Pharma’s Cutting Edge

It’s been a while coming, but 2006 has finally seen the introduction of legislation to the U.S. Senate that, if passed, would create a statutory pathway for FDA review and approval of genuine generic biologic drugs.  The Act, which the sponsors have asked be called “Access to Life-Saving Medicines Act,” was read into Congress yesterday.  The Senate version has No. S.4016 and has been referred to the Senate Health, Education, Pensions and Labor Committee (Chaired by Sen. Enzi ) for review and debate.

The U.S. generic manufacturers trade association, the GPhA, immediately announced its strong support for the legislation, while PhRMA and BIO, the innovators’ trade groups remained silent.  It’s likely that GPhA personnel played a prominent role in crafting this legislation, which has been speculated to have been in the works for over a year.

The text of the Senate bill is still at the printing office, but Rep. Waxman, who will be sponsoring the unnumbered House version, published the bill’s text on his website.  As there is a reasonable chance that the version that will eventually emerge from Committee will conserve some elements of the bill as published, and as there is also a chance that a competing bill (supported by innovators) will soon be introduced, I’ve decided to devote some of my time outlining it here.  For those of you would would like to read the official summary, Rep. Waxman has published that as well.

Just a bit of background for readers who may not regularly read my blog (have a look at the generics category for related posts).  This new bill is intended to amend the Public Health Service Act.  Biologic drug products are regulated primarily by Sec. 262 of the PHS Act.  “Traditional” small-molecule drug products are not regulated by the PHS Act, but rather are covered by the Food, Drug and Cosmetics Act.  Of particular importance to this discussion is Sec. 505 subsection (b) and Sec. 505 subsection (j) of FDCA, which provide for the major pathways by which new drugs gain introduction to the U.S. market. 

Although an accelerated development/approval pathway that relies on predecessor biologic drugs per se is not found within Sec. 505 (b) or (j) of FDCA, Sec. 505 (b)(2) does provide for accelerated development/approval of new drugs that rely on another sponsor’s investigations, when the original sponsor’s patent(s) and marketing exclusivity have expired.  FDA has published a draft guidance (2001) for how and when such investigations may be used to gain marketing approval for a new drug.  As one of the examples for types of applications that would be covered in 505(b)(2), FDA wrote the following:

Naturally derived or recombinant active ingredient. An application for a drug product containing an active ingredient(s) derived from animal or botanical sources or recombinant technology [my emphasis] where clinical investigations are necessary to show that the active ingredient is the same as an active ingredient in a listed drug.

Time does not permit me to review the debate–and lawsuits–that have surrounded FDA’s application of 505(b)(2) provisions.  Suffice to say, that innovators have generally opposed use of this pathway and that generic manufacturers have generally supported it.  No surprise there.  Nevertheless, prior to 2006 quite a few drugs, including several peptides and four recombinantly made proteins, have been approved using the 505(b)(2) pathway. 

In 2006, a bit of new ground was broken when the 505(b)(2) pathway was used by Sandoz used to gain US approval for Omnitrope, its “generic” human growth hormone produced recombinantly.  Omnitrope was a higher profile recombinant protein, potentially applicable to a larger patient population, than any of the previously approved recombinant proteins approved via 505(b)(2). 

Although FDA was clear in its stance that Omnitrope should not be considered a generic, since a bioequivalence determination was not made by FDA, the approval surely increased the confidence of manufacturers intending to submit their own 505(b)(2) abbreviated applications for recombinant proteins originally approved under Sec. 505 (note that nearly all modern protein therapeutics have not been approved using 505(b) but were instead approved via Sec 262 of the PHS Act).   I’ve previously listed some other biologic drugs that could potentially be approved under Sec. 505 (b)(2).

With that background, you begin to see why generic manufacturers that wanted to play in the recombinant-protein sandbox needed some legislative help.  Quite simply, most of the juicy generic biologic targets were approved under the PHS Act, and the PHS Act contained no provisions for generic biologics nor for accelerated approval using a reference product’s investigations.  Fast forward to the “Access to Life-Saving Medicines Act”.

