September 17,2004

Chairman Grassley urges quick adoption by FDA of new recommendations concerning the pediatric use of antidepressants

WASHINGTON — Sen. Chuck Grassley has urged the Food and Drug Administration toquickly adopt the recommendations made this week by an expert advisory panel concerning theeffect of antidepressants on adolescents and children and asked how the agency plans to addressthe matter of informed consent from parents and guardians when antidepressants were prescribedfor young people.

The text of Grassley's letter to the Secretary of Health and Human Services and theActing Commissioner of the Food and Drug Administration follows here. Grassley has beenconducting oversight of the Food and Drug Administration from his position as chairman of theSenate Committee on Finance.

September 16, 2004

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

Mr. 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 Commissioner Crawford:

I am pleased to note this week's very significant recommendation by its AdvisoryCommittee that the Food and Drug Administration (FDA) should now mandate a "black box"warning about the elevated risk for suicidal behavior among children and adolescents who havebeen administered certain antidepressant drugs, in addition to requiring appropriate "medguides". These measures are especially critical since I also understand from previously releasedstudies and from the Advisory Committee's own deliberations that only one of the nineantidepressant drugs has been proven to provide any benefit to children and adolescents. In fact,in almost all cases, the FDA's own data demonstrates that these drugs actually perform no betterthan do placebos.

Unfortunately, the poor performance data for these drugs has been coupled with the verycompelling and heart-wrenching testimony from parents and other public witnesses who identifythe medications themselves as triggering tragic and unexpected suicides and suicidal behavioramong users. I understand that the testimony yesterday even included discussions about patientswho had not been suffering from depression, yet were prescribed these powerful drugs byphysicians who may perhaps have been all too ready to medicate their patients.

I share the rather convincing opinions and concerns of the experts who haveindependently assessed the increased risks of suicide as a result of these drugs - especially incertain populations - and the absence of meaningful data supporting its benefits that wouldwarrant the enhanced risks. I trust that the FDA will very quickly and fully consider theAdvisory Committee's recommendations about the "black box" and "med guides", before thelives of more children are needlessly lost because parents and others lack adequate, readilyunderstandable information when they most need it - at the precise moment when they mustmake critical life and death health care decisions for themselves or their loved ones. Perhaps thisneed for better information is best articulated by a recent letter that I received from a physicianwhose 15-year old son committed suicide after being on Zoloft a mere 12 days. This physicianand father said:

There need to be warnings: warnings on a bottle, warnings on the product label, warningsin the package insert, warnings in the PDR. Doctors and patients need to be educated concerningthe risks and warning signs. Even if it is never scientifically "proven" that the medicines actually"cause" suicide, it appears to me that there is undisputable empiric evidence that patients are, infact, at risk. At the very least, patients and their families should be given the opportunity todiscuss and be aware of these potential side effects and to take reasonable preventative measuresto try to avoid these needless deaths.

As you know, suicide is the third leading cause of death among teenagers. This is aserious public health issue. For me, though, the issue is much more personal. I cannot sit idleand let this senseless tragedy happen to another family. With each day that goes by withoutwarnings or education, other people like me will continue to lose their precious children likeJosh.

Secretary Thompson and Deputy Commissioner Crawford, I want you to understand thatthis United States Senator also is unwilling to sit idly by and let this kind of tragedy befall otherfamilies. Moreover, I, for one, do not share the rather patronizing opinion voiced by some of theAdvisory Committee members this week. Specifically, some noted that providing complete,accurate, clear and understandable information to worried parents, concerned caregivers and busyphysicians will necessarily lessen the dispensing of pharmaceuticals to those patients who trulyneed and can benefit from them. In my judgment, better and more complete data about the veryserious risks and quite marginal documented benefits gives parents the ability to ask the rightquestions and arrive at the appropriate conclusions on a case-by-case basis about the besttreatment for their loved ones.

Complete information will better ensure that those who most require and can potentiallymost benefit from these drugs will receive them - and that all of the risks and benefits have beencarefully weighed and thoughtfully considered. I certainly would want to have that choice for myown children and grandchildren, and I find it difficult to imagine any caring parent or otherfamily member would want it to be otherwise.

While the "black box" warning is a major step by the FDA, I note that the Chair of theAdvisory Committee did not put to a vote another matter discussed during the meeting; that is,the issue of "signed informed consent." It is my understanding that at this time, the FDA will notrequire signed informed consent for the SSRIs in question. Accordingly, I am curious about theFDA's rationale for not requiring physicians who prescribe these antidepressant drugs to childrento provide a clear, informed consent document that parents or guardians must read, understandand sign before accepting a prescription from their physician, as the FDA did for Lotronex. Inthe case of Lotronex, I understand that signed informed consent forms were required by FDAbecause of the risk of ischemic colitis in about 1 in 300 patients. However, in the case ofantidepressants in children and adolescents, a suicide-related event involving Prozac (fluoxetine)is about 1 in 15 according to the TADS study, and about 1 in 30 for all SSRIs, according toFDA's own study.

Please note that I am not necessarily promoting that signed informed consents be requiredfor all SSRIs; but I am wondering how the FDA intends to make the decision as to whether or notsuch informed consent will be required. I am asking because, as noted above, the FDA requiredsigned informed consent for Lotronex; a drug that appears to have an adverse effect far lessdevastating than suicide. Although a "black box" warning and a "med guide" is a great leap inthe right direction, I am troubled by the timing and direction of such warnings. I understand thatthe black box report warning is most often directed to the practitioner and not to the consumer.

On the other hand, the "med guide" is directed to the patient, but only after the patient has left thepractitioner's office. It is my understanding that an informed consent document provides currentand reliable information on the risks associated with taking certain drugs, as well as the benefitsdocumented through valid test results. While more general class information is quite useful, theinformed consent documents specify the risks and benefits associated with specific drugs.Accordingly, I would appreciate knowing:

1. whether or not the FDA intends to make a determination as to thenecessity for signed informed consent for SSRIs and if not, why not; and

2. the rationale for FDAs views on Lotronex risks vis a vis the risks ofSSRIs, particularly when the risk of a suicide event is some ten ortwenty times greater from antidepressants than it is the risk of ischemiccolitis from Lotronex. 
I would appreciate your responses to these questions by October 18, 2004.

In the event that FDA decides to require "informed consent" despite the fact the Chair ofthe Advisory Committee did not bring this issue to a vote, it would seem that an informedconsent form should at least need to make the following points:

"Only Prozac has been shown to be effective in treating depression in children and adolescents,and it is the only drug approved for this by the FDA;

"All other SSRIs and antidepressants have been shown to be no different than a placebo, andtheir use in the treatment of depression in children and adolescents is not an approved use by theFDA;

"All antidepressants increase the risk of suicidality; and

"The risk of a suicide event (planned or actually attempted) is one suicide event for every 15 to30 children and adolescents taking the antidepressant

In closing, I am interested in hearing from the FDA about all that it is considering orplanning to do concerning educating the medical community and the public about therisk-benefits of antidepressants, especially in children. Therefore, I am requesting a bi-monthlyverbal or written briefing for my staff by the FDA, including any milestones, timetables, and anyidentified impediments that may require a legislative fix. The issue of the black box warning andthe med guides are not matters that can wait months and months and I intend to keep the FDA'sfeet to the fire to insure that the American public is knowledgeable about the risks of SSRIs.

Thank you for your attention to this important matter.


Charles E. Grassley