June 17,2004

Grassley questions FDA about information on antidepressants, suicide

WASHINGTON — In a letter this week, Sen. Chuck Grassley spelled out what he has learned to date in his investigation of the Food and Drug Administration's handling of information about antidepressants and suicide among young people and asked new questions about possible efforts by the agency to withhold certain information from the public. Grassley also described new concerns about the relationship between the Office of New Drugs and the Office of Drug Safety within the Food and Drug Administration.

The text of Grassley's letter to the Food and Drug Administration and the Department of Health and Human Services follows here. Grassley is chairman of the Senate Committee on Finance.

June 16, 2004

The Honorable Tommy G. Thompson
Department of Health and Human Services
200 Independence Avenue, SW
Washington, DC 20201

Dr. Lester M. Crawford, D.V.M., Ph.D.
Acting Commissioner
U.S. Food and Drug Administration
5600 Fishers Lane
Rockville, MD 20857

Dear Secretary Thompson and Dr. Crawford:

Last March, I instructed my staff to review whether or not Dr. Andrew Mosholder, whoworks in the Office of Drug Safety (ODS), was precluded from delivering his analysis of clinicaldata relating to children, anti-depressants, and suicidal events to a Food and Drug Administration(FDA) Advisory Committee Meeting (ACM) on February 2, 2004. My concerns at the timecentered around the public's right to know the possible effects of certain anti-depressants onchildren and reflected my deep and unbridled concern for the thousands of children acrossAmerica who are faithfully taking potentially life-threatening medication, which have been foundto be no better than placebo in the treatment of depression in children. In addition, I expressedconcern to you regarding the investigation that was launched into the "leak" of Dr. Mosholder'sanalysis.

Let me begin by saying that Dr. Mosholder appears to be a man of great integrity, placinghis findings and recommendations above all else, despite FDA efforts to limit and strategicallymanipulate information to be provided to the public. This country needs more civil servants withDr. Mosholder's devotion to doing what is right in the face of adversity.

Interviews conducted during the course of this investigation have provided the Committee with atrove of information to consider. To begin with, it is necessary to address the ODS, both itsfunction and mission. The ODS has a very specific mission: it "evaluates drug risks and promotesthe safe use of drugs by the American people." In essence, ODS maintains a system of"postmarketing surveillance" to identify adverse effects that did not appear during the drugdevelopment process. This mission makes perfect sense. Clinical studies conducted, prior to adrug entering the U.S. market, involve a limited number of highly selected individuals and asimilarly limited number of trials. In other words, the laboratory in which the drug is being testedfor its usefulness is understandably small and controlled. As a result, the full range of possibleadverse effects of a new drug does not always surface. Indeed, the real laboratory for new drugsoccurs once the drug is dispensed across large numbers of people after marketing begins.

The ODS learns about adverse events through reporting by companies and through voluntaryreports submitted to FDA's MedWatch program; a program for health professionals andconsumers to report adverse events to FDA. Staff in ODS, like Dr. Mosholder, use thisinformation to identify drug safety concerns and recommend actions to improve product safetyand protect public health. Unfortunately, interviews with FDA employees suggest that a disconnect exists within the ODS, between its mission and its current operations.According to staff interviews, Dr. Mosholder is a child psychiatrist who, prior to joiningODS, served for almost 10 years in the Division of Neuropharmacologic and Psychiatric Drugs(Neuropharm) within the Center for Drug Evaluation and Research (CDER) of FDA.

Neuropharm, located within CDER's Office of New Drugs (OND), is responsible for approvingdrugs for entry into the marketplace. During his decade in Neuropharm, Dr. Mosholder wasresponsible for reviewing safety and effectiveness studies on anti-depressants and children. As aresult of his unique knowledge and experience, Dr. Mosholder is the de facto expert at FDA forthe efficacy of anti-depressants in children, and accordingly was sought out by Dr. Katz, theDirector of Neuropharm, to do a "rush consult" to evaluate the clinical studies involving children,anti-depressants and suicide. This "rush consult" was sparked by several factors, including the availability of new data analyses indicating an increase in suicidal thoughts and behaviors inchildren treated with some of these drug agents. As a result of this consult, Dr. Mosholder was protected from all other assignments so that he could complete this important analysis quickly (the Mosholder Analysis).

Dr. Mosholder conducted his review of the clinical data, prepared his analysis, andprovided that analysis, without recommendations, to his peers and superiors including, Drs. MaryWilly, Mark Avigan, and Anne Trontell in September 2003. Overall, the Mosholder Analysiswas widely disseminated. Moreover, Dr. Mosholder's findings were and remain that there is alink between anti-depressant use by children and suicidal and self-injurious thoughts andbehaviors. His report was well received. In fact, his immediate supervisor Dr. Willy noted a jobwell done, while Drs. Avigan and Tronell, both of whom would later write dissenting opinions toDr. Mosholder's analysis, advised Dr. Mosholder that he had done a "great job" and "good job,"respectively.

