The "Truth" About Follow-On Biologics in America
The Boston Globe reported the other day that regulators at the US Food and Drug Administration (FDA) rejected a request by Framingham, MA-based Genzyme to continue to market and sell its Pompe Disease drug, Myozyme, which is being manufactured at a newly built production facility in Allston, MA. Myozyme is a recombinant version of alglucosidase alfa that is used to treat Pompe Disease, a rare enzyme storage disease. Genzyme is seeking to transfer Myozyme manufacturing operations from its Framingham production site to the larger Allston facility to meet increased market demand for the drug. Pompe Disease affects an estimated 5,000 to 10,000 patients worldwide.
According to Genzyme, FDA rejected the manufacturing transfer request because of slight differences that were detected in the carbohydrate array of Myozyme manufactured at the Allston site as compared with similar material produced in Framingham. Because of these slight but detectable carbohydrate variations, FDA is insisting that Genzyme conduct new clinical studies (safety and efficacy) with Allston-manufactured material before it will allow the company to sell it in the US. Company officials claim that they have data from approximately 900 patients who are currently taking the new version of the drug and will share this information with the agency. Interestingly, over 40 countries have already approved the new version of Myozyme manufactured at the Allston facility.
Personally, I think it is perfectly reasonable for FDA to request additional clinical studies to insure that the Allston version of Myozyme is as safe as the original. For those of you who don’t know, Myozyme was originally approved as an orphan drug. Typically, this means that only a small number of human safety and efficacy trials were conducted to gain initial approval for a product. Therefore, I think that Genzyme should only be required to conduct safety trials (not efficacy studies) before the Allston material is allowed to be sold in the US. That said, the safety data that Genzyme has already collected from the 900 patients using the Allston-manufactured drug may obviate the need for any safety studies at all!
If FDA forces Genzyme to conduct new efficacy and safety studies, then it wouldn’t be unreasonable for Genzyme to ask the agency to issue a second license for the “new” Myozyme. After all, it appears that FDA is treating the Myozyme manufactured at the two Genzyme –run production facilities as distinct and unrelated drug products. And, according to the provisions of the Orphan Drug Act, newly approved orphan products are entitled to receive seven years of market exclusivity from the their date of approval. Therefore, if FDA issues a new license for the Allston material, Genzyme ought to receive an additional seven years of market exclusivity for Myozyme!
As one Genzyme official noted, FDA’s decision regarding Myozyme sends “a very loud and clear message and sets a very high bar.” It suggests that FDA regulators will be reluctant to approve any generic versions of biologics or biotechnology drugs without clinical studies that prove that the new drugs are as safe and efficacious as the originalseven though there are only slight differences in the molecules. Unfortunately, this stance is consistent with the position that FDA has taken on the follow-on biologics aka biogenerics debate for the past 10 years. I guess the old adage, “you can’t teach “old dogs’ new tricks” is particularly apt here.
It appears to me that FDA is wedded to a one-size-fits-all regulatory approach rather than the case-by-case review process that was formally adopted by the European Medicines Agency (EMEA) for biosimilars that almost three years ago. EMEA regulators thought long and hard about whether a case-by-case or a one-size-fits-all a regulatory framework was the most appropriate approval process generic versions of biologics. Opting for a case-by-case review process has permitted EMEA to approve at least 5 new biosimilar products in the past three years. These newly approved biosimilar products have provided people in Europe and elsewhere with access to affordable and potentially life-saving biologics and biotechnology drugs.
To the best of my knowledge, nobody has suffered serious adverse effects or died from using any of the biosimilar drugs approved by EMEA. Maybe FDA ought to stop listening to Washington lobbyists and company insiders and, instead, follow EMEA’s lead to craft a reasonable regulatory framework to approve follow-on biologics in the US.
Until next time….
Good Luck and Good Job Hunting!!!!!!!!!!!!!!
Perhaps, Genzyme's main mistake was in not pursuing a follow-on biologic/biosimilar type supplemental approval. For example, if it had conducted comparative bioequivalence studies that actually showed that the products were clinically equivalent, despite their differences, the new product would likely have simply received a supplemental BLA. Otherwise, with the products detectably different and with efficacy data for nearly 1,000 patients available and with positive results from this study reported/hyped but not included in Genzyme's application, one can see that FDA is in a position where it has no alternative but to request this clinical data be included in a full BLA application (and it gets more user fees from a full application).
Besides full BLA approval granting 7 years orphan exclusivity (presuming this happens, with FDA criteria for orphan exclusivity seemingly different than for judging NCEs/NMEs and full vs. supplemental approvals), full approval for much the same product may get Genzyme a lot more (a windfall). From the vague language in proposed follow-on biologics bills, it appears that 12 (or whatever) years of exclusivity would be granted to all full BLAs (i.e., BLAs appear to be the criteria for what gets exclusivity). So, Genzyme could really come out ahead, if this simplistic method for determining what deserves exclusivity is adopted retrospectively. This shows how easy it will be for innovator companies to game such a proposed exclusivity-granting regime. All they will have to do is obtain full approval for minor manufacturing or formulation changes, and they've got a new product with renewed exclusivity. This is particularly relevant, if legislation of FDA requires follow-ons to be compared only against currently-marketed products, with companies needing only to modify their products when loss of exclusivity approaches. This will cost more than a supplemental or follow-on type of approval, but for over a decade more exclusivity, innovators would be foolish not to take advantage of this.
Ronald A. Rader
Author - Biopharmaceutical Products in the U.S. and European Markets
Web site: www.biopharma.com