FDA Says Genzyme Can’t Copy Its Own Biologic
In a decision that shows how difficult it is to copy biologics, the FDA has rejected Genzyme’s request to sell a version of its Pompe disease drug, called Myozyme, which the drugmaker planned to manufacture at an additional site. But the agency ruled that any Myozyme made at the second plant should be considered a different product because of small differences in its chemical structure, The Boston Globe reports.
In order to sell the latest version of the drug in the US, Genzyme will have to file another application with new data showing the drug is safe and effective in large numbers of patients. Pompe disease is a rare, debilitating genetic illness that prevents people from breaking down a common sugar called glycogen, which can then build up in the body’s cells and weaken the muscles. It affects an estimated 5,000 to 10,000 people worldwide, but Genzyme’s existing production site has limited capacity, and is currently supplying the drug to 140 US patients free.
The FDA decision, however, suggests that regulators may be reluctant to approve any generic versions of biologics - often called biogenerics or biosimilars - without clinical data proving the drugs are at least as safe and effective as the originals if there are even slight differences in the compounds. As a result, Genzyme will have to file a separate Biologics License Application to win approval. (Here’s the Genzyme statement).
“It sends a very loud message and sets a very high bar,” Alison Lawton, Genzyme’s senior vice president for regulatory affairs, tells the Globe. And she notes that Genzyme had the advantage of having full access to all the original information about the drug and still had trouble replicating the manufacturing process exactly.
While traditional “small molecule” drugs, like aspirin, are usually mixed from chemicals, biologics are made from living organisms and considered much harder to replicate. Myozyme, for instance, is based on specially designed proteins grown in Chinese hamster ovary cells, the paper writes.
In this case, Genzyme says the FDA was concerned about slight differences in the carbohydrate structures of the molecules. To make sure the differences weren’t important, the FDA demanded data from larger numbers of patients that proves the version made in the larger plant is safe and effective. So far, Genzyme says it has submitted data only from a very small number of patients, making it hard to tell whether the molecular differences were significant.
Nathan
Wow — that’s pretty clear evidence that generic biologics may not be nearly as close as we thought. I wonder what the lawmakers sponsoring the biosimilars bill think of this.
Melody
Are any readers here interested to know that the insulin cartel (especially Novo and Sanofi-Aventis) have been skirting the issues brought into focus by The Boston Globe article. They never had to PROVE the insulin species, protein contaminants and other ingredients in the vial were—in truth—actually identical to the label. In fact, there is now proof that Lilly has been making biogeneric, rDNA insulin through subcontracted manufacturing companies. This tells me the FDA, the NIH and anyone else who has regulatory input over the safety of medications for the diabetic population really don’t care how badly this large minority population is abused.
Among the scientists involved, it has ALWAYS been known that synthetic human insulin molecules contained in a vial of “insulin” do not necessarily have the same three-dimensional spatial configuration as the human insulin molecule produced by the human body. The resultant molecule produced by a bacterial or yeast process (with later transcription of A and B chain to form the perfect human insulin molecule) relies on undisclosed proprietary information. This is a case where technology lags far behind “discovery.” Five million insulin users will tell you that their medication is NOT identical, vial-to-vial. (But of course, this can be ascribed to anecdotal patient non-compliance.) For two decades, no one has been willing to question the original NDA, and stop the abuse.
Biotech insulins, in today’s FDA formulary (including all of the synthetic analog insulins) are considered small-molecule drugs like aspirin. We now know biotech drugs cannot be compounded with safety, in the same manner as aspirin. All of us should entertain the possibility that because rDNA insulins are never batch-tested, the pharmaceuticals in question have escaped scrutiny. Checking a production plant for cleanliness and procedural methodology does not guarantee ‘what’s in the vial.’