Over the course of the next several months, Dr. Mosholder said that he continued to refine hisanalysis, but his findings never changed, i.e., the link between children, anti-depressants andsuicide was unmistakable. As a result of these and other events, a decision was made byNeuropharm and OND that Dr. Mosholder would present his analysis and findings at theFebruary 2, 2004 Psychopharmacologic Drugs Advisory Committee Meeting (ACM), as noted inthe Federal Register on October 31, 2003.

On December 10, 2003, the United Kingdom's Medicines and Healthcare ProductsRegulatory Agency (MHRA) issued a statement regarding children, anti-depressants and suicide.The MHRA noted that only Prozac should be given to children with depression and that the useof all other selective serotonin reuptake inhibitors (SSRI anti-depressants) was contraindicated.The FDA was well aware of this determination.

In anticipation of the February 2, 2004 ACM, a planning meeting took place in December2003. During the course of that planning meeting, Dr. Mosholder distributed to all the attendeesan outline of his talking points, which noted that a child taking an anti-depressant, other thanProzac, was twice as likely to have a suicidal event as a child taking a placebo. This was asignificant finding and was consistent with the MHRA findings and the Lancet study.Dr. Laughren, the Deputy Director of Neuropharm and formerly Dr. Mosholder's team leaderduring his tenure in Neuropharm, objected unexpectedly to Dr. Mosholder's methods at aDecember meeting. This was the case despite the fact that he had received a copy of the analysisand had an opportunity to review it several months earlier. It is my understanding that Dr.Laughren wanted to get further analysis of the data done by Columbia University before reachinga conclusion.

On January 6, 2004, Dr. Mosholder was contacted by Dr Katz. During a 20 minuteconversation, Dr Katz informed Dr. Mosholder that he would no longer be presenting at theACM because Dr. Mosholder: 1) reached a different conclusion than OND; and 2) utilizedincomplete data. This decision was neither embraced by Dr. Mosholder, nor by his superiors inthe ODS, but it appears that little could be done to ameliorate the situation.

During the course of this investigation, it has become increasingly more apparent that theODS and the OND exist in a relationship that is best described as "separate but unequal."According to staff interviews, the ODS serves a subservient role to the OND. Indeed, the ODSwas described by one employee as the "unwanted stepchild" at FDA, rather than a watchdog forthe public at large. This observation merits further in-depth review because of the seriousness ofthe impact of any organizational weakness at the FDA upon public safety.

Subsequent to the decision to remove Mosholder from the agenda of the ACM, the FDAengaged in a series of other activities that are also very troubling. In anticipation of the fact thatparties interested in the Mosholder analysis were expected to attend the ACM, including familymembers of children harmed by one or more anti-depressants, it appears the FDA: 1) preparedscripted answers for Dr. Mosholder to read if questioned at the ACM; 2) attempted to haveMosholder present data known to be unreliable and deceptively misleading; and 3) engaged inbehavior that overall is unexpected from an organization charged with ensuring and protectingthe safety of American consumers taking prescription medications.

To begin, Dr. Mosholder was advised at one point that if he were willing to modify hisrecommendations, perhaps he could present his analysis at the ACM. Indeed, newrecommendations were drafted for his consideration. However, Dr. Mosholder refused to acceptnew, alternative language, stating that the alternative language misconstrued hisrecommendations.

In addition, Dr. Mosholder was told that he was not sitting at the meeting table during theACM, despite the fact that he was providing information on another topic. This decision wasmade by the OND. Dr. Mosholder was advised that in the event he was asked any questionsregarding his anti-depressant analysis, he was not allowed to speak about his analysis, he couldonly speak from the "prepared" answers. This seems like a peculiar way to treat the "established"expert in the area of SSRIs and children.

Perhaps most troubling, however, was the fact that OND attempted to have Dr.Mosholder present "reporting rates" of suicidal thoughts, rather than the available clinical trialsdata on anti-depressants and children, which formed the foundation of his analysis. This isbothersome for several reasons. "Reporting rates" are considered marginally reliable and clinicaltrials data have long been regarded by FDA as the most reliable type of data based upon theexperts interviewed. As one interviewee stated, "clinical data trumps reporting data any time."

