Sunday, January 11, 2009

FDA Screening System Unreliable

Study criticizes FDA's screening system

An internal watchdog finds that financial conflicts involving outside researchers who test experimental drugs often remain hidden.
Associated Press
January 12, 2009

Missing information, loopholes and weak oversight hamper efforts to uncover financial conflicts involving researchers who test experimental drugs before companies seek government approval, an internal watchdog finds.

As a result, the Food and Drug Administration's screening system is unreliable, the Health and Human Services inspector general's office said in a report to be released today.

"We found a number of limitations in FDA's oversight, leaving FDA unable to determine whether [drug companies] submit financial information for all clinical investigators," the report said.

Investigators examined 118 new drug applications approved by the FDA in 2007.

Because scientists can be tempted by profits, the government requires disclosure of possible conflicts involving clinical researchers who review medications before drug companies seek FDA approval.

In all, 42% of the applications lacked complete financial information and not even 1% of researchers disclosed possible conflicts. Such limitations "could result in FDA being unaware of a clinical investigator's financial interest, and thus unable to gauge its potential bias on clinical trial results," the report said.

The FDA acknowledged the need for improvements while also disagreeing with some of the inspector general's findings and recommendations.

Drug companies hire outside scientists and doctors to test the safety and effectiveness of medications under development. Such tests provide raw data for the FDA to later decide whether to approve a drug. The process, which uses human patients as medical guinea pigs, is supposed to be governed by strict scientific and ethical rules, including financial disclosure.

The issue is not scientists' compensation for supervising drug development tests but the conflicts that could arise from other rewards, such as honoraria, grants and stock options.

Disclosure requirements were put in place after the 1999 death of a teenager in an experimental gene therapy trial. Among other problems with that clinical trial, it turned out that many of the scientists had financial ties to the drug company.

The inspector general's report found that in 2007, only 206 of 29,691 clinical investigators disclosed potential financial conflicts. By comparison, a study published in the Journal of the American Medical Assn. reported that between 23% and 28% of university researchers had financial ties to the drug industry.

For scientists who did report, the most common financial rewards were consulting fees or honoraria, with a midpoint payment of $47,252.

The report also concluded that financial information gets to the FDA too late in the process. Companies submit the data with their application for a drug's approval. By that stage, clinical tests are complete.
Hat tip to The LA Times


  1. I find the point of this piece a bit hard to follow. I assume _all_ clinical investigators receive compensation - sometimes considerable amounts - for each patient they enroll in a trial.

    The key point seems to be this one: "The issue is not scientists' compensation for supervising drug development tests but the conflicts that could arise from other rewards, such as honoraria, grants and stock options."

    Another ambiguity may be this - if a CRO is given "goodies" collectively (and up to them to divvy them up), it would also be harder to track who is getting what.

    Finally, even if "all" a doc is getting is compensation for each pt. enrolled - no additional perks - that can still be considerable moolah. I'm not imagining docs will, therefore, do clinical trials for free. But the issue goes to a fundamental policy question about essentially universal for-profit clinical trials.

    Is there an alternative? Does there need to be?

  2. Just found a slightly more detailed article on this in the NYT, accessible at:

    What comes through - at least to me - is FDA's virtual contempt toward anyone even raising the question.

  3. JIM - you make excellent points as always. It would and is very hard to track perks given through the CRO, one of the reasons working with a CRO is more enticing. The competition is fierce for top researcher time. That was why on a discussion thread on P'lot, I was arguing for a better system, more of a national and international clearing house for trials. This way the trials would be done more on the potential for the benefit of the disease category. Hopefully that would deter too many different takes on the same product, freeing up more time for newer innovative research. I am aware of one clinical trial right now that should be in many more major centers that it is, but it has been blocked by clinical trials that are no where as innovative and potentially curative as this treatment is. It becomes business/marketing strategy - again not the best drug making it to trials, but more the one with the most money behind it.

  4. Thanks FM. I recall a P'lot thread on which almost all the industry people bemoaned the overshadowing of basic science and testing by marketing plans. Indeed, many blamed pharma's current challenges on precisely that - short-term, market-centered planning.

