FDA Diabetes News

This week, there were a few interesting potential developments in the area of treatment for type 1 diabetes, two of which had to do with the U.S. Food & Drug Administration. This comes on top of another development which occurred late last year which might be worth mentioning here.

FDA Approves Generic Altace

Many people with living diabetes are taking ACE (angiotensin converting enzymes) inhibitors for either blood pressure control, to prevent kidney damage, or both. ACE inhibitors are routinely prescribed as prophylactics to prevent kidney damage even where signs of kidney damage do not exist. In November 2005, the FDA approved a generic version of ramipril, better known by its brand name Altace, the same drug on which several of the clinical trials related to kidney disease and ACE inhibitors were actually conducted. It is believed that because all ACE inhibitors work in a similar manner, they are essentially interchangable. But ACE inhibitors differ in how they are eliminated from the body and the necessary doses required for treatment. For example, some ACE inhibitors need to be converted into an active form in the body before they begin to work. Also, some ACE inhibitors may work more on angiotensin converting enzymes that are found in body tissues than on angiotensin converting enzymes that are present in the blood. The importance of this difference, or whether one ACE inhibitor is better than another, has not been determined. But because many of the actual trials were done using ramipril, we know that ramipril works on the tissues, and more specifically, the kidney tissues. The approval of a generic version of this drug is a significant benefit to patients, as the cost of taking this drug will decline significantly.

FDA Approves Generic Human Growth Hormone, Generic Insulin Could Soon Follow

The latest development occurred on Wednesday, June 1, 2006, when the FDA announced that it had approved a copycat version of human growth hormone made by a unit of Novartis called Omnitrope which is made by its Sandoz subsidiary. This was a very closely watched decision amid debate over how the U.S. should move toward generic biotechnology drugs. Prior to this approval, there were NO generic biotechnology medicines sold in the U.S., including generic insulin. The debate surrounding biotechnology "drugs" has been brewing for several years, but until the FDA approved this medicine, there has been little (if any) progress. First, some background on why this is an important development, even if it applies to a medicine totally unrelated to diabetes treatment.

Since 1984, when Congress passed the Drug Price Competition and Patent Term Restoration Act (better known as the "Hatch-Waxman" Act), generic drugmakers have had a cheap and relatively easy way to get copycat drugs on the market after the patent protections on the originals expire. Because most chemical drugs are made through chemical processes that have been refined for 100 years, the manufacturing of bioequivalent drugs is almost foolproof. The relative simplicity of making chemical pills enabled Congress to legislate via Hatch-Waxman that generic manufacturers did not have to repeat the extensive and expensive 3 phases of clinical trials normally required to prove the safety and efficacy of brand new drugs.

But none of this applies to so-called biotech "drugs" because they are not actually drugs at all, but synthetic proteins (such as insulin), enzymes or antibodies. They are made by splicing genes into fast-growing organisms such as bacteria or yeast using recombinant DNA technology, which then multiply to produce vast quantities of the desired medicine. Because of this, it is virtually impossible to test biogenerics for bioequivalency the way it is done with chemical drugs. Also, because these medicines are typically injected, other tests must be developed to determine whether a biogeneric will have the same therapeutic effect as a name-brand biologic -- therein lies the rub.

As one might guess, big pharma does not like generics because they effectively kill some of the industry's biggest cash cows. Not surprisingly, the industry is opposed to the FDA making it any cheaper or easier for potential competitors who make biotech drugs to enter the market. For example, the Biotech Industry Organization argues that making biologics is so complex that generic firms should have to prove their safety and effectiveness as if they were creating brand new medicines. Of course, this would make less expensive biogenerics virtually impossible to bring to market. As might be expected, pharmaceutical giant Pfizer filed a petition with the FDA opposing approval of Omnitrope claiming that it would not be safe to claim it is a bioequivalent to its pricy growth hormone. But the FDA did not call Omnitrope a bioequivalent, it called it a "follow-on" version.

Due to historic reasons, (most notably, the fact that insulin and human growth hormone were the only two biologic medicines on the market when Hatch-Waxman was passed in 1984), and their patents were still young at that time, these two biologic medicines are grandfathered under the terms of Hatch-Waxman, while virtually all other biotech medicines must wait for the FDA to outline guidelines for bioequivalency, which is something the FDA has delayed doing for several years. However, Hatch-Waxman allows approvals like Omnitrope's, or even potential approvals of true generics, because they are not forbidden under the law, "as long as the current state of science allows the evaluation necessary to support approval," the FDA said in its response to Pfizer's opposition. Apparently, the FDA was satisfied that the science for Omnitrope was sufficient enough for approval.

The FDA said that it found that the active ingredients in Omnitrope and Pfizer's brand-name Genotropin were "highly similar," therefore the agency could rely on its finding that the original Pfizer product was safe and effective in approving the Sandoz copycat drug. It was also supported by additional studies conduced by Sandoz. But the FDA noted that its approval didn't rest on proprietary information from the Genotropin application. Sandoz said that it had submitted an "abbreviated" version of the typical clinical trials performed to prove a drug's efficacy, as well as safety studies and a detailed document outlining how it planned to manufacture Omnitrope and ensure its quality.

