Memorandum by The Royal College of Psychiatrists
of the Pharmaceutical Companies (PI 103)
THE BENEFITS & SAFETY OF SSRIs IN CHILDREN:
THE THREAT TO EVIDENCE-BASED MEDICINE RESULTING FROM SELECTIVE
PUBLICATION OF CLINICAL TRIALS AND THE ROLE OF PHARMACEUTICAL
COMPANIES
INTRODUCTION
The decision to give/receive treatment should
be based upon the balance of risks and benefits. If the benefits
outweigh the risks, the treatment is worth considering. If the
risks outweigh the benefits, alternative treatments should be
sought. To make a decision to give/receive a treatment, the doctor
and patient should know about ALL the risks and potential benefits
of the treatment. Most of our knowledge about the benefit and
harm associated with any drug comes from clinical research undertaken
by drug companies. If pharmaceutical companies only publish clinical
research that is positive, and hold back on publishing clinical
research which is negative (selective reporting), then patients
may well be given treatments which, unknown to either the patient
or the doctor, are likely to do more harm than good.
We want to present evidence that at the present
time, neither doctors nor patients can be confident that they
that they will be have access to ALL the evidence needed to make
treatment decisions, and that this appears to be the result of
selective reporting of clinical trials by drug companies.
SUMMARISING THE
EVIDENCE
In December 2003, in an unprecedented move,
the Department of Health agency responsible for ensuring that
medicines meet appropriate standards of safety and effectiveness
(the Medicines and Healthcare products Regulatory Agency—MHRA),
released data regarding the risks and benefits of newer antidepressants
used to treat depression in children and young people.
The information published on the MHRA's website
included both previously published and never before published
data obtained directly from the manufacturers of the SSRIs ("selective
serotonin reuptake inhibitors") and other newer atypical
antidepressant drugs. These data were collected after earlier
work had raised concerns about the safety of paroxetine (Seroxat)
and venlafaxine (Efexor, Efexor XL) in children and young people
with depression.
Based on their review of the data, the MHRA
concluded that all of the newer antidepressant drugs, other than
fluoxetine (Prozac), carried serious risks that outweighed any
benefits. The MHRA, therefore gave warning of the potential that
these drugs could increase the risk of suicide-related behaviour
(rather than decreasing it—as would be expected of an antidepressant)
when using these drugs in the treatment of depression in childhood
and adolescence.
The MHRA, therefore, informed all doctors that
the use of SSRIs (except fluoxetine) was now "contraindicated"
in this context. However, this was not the commonly held view
in the published literature with recent studies in particular
suggesting that these drugs were beneficial and well tolerated
with no serious side effects.
At this time, we* had been commissioned by the
National Institute for Clinical Excellence (NICE) to produce national
guidelines for the whole of the NHS on the treatment of depression
in children and young people. We produce most of the NICE guidelines
in mental health, each one taking about two years to produce and
giving advice on the treatments which have the best evidence for
their effectiveness.
It is important to note that up until this point
in our work for NICE, all our guidelines (and all other NICE guidelines
as far as we are aware) have been based upon an in-depth assessment
of the PUBLISHED evidence. So, when the MHRA verdict on the SSRIs
became public, we became aware that the MHRA had a total of 11
trials, of which we had only seen five, since only five had been
published.
We had already written to all relevant drug
companies, asking them to furnish us with ALL relevant published
and unpublished trials of the treatment of children and young
people with depression—no unpublished trials were forthcoming.
Because of the inconsistency between the MHRA's
findings and the published literature, several members of our
guideline committee, decided to compare and contrast the published
data with the unpublished data. This work was designed as an experiment
to test out what the difference might (or might not) be if, in
producing a guideline, we had access to the unpublished as well
as the published literature. The results of this work** were published
in The Lancet, a British-based medical journal.
The authors of the Lancet article concluded
that the published evidence was more favourable than the unpublished
evidence, and most importantly that it was only when all evidence
was examined that it was clear that the risks (particularly the
increased risk of suicidal behaviour and thinking) outweighed
the benefits.
We also found evidence to suggest that at least
one of the drug companies who had undertaken trials of an SSRI
in the treatment of childhood and adolescent depression had withheld
publication of trial data on the grounds that it contained evidence
that the drug was unlikely to be effective in treating depression
in this age group.
The arguably profound implications of this study
are relevant, not just for the treatment of children and adolescents
who are depressed, but for the whole of evidence-based medicine,
which depends upon the honesty and transparency of all people
who undertake clinical research to publish ALL the findings of
research and not just selective and positive findings as a means
of encouraging the use of a drug.
SUGGESTED CHANGES
TO THE
CURRENT "REGULATORY
ENVIRONMENT"
1. Mandatory pre-trial public registration
of all clinical trials, with estimated completion dates, and rapid
release of all relevant safety data.
2. Clinical trials supporting licensing
applications should have been undertaken by an independent clinical
trials unit.
3. Thorough review of the regulatory framework
within which pharmaceutical companies currently operate and the
processes involved in licensing drugs.
4. Thorough review of the role and regulation
of medical practitioners in pharmaceutical companies by the GMC.
5. Consideration given to incorporating
health technology appraisals (NICE) into the regulatory process.
6. Ensuring that all NICE programmes (Health
Technology Assessment, Guidelines, Interventional Procedures)
have full access to published and unpublished data.
Notes
*The National Collaborating Centre for Mental
Health (NCCMH) on behalf of the National Institute for Clinical
Excellence (NICE). The NCCMH is an evidence-based guideline development
unit jointly run by the Royal College of Psychiatrists and the
British Psychological Society and funded by NICE.
**Whittington C, Kendall T, Fonagy P, Cottrell
D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors
in childhood depression: systematic review of published versus
unpublished data. The Lancet, 24 April 2004; Volume 363:
Number 9418, 1341-45.
The Lancet editors also penned a hard-hitting
and extremely critical editorial calling for new regulation of
drug companies in the light of an increasing weight of evidence
(including our review) suggesting that drug companies were not
publishing evidence that showed their own drugs may be ineffective
and/or harmful to patients ("Depressing Research" in
the same edition of The Lancet).
| 