These rates are derived from dividing the number of cases reported to the FDA by pharmacists,physicians and others and stored in the computerized Adverse Event Reporting System (AERS).AERS is a voluntary reporting system intended, among other things, to monitor the safety effectsof drugs once they are approved by the FDA for marketing. In order to determine the reportingrate you simply take the AERS data for a particular drug and divide it by the number ofprescriptions filled for that particular drug. This provides the "reporting rate" for that drug.In the instant situation, the OND wanted Dr. Mosholder to present "reporting rates" of suicidalthoughts and behavior for anti-depressants in children at the ACM. However, Dr. Mosholderrefused to do so because most serious adverse drug effects are never reported to FDA.

Consequently, any "reporting rate" would be extremely low, not because the SSRIanti-depressants do not promote suicidal thoughts and behaviors in children, but becausevoluntary reporting is so poor and infrequent. The use of "reporting rates" at the ACM would bedeceptively false and misleading and would provide a "false sense of security" to the public. Staffinterviews suggest that had these reporting rates been presented at the ACM, the public, themedia and the Congress probably would have concluded that anti-depressants are all extremelysafe for children.

On one hand, it can be said that the public should be grateful that Dr. Mosholder held hisground and refused to present "reporting rates" at the ACM; yet, on the other hand, the fact that ahigh-level official at the OND/FDA would consider such an alternative is alarming. In fact, itbegs the question: in how many other instances were reporting rates provided when more reliabledata was available? In how many other instances has the OND manipulated its advisorycommittee meetings to withhold from the public and misrepresent safety information aboutmarketed drugs of critical importance to patient safety?

It appears from this investigation to date, the turning point for removing the MosholderAnalysis from the ACM was not the fact that Columbia University was going to further analyzethe data or that Dr. Mosholder's superiors had not "cleared" the consult, as reported in the press.After all, it was repeatedly reported to us that consults/analyses that had not been "cleared" wereregularly presented to the ACM. The lynchpin for removal of the Mosholder consult from theACM was the insertion of "recommendations." Specifically, Dr. Mosholder recommended that"a risk management strategy directed at discouraging off-label pediatric use of anti-depressantdrugs, particularly the use of drugs other than fluoxetine (Prozac), in the treatment of pediatricMDD (major depressive disorder)."

During the course of discussions regarding the removal of the Mosholder Analysis fromthe ACM agenda, another matter of interest came to light. Specifically, staff interviews suggestthat inserting recommendations into drug consults are neither encouraged nor wanted by theOND. In fact, one employee at the ODS stated, that he was "hazy" on whether or notrecommendations should ever be written. Another employee stated that consult recommendationsare outright discouraged because they force the hand of the OND to "do something" and that theOND preferred that ODS consults remain "sterile."

The fact that ODS employees believe that they should not insert recommendations in theirconsults appears to be in direct contravention of ODS claims. Specifically, the ODS's websitestates that ODS is to "identify drug safety concerns and recommend actions to improve productsafety and protect the public health." It would seem that OND's decision to discourage scientistsat ODS from recommending action intended to serve the public interest is inconsistent with itsstated mission. More importantly, it is contrary to the basic fundamental principle upon whichour government is built: that is; having independent and objective reviewers of fact to protect theAmerican public in a timely and effective manner, particularly when it comes to the issues ofpublic health.

A review of the facts surrounding the removal of the Mosholder Analysis from the ACM,coupled with efforts to have "reporting data" presented as opposed to clinical data at the ACMand attempts to modify Mosholder's recommendations, in return for a seat at the ACM table, lendthemselves to a number of concerns. First, the relationship between the ODS and the OND doesnot appear to be in the best interest of the consumer. Indeed, some staff interviews noted thatODS is simply there to "serve" OND. Still others stated that perhaps ODS should considerre-naming itself to the "Office of Drug Safety Consultants" or the "Office of Dumb Simpletons."

In addition, I continue to be extremely interested in the investigation that was launched into the"leak" of information to the press and to Congress regarding the findings of the MosholderAnalysis. Although I am continuing my review of that matter, there is one point that must bemade. My letter, dated March 25, 2004, asked: "What was the purpose of this allegedinvestigation?" In response, I was advised that: "This investigation was initiated to determine ifthere was an inappropriate disclosure of sensitive information." This response appears to be 1)not true; 2) an insult to the process in which I am engaged; and 3) at best, a misleading responseto my inquiries.

It was well-established among ODS employees that the "leak" investigation was intendedto ferret out the name or names of the individuals who contacted the press with Dr. Mosholder'sfindings. The investigation was a catalyst for fear and was, according to those interviewed todate, intended to target the "leak." In fact, none of the individuals interviewed had anyrecollection of the "leak" investigation being driven by a concern about the disclosure ofsensitive information; rather they believed that FDA was after the "leaker," and if found, thatindividual(s) would likely suffer severe negative consequences. Accordingly, in the future, Iwould greatly appreciate that my inquiries be taken with the seriousness in which they are asked;I expect no less.

Thank you for your continued cooperation.


Charles E. Grassley