Tuesday, April 22, 2008

Why A Recent FDA Decision Should Have You Concerned

Today, the Boston Globe reported that the U.S. Food and Drug Administration rejected Genzyme Corp.'s request for permission to sell in the U.S. a version of its Pompe disease (a rare inherited and often fatal disorder that disables the heart and muscles) drug, called Myozyme, the company wanted to make at its Allston, Massachusetts manufacturing plant. Presently, the company can only make this drug at a smaller facility in Framingham, Massachusetts. The FDA ruled that any Myozyme made at the second plant should be considered a different product because of small differences in its chemical structure, and in order to receive FDA approval, the company needs to file another application with new data showing the drug is safe and effective in large numbers of patients. That means costly clinical trials and a lengthy approval process for the company.

But this decision demonstrates that drugs made with biotechnolgy via recombinant DNA manufacturing, even made by the very same company at a different facility, suggests that regulators are reluctant to approve other versions 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.

So what does this have to do with diabetes?

Well, since 2005, all of the insulin manufactured for human use in the U.S. is made by recombinant DNA technology (some FDA-approved animal insulin is still sold legally in the U.S. for veterinarians, but it is imported from the Netherlands), so insulin is a biotechnology drug -- sort of.

The regulation of insulin is an anomaly even within the FDA. Insulin, along with human growth hormone (HGH) are grandfathered as small-molecule drugs governed by the Federal Food, Drug & Cosmetic Act, while virtually all other biotechnology drugs including vaccines are ruled by the amended Public Health Service Act. The law considers insulin and HGH small-molecule drugs even though their manufacture is covered by the Center for Biologics Evaluation and Research (CBER) within the FDA, which is one of six main centers at the FDA responsible for assuring the safety, purity, potency, and effectiveness of biological and related products. Its primary objective is to ensure that all prescription and over-the-counter (OTC) medications are safe and effective when used as directed.

Some History

Congress enacted the insulin amendment in December 1941. This law served patients very well, had a very marginal cost to manufacturers and also helped to establish insulin as one of the safest drugs regulated by the FDA. A much more complete history of the insulin certification process can be found at the PubMed website.

But 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. In effect, governance of insulin had to comply with the FDA's good manufacturing standards, but the batch testing mandated on virtually all other biotechnology drugs became strictly voluntary.

Novo Nordisk: The Manufacture of Insulin Must Be Monitored Closely

Some manufacturers, such as Novo Nordisk continue to adhere to stringent manufacturing standards. 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."

That admission was important, because it suggests strongly that the FDA's decision regarding Genzyme Corp.'s request to make Myozyme at its Allston, Massachusetts manufacturing plant was correct. However, not all insulin manufacturers adhere to the same stringent manufacturing standards as Novo Nordisk does. For example, in February, I reported that Indianapolis-based drug giant Eli Lilly and Company has been farming out the manufacture of at least some vials of Humalog and Humulin R to a third-party.

If we are to believe rival Novo Nordisk's testimony before Congress, then the reality is that while Lilly is not violating any law, it seems clear that the 1998 removal of regulations regarding insulin certification was a dangerous decision which needs to be changed urgently to ensure the safety of patients. Why is it that Genzyme's manufacture of Myozyme made at a facility other than Framingham, Massachusetts needs trials to prove its the same drug, but Lilly can so easily have Hospira, Inc. manufacture Humalog and Humulin R in Kansas and its considered exactly the same drug? The simple fact is that it is NOT the same drug, and if we're going to insist that generic biotechnology drug manufacturers must undergo clinical trials, then the same needs to apply to Lilly's Hospira contract manufacturing.

What Needs to Be Done?

There is a simple way to resolve this issue. Congress must amend the section of the Food and Drug Administration Modernization Act (FDAMA) of 1997 which removed the Regulations Regarding Certification of Drugs Composed Wholly or Partly of Insulin. This will require more intense monitoring of these medicines to ensure consistency in the potency and safety of insulin. Another way is to pass a law mandating that insulin and HGH can no longer be governed by the Federal Food, Drug & Cosmetic Act, but must be governed by the Public Health Services Act like virtually all other biotechnology medicines. But in order for these changes to occur, you must write to your Representatives and Senators in Congress demanding that these changes be made. Tell them why it is important to you personally (they find personal stories very useful in letters they receive because it helps them to address these issues in Congress. If you suspect that your dosage for Humalog differs from one vial to the next, tell them it may be because its made by a different company!) To find your Congressmen/women, visit http://www.visi.com/juan/congress/.

5 comments:

Anonymous said...

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?
--Brent

BetterCell said...

"I reported that Indianapolis-based drug giant Eli Lilly and Company has been farming out the manufacture of at least some vials of Humalog and Humulin R to a third-party."

I wonder if China might be one of those outsourced countries that have also taken up Insulin manufacturing as part of their non-safety/obsession with "Money-Making by any means possible," This has of-course been responsible for the Deaths of many people here in the U.S.A., at least 81 so far because of contaminated Heparin.
.........The list goes on with the contaminated pet food resulting in the Deaths of many House Pets here in the U.S.A. and Europe along with contaminated Colgate toothpaste from China as well.
All in the name of outsourcing to countries that have a poor history of safety and where Life does not seem to be as precious and respected as in this country.

Scott said...