As anyone who has ever switched insulins has learned, being able to switch from one brand to another is seldom accomplished without adjustments. But this is also true for using these medicines every day. It is far more complex than swallowing a pill or two. As people with type 1 diabetes know only too well, dosing insulin is hardly a science, either, so the promise of having access to follow-on versions of insulin is potentially great news, as the cost of insulin has risen steadily over the years and there is currently no generic competition. But insulin analogs, which now command much of the market, still have patent protection until June 16, 2014, when the last patent on Lilly's Humalog (insulin lispro rDNA origin) expires. Novo-Nordisk (insulin aspart rDNA origin) will lose patent protection on Novolog/Novorapid very shortly thereafter. Poland's Polfa Tarchomin already has a Humalog clone called Liprolog sold in certain markets, but the more immediate prospect of any generic insulin formulations in the U.S. and Canada remains an important development.

Cangene Corp., a Canadian firm, was mentioned by the San Francisco Chronicle as one of the firms that initially expressed interest in bringing a "generic" rDNA insulin to the market. In 2002, Cangene spokesman Mark Langstaff told the San Francisco Chronicle that, based on initial FDA guidance, his company had run a small clinical trial comparing its generic against the Eli Lilly Humulin Regular insulin that came off patent in 2002. At the time, Langstaff declined to provide any details other than to say that Cangene, which already manufactures several other biotech products, had planned to seek FDA approval to sell its generic insulin in the United States. However, I recently contacted Cangene to inquire, and a company spokesman said "Unfortunately Cangene was misquoted by the reporter from the SF Chronicle. Cangene has never been involved with insulin. Our lead biotech products are HGH and GM-CSF." It is unclear whether the company might reconsider given the decision on Omnitrope, but it does appear to provide a way for them to pursue it if they wish. Other potential generic insulin makers include several pharmaceutical concerns based in India, including Wockhardt, Biocon, Zenotech Laboratories Ltd. and potentially Shreya Life Sciences Pvt. Ltd., as well as several companies based in Eastern Europe, including Poland's Polfa Tarchomin and Bioton. Although at least one firm based in Brazil (Biobrás S.A.) was acquired by the global giant Novo-Nordisk in 2001 and is therefore unlikely to enter the generic insulin market, Argentina's Laboratorios Beta remains a viable potential supplier which could emerge in the future. Laboratorios Beta could also enjoy a huge currency advantage in the U.S. since its profits would be tied to Argentinian Peso. Relatively small sales could deliver big profits to the company, although they may require assistance from a North American partner to mitigate the expense required to enter the market. Finally, Novartis' Sandoz unit appears particularly well positioned to pursue a generic insulin in the near future. The Wall Street Journal (see: http://online.wsj.com/article/SB114904669181067236.html to read the full article, subscription may be required for access) reported that Sandoz believes there is a viable pathway for getting a limited number of follow-on biotech drugs approved in the U.S., and it "is currently developing five others." Insulin is very likely to be among those being developed because it follows the same exemption as human growth hormone, and it is a relatively simple protein.

The industry bases its assumptions on sales of existing medicines, and some analysts believe that there is not room for more than a few large generic manufacturers. But in recent years, Lilly has eliminated animal-sourced insulins and chosen not to replace them with rDNA versions, and the company has discontinued several older forms of insulin, including the lente and ultralente varieties. The company had expected that consumers with diabetes would be forced to migrate to the company's more expensive analogs, but the emergence of lower-cost versions of its Humulin insulin formulations could really change the dynamics of the market. Also, resurrection of discontinued insulin formulations (including rDNA versions of animal insulin as well as other discontinued varieties) could potentially be an opportunity for generic manufacturers to market versions of these insulin formulations and capture customers on a basis other than price. Although there are no guarantees, it seems quite likely that we will soon see the emergence of some new insulin manufacturers as a result of this development.

Also Coming Soon: Generic Zocor

Finally, this week, Standard & Poor's Equity Research reiterated a "buy" rating on Israel-based Teva Pharmaceutical Industries after the company announced that it had received tentative FDA approval of a generic version of blockbuster cholesterol drug Zocor (known generically as simvastatin). The company said it expects to receive final U.S. Food and Drug Administration approval when Merck's patent for Zocor expires in late June. "Barring unforeseen circumstances, we see Teva able to launch the drug on or shortly after June 23" wrote analyst Phillip Seligman. (Incidentally, June 23, 2006 is the exact expiration date for Zocor's patent.) This will be among the first of the statin blockbusters to lose its patent protection, and like the other two developments I wrote about in this posting, it promises to reduce the cost of comprehensive treatment for patients with diabetes. Doctors try to aggressively treat any sign of heart disease with medications such as statins because the mortality rate is significantly higher in patients with all types of diabetes, although as my previous post indicated, the cause for heart disease in type 1 diabetes is now known to be unrelated to the cause of heart disease associated with type 2. Regardless, Zocor is Merck's largest selling drug and is the is the second largest selling cholesterol lowering drug in the world, with 2005 sales of $5.3 billion. It follows only Lipitor (atorvastatin), the world's bestselling drug manufactured by Pfizer, which recorded 2005 sales of $12.2 billion.

Teva also announced that the FDA had appealed a May 1, 2006 federal court decision, which ruled that the agency's denial of a review of a 6-month generic exclusivity on the drug was unlawful. Analyst Seligman was quoted as saying "our earnings model unchanged until its exclusive launch is certain."

Teva Pharmaceutical Industries is the largest generic drug manufacturer on earth. According to The Wall Street Journal, Teva fills more prescriptions for Americans than any other company except Pfizer Inc. (see: http://online.wsj.com/article/SB109890935431257528.html to read the full article).

What do all of these developments mean? Well, hopefully, lower costs and increased competition. True, they are not improved treatments for type 1 (or type 2) diabetes, but they do make it less costly. Not exactly a cure, but hey, a few more dollars in our pockets could easily be donated to a diabetes charity of your choice, so I will take these developments as welcome news.