anti-"Evergreening" Language" - Pink Sheet, 15 Apr, 2009.).

To Kennedy's list of products that are ineligible for exclusivity, Brown's measure adds those that are closely related, complex, partly definable biological products with similar therapeutic intent, such as live viral products for the same indication.

Mikulski would allow a single one-year extension of exclusivity if FDA approves a supplemental application for the reference product. However, to qualify, the supplemental must be for a new therapeutic indication and the reference product must provide a significant clinical benefit compared to existing therapies. The benefit could be improved efficacy or safety, and "shall reflect a major contribution to patient care."

A six-month extension of exclusivity is provided for pediatric studies.

For products for rare diseases, exclusivity would be lengthened from seven to nine years. Kennedy and Brown would extend this exclusivity by only six months. Under the McCain amendment, this exclusivity could be as long as 10 years, instead of the current seven.

Exclusivity Isn't The Only Issue

Beyond the exclusivity periods, the amendment's other provisions also seem to tilt towards the brand perspective. Whereas Waxman's bill basically adds new types of applications to the Public Health Service Act, even Brown's new language sets clinical requirements for follow-on applications, although it notes, "The Secretary may determine, in the Secretary's discretion, that an element ... is unnecessary in an application."

The patent challenge procedures of the amendments, while they appear livable from the generic perspective, they embrace many of the brand industry's concerns, including limiting declaratory judgment actions.

- M. Nielsen Hobbs ([email protected]) and Cathy Dombrowski ([email protected])