    Do we need, indeed, to think more radically to save the ship - which means genuine innovation, and putting science back at the core?

  5. Not only that:

    CDER says that the holder of an innovator drug can gain approval for a reformulation using the same criteria that a generic drug maker uses. Cmax, AUCo, Tmax, and T-1/2. In many drugs that is fine. In many other drugs more precise dosing (tighter than FDA bioequivalency) is required for effectiveness, making those ANDA approvals dangerous. (paragraph 4)
    "Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation."

    There is evidently no requirement to inform consumers, doctors, or pharmacists of the changes to these medications, which makes the DAW (Dispense As Written) pointless. It means that doctors cannot know precisely what they are prescribing & pharmacists cannot know precisely what they are dispensing when a reformulated drug retains the name of it's previous formulation.

    How is FDA not contributing to consumer fraud if "consumer fraud occurs when a product or service does not perform in the manner in which it was advertised or represented to perform"?
    In the arena of drugs a generic (or branded reformulation to generic standards) can and will have a different dissolution than the original product. If further testing is not required how can FDA know if the drug is still effective for all of it's indications or for long time users with a narrow therapeutic index?

    They can't.

    I was a guinea pig where a reformulation was physically and financially devastating. According to CDER rule- nothing illegal took place.

  6. Anon - Can you be more specific, as comfortable, about the kind of changes that affected you = meaning: different amount of 'active ingredient,' different fillers, different absorption, etc. This is a different issue than researchers on take, but certainly of interest.

  7. As comfortable, lol.

    These are two bioequivalency comparisons against one innovator product. Both comparisons under fed conditions.
    Notice that the numbers for the same innovator product differs in each comparison.
    This is a published comparison between a generic v the innovator.

    Generic: 1.18 v Innovator: 1.36~ Ratio 87.0, 90% Confidence interval 80.6 to 93.8
    Generic: 29.4 v Innovator: 33.9~ Ratio 86.7, 90% Confidence interval 81.4 to 92.4
    Generic: 6.50 hrs v Innovator: 7.48 hrs
    Generic: 15.1 hrs v Innovator 15.5 hrs

    Now the numbers provided by the manufacturer for their new product as compared to the innovator- as given to a licenced pharmacist.

    NMP 1.19 v Innovator 1.26~ Ratio 94.8, 90% Confidence interval, 81.95 to 109.62
    NMP 33.5 v Innovator 31.8~ Ratio 105, 90% Confidence interval, 99.29 to 111.47
    NMP 5.04 hrs v Innovator 6.01 hrs
    NMP 13.7 hrs v Innovator 12.8 hrs

    If the first set of innovator numbers used were compared to the NMP it would look like this:

    NMP 1.19 v Innovator 1.36 (you do the math)
    NMP 33.5 v Innovator 33.9
    NMP 5.04 hrs v Innovator 7.48 hrs
    NMP 13.7 hrs v Innovator 15.5 hrs

    You can decide which set of numbers for the innovator product you choose but in my opinion it makes the science of bioequivalency sketchy.

    As for inactive ingredients: The manufacturer told us they were the same and they made a public statement to that effect. Any chemist could tell you there is more than a few pharmaceutical grades of lactose. When they list lactose and are not more specific you wonder if they are using wet or dry granulation, if there is a difference in density or porousness, how the active ingredient binds to the excipient, and in return, how it is delivered into the system. That is the role of excipients and it is the job of R&D to make an effective product from them. Another issue is the recent movement from a bovine based magneseum sterate to one of a vegetable base. FDA admits not knowing the result of this change but also admits that the ingredient is significant in product quality.
    On the list of ingredients you will read lactose and magneseum sterate. That does not mean the excipients are the same. The drug maker admits the AUC has changed.

    While the drug maker said the excipients are the same- they also made the comment to one man's congressman that they believe it was the change in excipients that caused his adverse events after the reformulation.

    It doesn't matter because the manufacturer claims the FDA suggested the reformulation. FDA is desperate to find a way to better monitor and create more consistent drugs. We were used in a failed attempt to do that. Scary thing is that FDA recently contracted for more work in this same area of study. Evidently our MedWatch reports did not deter them. What drug do you suppose is next?


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