Tuesday, January 13, 2009

FDA, Thanks for the Warning!

As reported in the Associated Press, the FDA just announced that it had completed its analysis of Singulair for suicide, and found absolutely no link.

"Regulators said that only one in nearly 10,000 patients taking Singulair in clinical trials reported suicidal tendencies. No patients committed suicide."

I blogged about this when the FDA announced it was going to look into the matter back in March. I am no fan of Singulair (see here ), but was extremely skeptical of this link given the relatively clean safety profile of singulair, the lack of biologic plausibility, and the fact since millions of patients with allergies and asthma take Singulair (which is unfortunate, because it doesn't work all that well and extremely expensive), if there was a really link it would've shown up by now.

I have no problem with the FDA investigating concerns with medications. This is what they are supposed to do. The problem I have is that they report the fact that they are investigating a problem, without any data or information to be informative to doctors or patients. I raised these concerns when the FDA initially proposed this strategy. There is a reason that in the United States a person is presumed innocent until found guilty. Because of our 24/7 media cycle and their desire to publish scary stories about medicine, when the FDA announces it is looking into a medication, this automatically makes headlines. Patient and physicians, being provided limited to no data as well as no clinical context, assume the worst. Many patients will simply stop taking a medication, without even informing their doctor.
Please recall that though the Vioxx scandal was one of the first events to put the spotlight on the FDA, the Avandia scare magnified this. As I have mentioned multiple times, well done studies on Avandia (see here ) have not led to the same conclusion as Dr. Nissen's poorly done meta-analysis. The ramifications of that dreaded publication by the New England Journal of Medicine have been numerous and include decreasing the availability of newer drugs for diabetes, guidelines which push patients onto insulin sooner, and the FDA needlessly worrying the public about safe (though ineffective) medications with these early warnings of investigations.


Anonymous said...

Dear Dr. Mintz,

Did you even read the article you cited? The FDA update stated that since the clinical trials were not designed specifically to examine neuropsychiatric events, some events may not have been reported.

This does NOT mean there is no connection. Just that one has not yet been established based on the available information from the clinical trials.

And they have not concluded the investigation! What does we are not closing the book on suicide mean to you? That they think there is no possible connection?

What do you think this means?
"The clinical details of some reports involving montelukast are consistent with a drug-induced effect...Accordingly, at this time, patients and prescribers should monitor for the possibility of neuropsychiatric events associated with these agents."

Isn't suicidal behavior a neuropsychiatric event?

I really think you should read the Institute of Safe Mediaction Practices' QuarterWatch at: http://www.ismp.org/quarterwatch/200901.pdf and gain some valuable insight into how important the FDA's spring announcement of the Singulair Investigation was.

In closing, you are wrong about there not being a connection between Singulair and suicide - and I am confident that it will be confrimed in the future.

My friend's child completed suicide after this drug destroyed his mental health. No other factors could account for the changes in his personality and behavior that occurred before he died - except that he started Singulair! IT WAS NO COINCIDENCE!

When you have absolutely no experience with something, have not done the research, and are unable to keep an open mind, you should refrain from making comments detrimental to your credibility as a doctor. Shame on you!

Anonymous said...

And another thing, people stop taking medicines all the time and don't tell their doctors. Don't blame an FDA warning for causing this.

The investigation is not and was never just about suicide. As a doctor, you should know that suicide does not occur in a vacuum and is often accompanied by mental illnesses, which are characterized by mood and behavior changes.

The announcement of the investigation provided people with important information to make decisions about their health. This is something their doctors should have done but failed to do. How sad is that?

Stop being so simplistic. This is why so many have suffered from this drug!

Dr. Matthew Mintz said...

Yes, I did read the report quite carefully. Immediately before the part about that the trials were not designed to examine neuropsychiatric events the report states "these data do not suggest that montelukast, zafirlukast, or zileuton are associated with suicide or suicidal behavior."
Does this definitively prove that there is absolutely no link between Singulair and suicidal behavior? Of course not. Should the FDA continue to look into this and follow reports? Absolutely! However, the vast weight of the evidence which the FDA reviewed that included tens of thousands of patients does not indicate a link.
The issue is not really whether or not there is a possible link, even if very, very small. The issues are:
1. How likely is the link if any, and how common would it be expected?
2. Is the evidence sufficient to warn the public?
I would argue that based on the data available in March (a few reports), there was not sufficient evidence to warn the public. I would also argue that based on the evidence presented by the FDA just now, the likelihood that a common link exists is extremely low.
In the ISMP report in your response it states that a spike in reports occurred after the FDA made the announcement in March. Though it is possible that patients and doctors, now aware of a link, were more likely to report this; it is also possible (and in my opinion much more likely) that hearing of this possible link, patients were scared and reported symptoms. This phenomenon was seen after Baycol was removed from the market. Reports of muscle pain with statins had a sharp rise, but then fell back to baseline. There is tons of data on statins and muscle issues and it has been pretty stable before and after Baycol.
The larger issue is that we have a real problem with safety monitoring once a drug is approved, which relies on doctors and patients to report connections between a medication and a possible side effect. One solution I would propose is to only allow a limited number of physicians to prescribe a brand new drug to patients and closely monitor them for the first 12 months before the medications can be approved for everyone.

