This is clarity?

This is clarity?

Yesterday Diabetic Investor published our annual list of holiday gifts for the diabetes industry. Our holiday gift for the Food and Drug Administration (FDA) was; “To the Food and Drug Administration (FDA) – Clarity. President Elect Obama has pledged to bring transparency to the Federal government, let’s hope this transparency extends to the FDA. The fact is millions of patients will continue to suffer if the FDA continues on its present path. While it may seem obvious that drug companies need to know just what the FDA is looking for to approve a new drug the FDA does not have any clear guidelines as to exactly what a diabetes drug should and shouldn’t do. The fact is trying to get any drug approved under current conditions is like Wiley Coyote trying to catch the Road Runner, the target keeps moving and it’s next to impossible to hit a moving target.

Diabetic Investor had no idea the FDA was paying any attention and issued new guidance for drug companies as to how new drugs would be evaluated. According to a press release from the agency, “We need to better understand the safety of new antidiabetic drugs. Therefore, companies should conduct a more thorough examination of their drugs’ cardiovascular risks during the product’s development stage” said Mary Parks, M.D., director, Division of Metabolism and Endocrinology.

The press release goes on to state “The new guidance, which is effective immediately, defines more robust and adequate design and data collection approaches for Phase 2 and Phase 3 clinical trials than were previously required. Specifically, the guidance recommends that these studies demonstrate that new antidiabetic therapies do not increase cardiovascular risk in comparison with existing therapies—especially when the drugs are used by patients of advanced age or by those with advanced diabetes or renal impairment.”

Reading through the new guidance Diabetic Investor was struck by a few notable items. According to the new guidelines “To establish the safety of a new antidiabetic therapy to treat type 2 diabetes, sponsors should demonstrate that the therapy will not result in an unacceptable increase in cardiovascular risk.” Yet nowhere in the document does the agency define what an unacceptable increase in cardiovascular risk is. The guidelines state “Sponsors should establish an independent cardiovascular endpoints committee to prospectively adjudicate, in a blinded fashion, cardiovascular events during all phase 2 and phase 3 trials.”

Stranger still is how this data is supposed to be analyzed. “Sponsors should ensure that phase 2 and phase 3 clinical trials are appropriately designed and conducted so that a meta-analysis can be performed at the time of completion of these studies that appropriately accounts for important study design features and patient or study level covariates.” Excuse Diabetic Investor for being somewhat skeptical here but haven’t we’ve been down this road already with the Avandia controversy. Here we go again with the dreaded meta-analysis. We can only imagine these independent committee members sitting around and arguing over the conclusions drawn from the dreaded meta-analysis. This is exactly what happened during the Avandia controversy.

Worse for drug companies; “It is likely that controlled trials will need to last more than typical 3 to 6 months duration to obtain enough events and to provide data on longer-term cardiovascular risk (e.g., minimum 2 years) for these chronically used therapies.” So much for making the approval process swifter and cost-effective, thank you very much.

For companies that have already have completed studies the guidance isn’t much better. “Sponsors should compare the incidence of important cardiovascular events occurring with the investigational agent to the incidence of the same types of events occurring with the control group to show the upper bound of the two-sided 95 percent confidence interval for the estimated risk ratio is less than 1.8.” Once again we have absolutely no idea what an important cardiovascular events is.

The guidelines concluded by stating “Sponsors are encouraged to contact the division to discuss specific issues that arise during the development of a new antidiabetic therapy to treat type 2 diabetes.” To Diabetic Investor this last statement proves the agency has a sense of humor. For a document woefully short on specifics Diabetic Investor is surprised the agency even knew how to spell the word let alone use it in a sentence.

Once again the agency has proved beyond a shadow of a doubt they are more interested in passing the buck than providing true clarity.  Instead of more clearly defining just what a drug should and shouldn’t do so that drug companies can design effective clinical trials the agency has once again has created another Pandora’s Box. We can only imagine what happens when this box is opened. If anyone thinks these guidelines will avoid another Avandia controversy please provide Diabetic Investor with whatever it is your smoking.

We can only imagine how someone like Dr. Nissen will jump all over data presented by sponsoring companies. Or watching researcher’s battle over the conclusions that are drawn from the dreaded meta-analysis, just as we did with Avandia. Equally interesting will be just which cardiologist will participate in these “independent committees.” Just as critics jumped all over members of the panel that analyzed the Avandia data for their various ties to drug companies; what qualified cardiologist wants this type of public scrutiny and grief.  In the real world you can’t swing a dead cat without hitting a researchers who does not have some type of association, financial or otherwise, with a drug company. Like it or not researchers need money for research and drug companies are the banks that provide the funds needed.

The bottom line the FDA has asked sponsoring companies to travel down a path with no clear destination.  This isn’t a road map to success but a recipe for disaster. Just in case the FDA forgot Webster’s defines clarity as “the quality or condition of being clear; clearness”.  Or as Ralph Waldo Emerson noted “Strange that our government, so stupid as it is, should never blunder into a good measure.”