FDA Criticized For TB Drug Approval

FDA Criticized For TB Drug Approval

April 3rd, 2013 // 4:41 pm @

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Late last year, the FDA approved a first-in-class medication to treat multi-drug resistant tuberculosis. The agency did so after an advisory committee unanimously recommended accelerated approval for the drug, which is called Sirturo and marketed by Johnson & Johnson. But the FDA is being criticized for its decision and questions are being raised about its reliance on surrogate markers.

An essay in the Journal of the American Medical Association notes that the pivotal Sirturo trials were small and produced troubling data. Ten of 79 patients given the drug died, compared with two of 81 in the control group. And five of the 10 deaths were due to TB, indicating treatment failure. The trials measured the ability of the drug to convert a patient’s sputum culture from positive to negative.

Of course, MDR-TB is a serious illness, although less so in the US, where the biggest concern is among the foreign-born, according to the US Centers for Disease Control and Prevention (click here).  But few effective medicines have emerged and, in general, the FDA is under considerable pressure to approve more drugs more quickly.  This helps explain a growing reliance on surrogate markers.

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This is why the Sirturo approval is problematic, according to Jerry Avorn, a professor of medicine at Harvard Medical School and chief of the division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital. He writes in JAMA that, given the trial results, the FDA was too lax in its requirement for J&J to conduct a mandated confirmatory trial.  And he points out the required trial will not start until later this year or early 2014, and the results are not due until 2022.

“It is not clear why the agency did not defer its decision about approval until further outcome evidence was available and demand it sooner than 2022.  Further research might reveal that the novel mechanism of action could prove helpful to patients with MDR-TB,” he wrote in JAMA. “But adequate clinical outcome data are not available to demonstrate that this is the case, and there is worrisome evidence in the opposite direction” (here is the piece).

Meanwhile, J&J (JNJ) can benefit considerably. Sirturo was given orphan drug status due to the low incidence rate in the US, which brings R&D tax credits. Also, J&J received a voucher since Sirturo will treat a neglected disease. This voucher grants J&J expedited review of another drug of its choice. The value can reach untold millions of dollars, because J&J can use this to seek approval for another drug with great sales potential or sell the voucher to another drugmaker.

In Avorn’s view, “the potential financial benefit-risk profile of (Sirturo) for its manufacturer appears to be clearer than its potential clinical benefit-risk profile for patients.”  Avorn, by the way, is not the first to express concern about Sirturo trial results. Public Citizen, the consumer watchdog, complained in vain last year that the FDA should not approve the drug (read back story here).

Avorn then introduces a broader issue – other instances where the use of surrogate markers went awry, such as the Avandia diabetes drug and the Vytorin cholesterol-lowering agent. Of course, surrogate markers have proven viable for use in approving other medicines. But Avorn suggests surrogate markers are being used by an agency constantly pushed to issue approvals. Sirturo, for instance, was approved just as 2012 drew to a close, raising its approval numbers for the year.

“FDA officials may believe they boxed themselves in if they agreed to approve the drug based only on its effect on sputum, and perhaps they felt committed to that decision even if the drug might not actually treat TB effectively, or might even increase the risk of death,” he writes us.

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“But despite that, there is still the regulatory requirement that a company has to do a confirmatory randomized clinical trial for a drug that was given fast-track approval based on such a surrogate measure. It’s hard to understand why the agency would approve the drug and then give the company a full ten years to do that confirmatory trial. In the face of the worrisome initial data, who could possibly think that timeline was a smart idea?

“This is a clear example of how over-reliance on surrogate measures can cause problems. As the agency makes more decisions based on such markers, we may see more examples like this in which a new product is approved based on an easy-to-achieve change in a lab test or imaging marker, but isn’t ultimately shown to improve actual clinical outcomes. It’s like the pharmaceutical version of the canard that the operation was a success, but the patient died.”


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