Anonymous said...

Well i find your comments typical of most doctors i have run into,but i for one and i am sure not alone thank the FDA for putting out its warning in March,as it saved my childs life,changed a 3 year road of dispare,and gave me answers.I find the medical community quick to put it down to bad parenting and slow to look for a physical reasons,I fired my doctor just as i would proberly fire you for closed minded opinions and not listening.The FDA may have given merck a belated christmas present in allowing the suffering of children to continue for a few more months,but the truth will come out eventually,and paybacks will be due

Anonymous said...

Just a thought,with all that you have available to you ,why not research and try to find the answer to this priblem,maybe your students can help.In 1998 Churg Strauss syndrome and other forms of vasculitis were associated with the use of singulair,as put out in a dear doctor letter to physicans.It is indeed possible that all these symptons of an adverse reaction to singulair could be associated to vasculitis in some form or another.With that being said something as simple as a blood test could reveal after the start of singulair who could and who could not saftly take this drug.It does not even have to stop there,maybe all who suffer psych effects could have a blood test to rule out a physical reason for their problems.I do believe it is an avenue worth exploring,you could blow the lid off this,make the scientist look inept,at both merck and the FDA,although taking 10 months to investigate research that wasnt even there to begin with dosnt bowd well for their repution anways. A treatment for vasculitis would be steroids,the association with singulair was noted as when steroids were being reduced or ending,so to me as a retired waitress tells me the problem actually would show its head when stopping the treatment to cure it.So Dr Mintz my challenge to you is help figure this tradegy out,help save the children that are suffering everyday to the ignorance of some.

Anonymous said...

