Biotech’s double standard on biogenerics

August 10, 2007 | David P. Hamilton | Comments | |

(UPDATED: See below.)

generic-beer.jpgYesterday, the WSJ Health Blog cited a WSJ story as evidence that “biogenerics” — that is, generic versions of biotech drugs, which currently don’t exist — need to be treated with caution. Unfortunately, that post missed a much more important point about biogenerics: The double standard that the biotech industry holds when it comes to determining whether different batches of biotech drugs are equivalent or not. The subject is still widely misunderstood, thanks in part to chaff kicked up by the biotechnology industry itself. (See our previous coverage here and here.)

The original WSJ story, written by David Armstrong and Geeta Anand, concerned production problems at a new Genzyme plant making Myozyme, the company’s new drug for a rare genetic condition called Pompe disease. Myozyme produced at the new plant, it turns out, differs measurably from that pumped out by the same genetically engineered cells at the company’s older manufacturing facility. In particular, the “new” Myozyme appears to contain less of a carbohydrate that helps muscle cells take in the drug. Because of this difference, the FDA has so far refused to approve the new manufacturing plant, which raises the prospect of Myozyme shortages and a financial hit for Genzyme.

The WSJ story itself didn’t delve into the issue of biogenerics. On the health blog, however, Armstrong wrote:

Making biologics is complicated work, and that’s one reason the biotech industry has voiced caution about legislation to allow generic versions of the medicines.

In the case of Myozyme, billions of cells from hamster ovaries growing in large stainless steel tanks produce the enzyme Pompe patients lack. The fact that Genzyme, which has loads of biotech experience, is having such difficulty ramping up production of its own drug heightens worries about the ability of generic manufacturers to accurately copy brand-name biotech drugs.

The first issue here is that there’s nothing new about biotechs finding that new production batches of a complicated protein differ in certain ways from older batches. I listed several examples in an online column I wrote for the WSJ more than three years ago, and there have undoubtedly been others since. Sometimes these differences are serious; more often, they’re not. When there is a major discrepancy, as there was for Genentech’s drug Raptiva (then called Xanelim) in 2001, the FDA requires the biotech to carry out clinical trials to ensure that the new production line is pumping out a drug that’s equivalent to the old stuff. So far, the FDA isn’t requiring Genzyme to conduct new clinical trials of Myozyme produced at the new facility, company spokesman Dan Quinn told me.

The second issue — and those of you who’ve followed these debates can probably see where I’m going — is that the biotech industry wants to have it both ways when it comes to the “complicated work” of making biologics. Where biogenerics are concerned, the industry insists that copycat versions of biotech drugs must undergo those expensive and lengthy clinical trials in the interests of “patient safety.” When it comes to their own drugs, however, biotech companies are perfectly willing to rely on a battery of simpler tests to ensure that a new production batch is equivalent to an old one, and only run clinical trials as a last resort (and when forced to by the FDA).

All of which suggests that it would probably suffice to subject any would-be copycat drug to the same set of tests that biotech manufacturers themselves must meet for a new production facility. If it passes, it’s approved. If not, then it’s time to consider clinical trials. In fact, this is pretty much the “case-by-case” strategy adopted by the House and Senate biogenerics bills — ones that I’m pretty sure the Biotechnology Industry Organization opposed. In any event, it doesn’t seem too much to ask that journalists covering these debates realize that the case against biogenerics is a lot weaker than the industry would like us to think.

UPDATE: This NPR story (via the LAT) makes some of the same mistakes. It’s not the complexity, folks — it’s whether there are reliable tests for ensuring that batches of these complex molecules are equivalent to one another short of clinical trials, which there most certainly are.

UPDATE REDUX: The In Vivo blog weighs in with a related story about the slow start to sales of Omnitrope, a generic human-growth hormone (which they refer to as a “biosimilar,” a word preferred by the biotech industry).

UPDATE, TAKE THREE: I revised the headline and first paragraph to better reflect the post’s main point. I also wanted to belatedly credit David Williams of the Health Business Blog for sparking this train of thought in the first place with this post. (I’d written about his thoughts on the subject earlier, but now that I’m thinking about it, there was no good reason not to mention it again.)

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About the Author, David P. Hamilton

David Hamilton has been writing for VentureBeat LifeScience since April 2007. He formerly spent 14 years as a reporter for the Wall Street Journal in its San Francisco and Tokyo bureaus. Prior to that, he spent several years as a reporter at Science Magazine and as a reporter/researcher for the New Republic, both in Washington.

  • jason
    I think you have to allow for a few differences between a scale-up issue like this and the general debate around biosimilars.

    1. Scale-ups are produced with cells cloned from the original production system, biosimilars are not.

    2. Originating companies may hold process patents and other know-how that the biosimilar company has to invent around.

    3. Biologics have a wide range of complexity. Some are shorter, more simple and without complex sugars, some are not.

    Lumping all biologics together (HGH vs. Myozyme) doesn't address these issues. Unless you think that the differences between the two is not that great.
  • You are absolutely correct in that the biotechnology industry wants to have it both ways. I disagree slightly with Jason's characterization that lumping all biologics together (HGH vs. Myozyme) doesn't address these issues. Last year, on March 26, 2007, Novo Nordisk A/S sent one of its executives, Inger Mollerup, Vice President for Regulatory Affairs to testify before Congress. Mollerup said "While some of the best known peptide molecules - like insulin - can be largely characterized with today's technology, we do not yet have the tools and models that enable us to predict safety and efficacy from that characterization without undertaking human clinical trials."

    In effect, Mollerup told Congress that even those biotech medicines (insulin) whose sequence is completely characterized is insufficient to predict safety and efficacy. Of course, in 1997, the geniuses in Congress passed the Food and Drug Administration Modernization Act (FDAMA) of 1997. The FDAMA repealed the statutory provision in the Federal Food, Drug, and Cosmetic Act (the act) under which the FDA certified drugs containing insulin, in effect saying that batch testing was not a necessity for that drug (presumably because its a relatively simple molecule), and the pharma-biotech industry has abused this privilege. In 2003, Eli Lilly and Company received FDA approval to outsource the manufacture of at least some of its blockbuster Humalog and Humulin to third-party Hospira, Inc. Just a few days ago, Lilly announced it was closing the plant in Indianapolis that made Humalog and Humulin and would concentrate production at its other facilities in Puerto Rico and France, but would also use third-party contract manufacturers to a greater extent. Anyone who uses insulin knows that part of the unpredictability of using it is derived from sloppy manufacturing processes, so while the Genzyme issue affects a larger-molecule protein, the rules need to be enforced even for the simplest of molecules such as insulin -- they aren't the same, but the dysfunctional regulatory environment which governs most biotechs by the Public Health Services Act, but grandfathers insulin and HGH under the Federal Food, Drug & Cosmetic Act need to resolve these issues. Someone is going to be hurt otherwise, but we need Congress and the regulators at the FDA to address these issues, and the FDA mistakenly believes that the user fee act means they work for the pharmaceutical industry.

    But if the industry is to have any shred of credibility