BioWorld Today Columnist

The Biotechnology Industry Organization (BIO) has been vocal in its opposition to H.R. 1038 and S. 623, the "Access to Life-Saving Medicines Act" introduced in the House by Rep. Henry Waxman (D-Calif.) and in the Senate by Charles Schumer (D-NY) and Hilary Rodham Clinton (D-NY). These bills would establish an abbreviated pathway for the approval of "follow-on" biologics, colloquially if inaccurately called biogenerics. The idea behind the bills is to do for biologics what the 1984 Hatch-Waxman Act did for conventional drugs, streamlining the process for approving cheaper substitutes to branded biologics that have gone off patent.

This bill didn't make it out of committee before Congress went on recess in August, which is some small victory for BIO, but the trade group can count on this issue coming back when Congress reconvenes in September.

Of course, BIO is an advocacy organization, so expecting it (or any trade association) to hold anyone's interests above those of its constituents is like asking a pit bull to see things from the repo man's point of view. It isn't going to happen. And in that context, BIO deserves an eensy bit of credit for seeing some sort of abbreviated path for biogenerics as inevitable. The trade group came out with at least tepid support of H.R. 1956, an alternative bill introduced by Jay Inslee (D-WA) that, unlike Waxman's proposal, would mandate clinical trials for follow-on products and provide 14 years of non-patent data exclusivity for innovators. (Inslee, for what it's worth, represents a district that includes Redmond, Bothell, and the northern suburbs of Seattle, an area that a lot of biotech companies call home. Waxman represents western Los Angles County, stopping just short of Thousand Oaks.)

In contrast to Inslee, Waxman would give FDA broad latitude in deciding what kinds of clinical studies it may or may not need to support approval, but would provide no data protection beyond what patents already provide. His bill is championed by, among others, the Generic Pharmaceutical Association.

So there you have the two poles of the debate. What's remarkable is that out of this, a compromise has quickly emerged. Introduced by Sens. Ted Kennedy (D-MA), Mike Enzi (R-WY), Clinton, and Orrin Hatch (R-UT), S. 1693, the "Biologics Price Competition and Innovation Act," keeps most of Inslee's data exclusivity (12 years instead of 14) but avoids mandating clinical studies that may not be necessary in every case, leaving broad discretion to FDA. The bill was reported out of the Senate Health, Education, Labor and Pensions Committee by voice vote in late June but is in limbo until Congress reconvenes. There is no equivalent House bill yet.

BIO, while naturally finding the bill preferable to Waxman's proposal, still doesn't like what it sees. Many of its arguments come down to assertion that there is just no such thing as two truly equivalent biologics. As BIO President Jim Greenwood states in a release, "Even small changes can render the biologics ineffective or even potentially harmful." Any law, according to BIO, should require a follow-on biologic to go through clinical trials. Even so, any approved product should not be considered "substitutable" in the manner of generics; only a physician should be allowed to switch a patient from one drug to another.

But wait...isn't there already a pathway that allows a company to conduct clinical trials on an off-patent biologic and apply for approval as a non-substitutable product? It's called the Biologic License Application (BLA).

In any case, methinks BIO doth protest too much. Let's not forget that the modern BLA was created to provide some relief from regulations that grew out of an abundance of caution for the minor variances of biologics manufacturing. Prior to regulatory changes culminating in the FDA Modernization Act of 1997, a manufacturer that wanted to change so much as a pH meter in a fermentation tank needed prior approval from the FDA. Every production lot required a separate FDA release because there might be variance from batch to batch. Companies wanting to expand production to a new facility needed to file an entirely new Establishment Licensing Application (ELA) — a predictably arduous regulatory process.

In reconsidering this approach, the agency stated (in May 1996): "technical advances over the last 15 years have greatly increased the ability of manufacturers to control and analyze the manufacture of many biotechnology derived biological products. After over a decade of experience with these products, the agency has found that it can review the safety, purity, potency, and effectiveness of most well characterized biotechnology products without requiring submission of a separate ELA."

The term well characterized proved a bit tricky, and the agency ultimately backed away from a strict definition. But the basic idea remained: While it is essentially impossible to determine if a recombinant protein is identical from batch to batch or facility to facility, there are analytical techniques that can provide an accurate enough picture, and these have improved with time. Mass spectroscopy, high performance liquid chromatography, advanced immunoassays, and other techniques can determine sequence and even certain structural and carbohydrate linkage details of proteins and antibodies. Though imperfect, these have proven good enough over the past decade for many products, and allowed the industry to get out from under some arduous regulation. I don't think many would want to go back to the bad old days, which made it prohibitively difficult, slow, and expensive to change facilities or even match production to demand. Certainly not BIO, which spearheaded these regulatory changes in the mid-1990s.

Of course, lot-to-lot variation, or even changing a manufacturing facility is not the same as potentially changing a whole manufacturing process. But it's a stretch to say that in no case can anything short of extensive clinical trials establish similarity, no matter what drug is involved. Will follow-on biologics be absolutely identical to the reference drug? They can't be, since the reference drug is not absolutely identical to itself. But we've already learned that there is such thing as good enough.

While some biotech drugs may not now meet even the fuzzy definition of "well-characterized," lab techniques continue to improve. Demanding that the FDA treat a protein for which it is known that surface carbohydrate plays no active role the same way as a biologic where glycosylation controls activity is just throwing up an extra obstacle to getting follow-on products on the market. But as the saying goes, the more things change, the more they stay the same.

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