Just an example: Humalog and Humalin are both produced by Eli Lilly and Company. When analyzed by the latest Maldi-Tof method, the results are identical for these two very different products. They both have the same molecular weight (Daltons); only the patient knows whether he gets a peak of action in 45 minutes . . . or in 3 hours. Every vial should be analyzed with a technology adequate to determine the exact STRUCTURE of the compound within each batch. Does being ‘the first in the game’ (as was Lilly and its rDNA insulin) allow a company to both set the rules and exempt themselves from oversight?
Scott
As a sort of follow-up to Melody’s comment, I would mention that Novo Nordisk A/S testified before Congress on March 26, 2007, Novo Nordisk sent one of its exectutives, 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.” We have no reason to doubt that the company is adhering to good manufacturing standards for biotechnology medicines.
However, since 2007, rival Eli Lilly and Company has been outsourcing the manufacture of its blockbusters Humalog and Humulin to Hospira, Inc., both of which are biotechnology medicines. But Lilly is not breaking any laws because 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. As a result, in 1998, the FDA repealed virtually all of its regulations governing certification of drugs containing insulin and made amendments to other relevant sections of their regulations. Last week, Lilly announced it was closing a facility in Indianapolis and laying off close to 500 people who worked in the facilities who made Humalog and Humulin as well as for the osteoporisis medicine Forteo. The company plans to increase its use of contract manufacturing, including for biotechnology medicines.
If we are going to require this of generics manufacturers, the same standards need to apply to giants like Eli Lilly and Company, and that means no to contract manufacturing unless it is the ONLY facility making the drug.
Nathan
Melody,
That was an interesting read. I don’t know how to answer you — but I thought I would point out something of interest. The molecular mass of insulin is 5808. It is a very small protein — only 51 amino acids. If there is debate about biological equivalence of such a small protein, imagine the hurdle of trying to prove chemical equivalence for a protein of, say, 60000 (only ~500 amino acids). Epogen has a molecular mass of only 38000.
Bottom line: If biological equivalence of insulin cannot be adequately established, there is NO WAY IN HELL that biological equivalence of larger proteins can be established
Jack2
What about siRNAs. Biologic or small molecule?
Nathan
A typical siRNA has a MW of approximately 7000-8000. From that standpoint, it would likely be considered more of a “biologic”. However, part of the trouble with proteins is that you have post-translational modifications to deal with (phosphorylation, glycosylation). These post-translational modifications can be species-specific and vary depending on growth conditions. siRNA is obviously not a protein, so you don’t have to contend with these factors. In that sense, it might be more of a “small molecule” (just a very, very large small molecule!).
Melody
Nathan–
If you had read the NDA for human insulin, I think you would be astounded. The technology was AWESOME . . . so much so that at least one (and perhaps other) scientist, I believe, let his AWE outweigh his scientific integrity. This is truly a case where the discovery far outpaced the technology . . . and patients (and doctors who prescribed for them) were TRUSTING that pharma ’science’ and pharma ‘propaganda’ were the same. They were not. So for almost two decades, insulin-using diabetics have relied more on trust (and a willingness or need to embrace myriad add-on protocols/medicines) and achieve no better–only more expensive–outcomes. As you said . . . if technology cannot (yet) prove bioequivalence for this small (non)biotech molecule, I think (if this is to be truly 21st century medicine), research funds need to be spent on improving analytical methodology BEFORE we rush headlong into biotech generics.
Human insulin, porcine insulin and bovine insulin can all be made by rDNA technology (none of the molecules are PATENTABLE.) Let’s compare bioequivalency of these synthetic molecules to cadaver pancreatic extraction and natural animal insulins BEFORE we jump ahead with MORE rDNA discoveries. IOW, let’s start with this small molecule and prove the methodology (not that it can be CREATED, but that it is EQUIVALENT to natural).
(And you thought I was anti-pharma.)
Blow to Biogenerics: Genzyme Can’t Scale Myozyme — Pharmababble
[...] (From The Boston Globe via PharmaLot) [...]