The FDA Advisory Committee meeting is now in the history books and the hopes of JAZZ Pharmaceuticals for Xyrem having a fibromyalgia indication seem lost forever. We monitored the discussion throughout the day and were happy to see that the Panel members weren’t pulling any punches. They confirmed our August 19, 2010 opinion that the risk clearly outweighed the benefits. The only surprise of the day came when the FDA ended the voting after the Panel declared that the proposed REMS program from JAZZ was inadequate. This avoided an up and down vote on the safety of the drug. We imagine that the Panel would have voted overwhelmingly negative on the safety of the drug. Accompanying that vote would have been an equally negative dialog that would have challenged the wisdom of keeping the drug on the market. In the absence of that negative vote, FDA and JAZZ can strengthen the existing REMS program and be in a stronger position to respond to the calls to withdraw the drug which are likely to be made.
Archive for August 2010
Bloomberg today announced that the FDA review of Xyrem that has been provided to the Advisory Committee members reports that the drug is safe and effective for its intended proposed use in patients with fibromyalgia. As has been reported widely, the active ingredient, gamma hydroxybutyrate, has been illegally formulated as a street drug and associated with date rapes.
The FDA review really shouldn’t come as a big surprise. The drug is currently approved as safe and effective for the treatment of narcolepsy BUT… And this BUT is the detail in which the devil usually hides. It is currently considered a Schedule III controlled substance with a well thought out, limited distribution system. Even with this rigorous control system and even with the more rigorous system of a Schedule III drug in a controlled clinical trial, it is being abused and misused by other people, and has been associated with date rape. While the diversion rate is remarkably low, so is the use of this drug. The sponsor, Jazz Pharmaceuticals Inc, reports 26,000 narcolepsy patients treated between 2002 and 2008, certainly in keeping with its Orphan Drug status of less than 200,000 patients. Fibromyalgia on the other hand represents a patient population of 5,000,000. Doing the arithmetic (5,000,000/26,000), we find this almost 200 fold increase in the exposure to represent a significant challenge to an already cumbersome distribution system. Will the FDA take the chance that approval of this drug could result in a potential 200 fold increase in the number of date rape cases reported?
Will the sponsor, Jazz Pharmaceuticals Inc, be able to jazz up the current REMS program, including the distribution system, to plug existing holes and accomodate the increased number of patients?
The Advisory Committee discussion should be interesting. We think it will focus less on efficacy and safety and more on REMS and distribution systems. We think the Panel will conclude a 200 fold increase in the potential number of date rape cases has the same negative effect on the approval of a drug as would a 200 fold increase in the number of heart attacks for any “me too” drug trying to expand its approved indication. If they don’t, the FDA will. Remember, its all about benefit/risk and benefit/risk on this one is NFC!
Abbott Laboratories drug Meridia will be discussed at a Sept 15, 2010 Advisory Committee Meeting. This presents a significant challenge to Abbott. They have data suggesting an increased risk of cardiovascular side effects with Meridia compared to placebo and have strengthened the Warnings section of the US package insert. These risks however were troublesome enough to withdraw the drug from European markets. While Abbott will bring their best case to the Advisory Committee Meeting, it is difficult to think that the FDA will take a softer stand than Europe and allow the drug to remain on the market, especially when alternative treatment for obesity remains diet and exercise. We think the Advisory Committee and the FDA will “push themselves away from the table” on this one.
Reuters and the Los Angeles Times have opined on a recent study published in the Annals of Internal Medicine that raises questions about possible bias in clinical trials that are funded by the pharmaceutical industry. There are 2 points that need to be emphasized, so listen up. First, the pharmaceutical industry is spending its own money on clinical trials, not government grants, not money from charitable organizations. They are accountable to share holders for wisely spending these monies. Therefore, they design studies that are generally simple – simple questions that are either yes or no. Second, they are goal oriented, seeking information that is useful in determining the safety and efficacy/effectiveness of a particular drug, unlike government and academic research that tends to design studies which raise unanswered questions which must be answered in yet another government-grant sponsored study.
The article also challenges the delay in publishing industry-paid studies. Leaving the proprietary nature of the information aside, it costs money to publish a study – physicians must prepare the data for publishing, biometricians must analyze the data for the writing team, medical writers must prepare the documents, and all of this must be subjected to a quality review. All of these are resources that are also needed to prepare documents for regulatory submission. Now, I ask you – does it make sense for a company to prepare Phase I and Phase II studies for publication before there is an indication that the drug is acceptable for submission to a regulatory authority in support of a marketing application? Of course not.
The academics that raise the concern should look within their own ranks. They should ask themselves why their colleagues are not doing Phase I studies. They know the answer. Phase I studies are cookie cutter design studies with no opportunity for the opinion leaders to introduce new concepts or analysis. In other words, Phase I studies do not enhance their bibliography.