Intended for healthcare professionals


Rational prescribing for children

BMJ 2006; 332 doi: (Published 22 June 2006) Cite this as: BMJ 2006;332:1464

Open Letter to the US FDA

Open Letter to the FDA

US Senate Finance Committee

Charles Grassley (R-IA)

Max Baucus (D-MT)

Andrew C. von Eschenbach, M.D.

U.S. Food and Drug Administration,
5600 Fishers Lane,
Rockville, MD 20857

Max Baucus, Chairman

Charles Grassley, Ranking Member

United States Senate Committee on Finance,
219 Dirksen Senate Office Building,
Washington, DC 20510-6200

Dear Commissioner Eschenbach:

As reported in Bloomberg News by Rapaport, Pettypiece and Waters on
24 May 2007, several manufacturers of atypical antipsychotic medications
have discussed pending applications/approvals from, and/or plans to submit
such ‘new indication’ applications to, the US Food and Drug
Administration(FDA). According to the article, the manufacturers would
seek to obtain FDA approval for the specific ‘indication’ to use atypical
antipsychotics in teenagers. Already approved in the US adult population,
marketing for atypical antipsychotic drugs from Eli Lilly (makers of
Zyprexa), Janssen, a division of Johnson and Johnson (makers of Risperdal)
and Bristol Myers Squibb/Otsuka (makers of Abilify) would be affected.

Dr. R. Findling mentions that these new ‘indications’ would be able
to enhance the confidence level of providers and parents when they,
respectively, prescribe or permit these potent psychotropic agents to be
used in a younger population.

Schizophrenia and Bipolar Disorders are painful mental illnesses,
often with varying courses of stability/instability and unpredictable
functional disabilities. We agree that all available therapies should be
sought to minimize the emotional damages and maximize the return to health
for individuals and their families affected by the symptoms categorized
under these diagnoses. However, second-generation atypical antipsychotic
medications have not clearly proven to be safer, more efficacious or more
effective than older agents. Furthermore, some of the atypicals
medications may have risks (significant weight gain, pancreatitis,
diabetes, cardiovascular complications, hyperprolactinemia, or infections)
that may outweigh their benefits when compared to other first-generation
agents. Studies already suggest that younger patients may be more prone
to suffer from severe side effects for longer periods of time. We are
unaware of any evidence suggesting that an indication will make
prescribing habits safer.

We see no compelling reason for the drug manufacturers to seek
specific FDA approval of atypical antipsychotics in the teenage
population. Our reasons are not complex. They include:

1. All of these drugs are already available in the marketplace.

2. These drugs are already widely prescribed/over-prescribed in the
adolescent population.

3. Doctors are already permitted to use these drugs off-label.

4. A patient is not declined care because he or she is under the age
indicated by the FDA approved package insert. A doctor may still
prescribe the correct medications after discussing the off-label nature,
risks and benefits with the family of the minor.

5. There is no safety gain by requesting the FDA to approve this new

6. If the pharmaceutical manufacturers have additional efficacy and safety
data about these drugs, the release of that data does not require FDA

7. By seeking this indication, there is no possible clinical benefit to
any individual young person since the drugs are currently and widely
prescribed to them.

8. There is no life-saving or novel approach to chemotherapy in seeking
this indication.

9. Requesting the abundant time and resources required from the FDA to
accept, review and consider this indication is untimely when the FDA is
already inundated with requests for reviews of novel or orphan drugs or
indications for drugs used in novel ways.

10. There is the very likely possibility that FDA approval of a teenage
‘indication’ will provide a false sense of security and reliability for
physicians not sufficiently trained (pediatricians, primary care
physicians) to accurately assess, diagnose and treat individuals with
these complicated disorders. It would not surprise us that this
‘indication’ approval would function as the means by which aggressive
pharmaceutical marketing could easily persuade more practitioners to
prescribe more potent medications without the concomitant ability to
provide risk-benefit analysis or informed consent and thereby rapidly and
seriously escalate the potential harm that comes from the effects and
side-effects of overzealous prescribing.

11. We heartily urge the companies involved in teenage ‘indication’
proposals to release all their data that support and do not support their
request. Release of this data depends upon a willingness to be
transparent, not any FDA action.

12. Failing to approve this indication or delaying its approval should
have no effect on any patent extension requests for these atypical
manufacturers since the ability to obtain six-month pediatric extension
for patent protection is based upon the agreement to conduct appropriate
pediatric research, not the ability to successfully obtain a ‘new’

We strongly recommend that the FDA re-consider and delay
administrative reviews and approvals for indications that have little
merit other than for ostensible marketing purposes. That delay does not
compromise patient care. Doctors who assess young patients with
diagnostic accuracy and treat them carefully and compassionately will not
increase their personal liability if they apply informed consent to use
off-label medications correctly. Furthermore, delaying the administrative
FDA approval for this ‘new’ indication (but current practice) may prevent
the escalation of excessive use of atypical antipsychotic medications
whose occasional and predictable serious side-effects can compromise both
medical and psychiatric care.


Steven G Klotz, MD;

Stefan P. Kruszewski, M.D.

31 May 2007

1. Rapaport L, Pettypiece S. Bristol seeks U.S. approval for
antipsychotic Abilify in teens [Online]. Bloomberg News 2007 May 24 [cited
2007 May 30]; [3 screens]. Available from:

2. Rapaport L, Pettypiece S. Bristol seeks U.S. approval for
antipsychotic Abilify in teens [Online]. Bloomberg News 2007 May 24 [cited
2007 May 30]; [screen 2] Available from:

Competing interests:
Dr. Klotz is an academically trained child, adolescent and adult psychiatrist now in private practice in central Pennsylvania. Dr. Kruszewski is an adult, geriatric, adolescent and addiction psychiatrist practicing in Harrisburg, Pennsylvania. Both Drs. Klotz and Kruszewski have previously consulted for and spoken on behalf of multiple pharmaceutical companies.

Competing interests: No competing interests

12 June 2007
Stefan P. Kruszewski, M.D.
Psychiatrist, addictionologist
Steven G. Klotz
Harrisburg, Pennsylvania 17112 USA