While I would not put anything past the company, it seems highly unlikely because while they can outsource manufacturing without much effort, the factories that they outsource to must still be FDA approved, and there are not currently any companies in China who have FDA approval to make synthetic "human" insulin (although China's Wanbang Biopharma Ltd. may be seeking approval, so far they do not have it).

However, the issue is that safety of rDNA insulin is not required of the manufacturers beyond the intial plant approvals and very general good manufacturing standards. Batch testing would ensure we are getting what we pay for; Lilly cannot ensure this with a subcontractor, Novo does do it with its manufacturing facilities which are FDA-approved, and I'm not completely certain about Sanofi Aventis' procedures -- to the best of my knowledge, the insulin they sell in the U.S. is manufactured exclusively at the company's plant in Frankfurt, Germany.

Anonymous said...

Scott - You really don't understand the whole story here...
Presently, the company can only make this drug at a smaller facility in Framingham, Massachusetts. The FDA ruled that any Myozyme made at the second plant should be considered a different product because of small differences in its chemical structure, and in order to receive FDA approval, the company needs to file another application with new data showing the drug is safe and effective in large numbers of patients. That means costly clinical trials and a lengthy approval process for the company.

But this decision demonstrates that drugs made with biotechnolgy via recombinant DNA manufacturing, even made by the very same company at a different facility, suggests that regulators are reluctant to approve other versions 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.

1. These products were not simply made at a different facility - the product was MADE IN A LARGER REACTOR so technically the process was different. Becuase the cells used to make this product BEHAVE differently they produced a DIFFERENT MOLECULE

2. Now the difference in the molecules to you may have seemed small, they are not. The changes that happened on the drug happened in a CRUCIAL place - potentially affecting how the drug works. Take for instance a key - it has a bunch of little grooves on it - if the grooves are wrong they will not open YOUR front door. Well they figured out that when the cells were grown in a bigger vat, the "grooves changed". Potentially if they hadn't figured this out - well many people may have been taking a drug that didn't work. Not as life-threatening as non-functional insulin, but still.

3. Comparing insulin (with a molecular weight of 5.8 kda and a length of 51 amino acids) to myozyme (110 kda and 896 amino acids) is like comparing something build with legos to a real structure. Making large molecules is TOUGH, insulin is little & easy.

4. Drug manufactures manufacture biologic drugs OFTEN in multiple locations - but they do it AT THE SAME SCALE SIZE AND may not depend on certain "key grooves" like Myozyme.

Just some things I thought you you should know for future reference on this subject.

Scott said...

Anonymous,

I'm afraid you seem to be overlooking the very issue this post was about; I don't have much concern about Myozyme per se. This post had almost nothing to do with Myozyme, rather it was about the lack of monitoring of biosynthetic insulin production and few remainding protections which existed were arbitrarily removed without much thought by lawmakers thanks to incessant lobbying by the drug industry back in 1997. The issue of Myozyme's manufacturing and the issues that were cited by the FDA were cited as an example, but were really meant to introduce the subject I wrote about. You seem fond of demonstrating your knowledge on the subject by pointing out the molecular weight differences between these two molecules (meaning, insulin and alglucosidase alfa, better known by its brand-name Myozyme), but seem to neglect the fact that because both are proteins, the molecular weight isn't all that renders a protein-based therapeutic effective, even if it is applicable to Myozyme specifically. Grooves are an issue for alglucosidase alfa, while folding is a critical issue for insulin, and lack of monitoring for BOTH can have dire consequences.

As a proteins, misfolding of the insulin molecule can have a profound impact on its time-activity profile, and potentially invoking an immune response rendering the protein less predictable and far more dangerous, in spite of its relatively smaller molecular weight. Immediately after biosynthetic insulin was introduced, for example, there were complaints from around the world that patients reported dramatic increases in hypoglycemia unawareness (where blood glucose levels plunge to dangerously low levels without any symptoms) with the synthetic version, but not with the natural product. While considerably less complex than Myozyme, insulin is NOT a small-molecule chemical drug (even if the law considers it one), but a protein. You are correct in that glycosation is more of an issue for larger-molecule proteins, but that does not really validate your presumption that because insulin is a well-characterized protein that is "little & easy" as you have stated.

The bottom line is that the FDA is here to protect U.S. Citizens' Food and Drug Supply, it does not work for the drug and biotech industry and owes absolutely nothing to drug manufacturers, nor is the FDA industry's partner (in spite of what Andrew von Eschenbach may have suggested under his leadership during the preceding 8 years). We should not care so much about delays or costly clinical trials but about the ultimate safety of the products biotech companies are pushing (and in the case of insulin, literally pushing on patients, as some 300,000 patients who preferred insulin derived from the pancreatic glands of abattoir animals, were never given a choice when the industry suddenly removed those products from the U.S. market, in spite of never having proven its bioequivalence, or even demonstrating a market necessity for the product; rather, we served as guinea pigs that spawned an entire biotechnology industry that routinely abuses patients for profit, yet the clinical evidence of the benefits of these products have routinely been disputed in every major meta-analysis that has looked at them). It is wonderful if biotechnology medicines have saved the lives of some individuals, but you seem to be blithely naive to some very serious issues that will ultimately impact the safety of individuals whose very lives depend on these products. I hope in time you will reconsider your comment relative to the entire context in which this post was intended.