Here are the bill’s key provisions:

• Creates a comparable biogical product, defined by “the absence of clinically meaningful differences between the comparable biological product and the reference product in terms of safety, purity, and potency….”
• Defines a comparability determination based on “data derived from chemical, physical, and biological assays…and…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.”
• Defines a requirement for comparable principal molecular structural features of the reference and comparable biological product based on “an analysis of structural features [using] appropriate analytical and functional testing sufficient to identify differences between a new and reference biological product relevant to safety, purity or potency.”
• Defines comparable principal molecular features to include products that:

1. “differ in [my emphasis] structure due solely to post-translational events, infidelity of translation or transcription, or minor differences in amino acid sequence;”
2. have “similar saccharide repeating units, even if the number of units differ and even if there are differences in post-polymerization modifications;”
3. are glycosylated and have characteristics of #1 and/or #2 above;
4. have identical polynucleotide sequence;
5. are “closely related, complex partly definable biological products with similar therapeutic intent, such as two live viral products for the same indication.”   

• Requires data “demonstrating that the comparable biological product and reference product utilize the same mechanism of action….”
• Requires applicants of the comparable product to propose in labeling the same, previously approved “conditions of use prescribed, recommended, or suggested….”
• Requires the comparable product to use the same route, and have the same dosage form, and strength as the reference product.
• Requires data demonstrating that the manufacturing facility of the comparable product meet standards “designed to ensure that the comparable biological product continues to be safe, pure and potent.”
• Provides for applicants that don’t have access to the innovator’s study data to submit an application with their own data to demonstrate that the comparable product application ”contains sufficent information to establish the safety, purity, and potency of the biological product relative to the reference….”
• Gives the comparable product applicant the option [my emphasis] to perform a post-marketing study(ies) similar to those required [my emphasis] of the reference product bot no others.
• Sets a final action date for FDA review of an abbreviated comparable biological product application at eight (8) calendar months following Sponsor’s submission of the application or 180 days after FDA notifies the Sponsor that its application has been accepted for filing, whichever is earlier.
• Allows comparable product manufacturers to state that their product is interchangebale with the reference biological product.
• Provides for a period of market exclusivity for the first-apporved interchangeable comparable product but also provides for subsequent approvals during the interchangeable product’s exclusivity period for a comparable product that elects to forgo labeling as an interchangeable product.
• Provides for patent dislcosure and patent challenges of reference biological products similar to those in “Paragraph Four” of FDCA.
• Provides a 50% credit against taxes for qualified clinical testing used to demonstrate comparability and defines such testing.

I hardly know where to begin with this one.  There’s so much I could say, but I suspect that I’ll have to repeat myself later when alternative bills are submitted.  So, let me just say what I believe are the most obnoxious and contentious elements of the bill.  Three, in particular, stand out:  (1)  the lack of an efficacy demonstration requirement in the absence of a bioequivalence determination, (2) the “micromanagement of science” that hamstrings regulators from making incomparability determinations when certain key molecular differences between two products exist (e.g. posttranslational modifications), and (3) the provision that allows applicants to bypass certain comparability determinations if they don’t have access to a reference product’s data.

Reading these three provisions, I have to think that they flowed right from the broadband connection in GPhA headquarters to the Senate floor, without even a spell-check to delay them.  My gosh, what a gift to generic manufacturers if these provisions became law as is.  If you’re a biological product manufacturer don’t worry; they won’t.

What do I like about the bill?  It’s a step in the right direction.  We need a law that provides for an accelerated pathway to the market for comparable “generic” proteins and other biological products.  It’s a starting point that others can use to build from, so it’s better than nothing.  I also like that it has some of the same provisions contained in Hatch -Waxman, such as the exclusivity period for first applicants.  Other than that, I’m not thrilled.  I’d like to see a law that gives regulators the opportunity to apply the latest scientific thinking to their comparability determinations in all circumstances.  I’d like to see a law that ensures that the comparable products really are interchangeable with the reference products–that they will have the same efficacy, that they will have the same immunogenic potential, etc. 

This is just the beginning of this story, but now that we have some credible legislation up for debate, I expect momentum to build.  Perhaps legislation will pass as early as next year.  In the meantime, I’ll keep up with this bill and alternative legislation and will update the blog as news warrants.