The Conversion of Our Protector

Not long ago, what we as American citizens ingested into ourselves what may have been at times possibly dangerous due to flaws in the process of producing food and drugs in particular at that time. With the absence of regulation of the manufacturers of such items, American citizens could not be assured of what they may take to eat or restore their health was safe for them, and this was understandably concerning for many people.
Nearly 100 years ago, one man changed the fears and concerns of American Citizens regarding what they may eat, or what medicine they may be given to restore their health. And this man simply improved the way things were without intent, and by writing a book.
The Food and Drug Administration originated in its primitive form several decades ago to ensure the health and safety of the citizens of the United States in regards to what they consume. The administration was created to regulate the manufacturers who make items people do consume are safe for them.
The man responsible for the development of the Food and Drug Administration was a socialist named Upton Sinclair, who was a writer. One particular book he wrote several decades ago, while fictional, addressed the working conditions in a meat packaging company that were quite shockingly described by Upton in his book. Called, “The Jungle”, the one particular issue in his book regarding the lack of food safety is what caught the attention of the public who read his book, and this included the U.S. president. The impact caused by this book on others is what ultimately led to the development of the FDA.
However, and with great disappointment, the purpose and function of the FDA seems to have changed in the past few decades. The FDA appears to have decided to instead ensure the health of the pharmaceutical industry, an industry the FDA was designed to regulate. This is one of many disturbing flaws and concerns expressed by others regarding the FDA.
One example is the large amounts of money the pharmaceutical industry gives the FDA for various reasons created recently, which the FDA accepts without objection. These various amounts of money are so large that the money given to the FDA accounts for nearly half of the FDA’s entire budget. An example of what was a stated reason by the FDA for receiving these funds is due to what is known as the PDUFA ( the prescription drug user fee act), which began in 1992. Basically, the drug industry has been authorized and is now required to pay the FDA for faster approval of their medications awaiting approval by the FDA. The FDA also accepts from this industry over a million dollars from certain drug companies in order to give their pending new drugs a priority review of 6 months instead of a year, along with a creating an etiology for this urgency to occur, others have said.
Results of this relationship between the FDA and the pharmaceutical industry, which some have called collusive and pathologically intimate, may be a reason some newly approved drugs by the FDA are quickly proven to be unsafe, if not deadly.
The lack of regulation and monitoring required by the FDA of the pharmaceutical industry has resulted in such dangerous safety concerns, one could safely say.
The FDA and the drug industry continues to attempt to validate and explain often what many others have questioned about the FDA and its lack of focus on the safety of the public- the public the FDA is suppose to protect to assure their safety. Yet the protection by the FDA is not observable at this time.
The presumed intimacy between these two organizations, the pharmaceutical industry and the FDA, does in fact seem to continue to worsen. For example, and recently, the FDA announced they were allowing the pharmaceutical industry to allow their promoters of their branded drugs they market to discuss these products for disease states and medical conditions that have not been studied or evaluated by the FDA, if thoroughly studied at all. This process use to be mandatory before a drug company could claim that their drugs were beneficial for a particular disease state. Many remained shocked on this decision made by the FDA that is now in effect- speaking about drugs for medicinal uses that have not been validated.
Yet the FDA claims that this proposal would enhance the education and knowledge of the prescriber by the pharmaceutical representative of the marketer of a particular medication, which remarkably mirrors the premise and objective of this industry already. So this strategy, void of any protection of the public health, allows for potential dangers associated with this practice. This autonomy of the FDA illustrates once again the present state of the FDA and its need for reform.
A prescriber, upon their own discretion, can in fact prescribe a drug off-label, and they do so based upon their own discretion, and they often do. Historically, however, a pharmaceutical drug promoter was legally forbidden to suggest to a health care provider to use their promoted drugs for disease states not approved by the FDA already.
In fact, it was a federal offense for such drug representatives and their employers to speak off-label about the drugs they promoted to health care providers. In the past, drug companies have had to pay settlements to the DOJ when they fractured these laws regarding off label promotion of medications.
This new and frightening off-label FDA protocol for drug representatives that has been allowed by our FDA with presumed encouragement by the pharmaceutical industry is called, “Good Reprint Practices.”
This overt and absurd benefit for the pharmaceutical industry is that now they can have their pharmaceutical sales representatives, unregulated themselves, speak about their promoted medications to health care providers essentially in any way they choose.
Furthermore, this proposal is flawed in that most pharmaceutical representatives lack necessary medical and clinical training to discuss the complex considerations a health care provider is able to do because of their microscopic training related to such areas.
Most drug representatives have little medical or clinical training in any objective way, and they are not chosen to be hired for having such a background, usually. So this seems to further complicate the idea of this off-label authorization by the FDA due to the ignorance of the representatives to discuss such clinical matters. In addition, the relaxation of previous restrictions regarding off-label promotion could prove to be a catalyst for representatives of the pharmaceutical industry to further embellish statements to prescribers for their own benefit in regards to their promoted medications they present to them.
In fact recently, a study by Sermo concluded that 90 percent of doctors want clinical evidence based medicine from educated and trained professionals instead of the typical pharmaceutical sales representatives that now exist. This study also concluded that around 80 percent of health care providers prefer not to interact with pharmaceutical representatives, yet still accept drug samples from them for their patients. The results are rather understandable considering what we now know.
So, our previous safety government association we created for our needs as citizens, the FDA, appears to be evolving into a harmful association with the pharmaceutical industry by suggesting such practices that aggravate and further illustrate the unsafe conditions we are now faced with as we were before the FDA was created.
It is unbelievable this good reprint practices that was somehow created ever came into existence- with the delusional fallacy that it would be of any benefit to the patient and the restoration of their health. Furthermore, this may complicate if not increase existing patient medication errors, such as in the elderly or dosing for children.
So there are enough problems with prescribing medications, and adding this FDA seems to be making the issues with medications in the U.S. worse instead of better, quite clearly. We as citizens are no longer the concern of the FDA, one could safely conclude, and this is clearly dangerous to the health of the public.
Perhaps another alternative to the FDA’s Good Reprint Practices would be to have clinically trained people discuss such issues regarding the benefits of medications with prescribers, unaffiliated with the makers of such medications. Instead, pharmaceutical marketing representatives, whose sole objective is to increase the market share of their promoted medications, are assigned to be the clinical experts they most certainly are not.
Because historically, medications have in fact proven to be beneficial for other disease states other than what a certain drug was initially indicated for upon approval. Yet this should not be determined by those who promote such drugs. Now, unfortunately, pharmaceutical representatives are allowed to determine how they can promote their drugs for their employer’s benefit. I find this rather frightening.
Regardless, awareness needs to happen by the citizens involving these tactics progressively allowed by the FDA that are dangerous and deceptive to the health of the public. As citizens, we have the right to insist that the FDA- our FDA- maintains focus on the safety of the public and their health. Reform of the FDA appears to be necessary for this to occur to re-establish the FDA as the administration that was created for our protection, and not to protect others financially.
About half of all drugs approved presently by the FDA have had serious post-approval side effects that should have already been known or suspected of these drugs. Well over 100 thousand people die every year from drug reactions or mistakes. This seems to be a rather significant concern for those who are need to restore their health. But it does not to be a concern of some.
Dan Abshear