Healy on realisation the North Wales staff participate in SSRI trials

[Guest guest]

http://www.seroxatusergroup.org.uk/images/_38329933_davidhealy315.jpg

> > >

> > >

> > > Professor Healy advises the MHRA that Prozac leads to

> > > testicular shrinkage of approximately 25%.

> > >

> > >

> > > Can be found at

> > >

> > >

> > > http://www.socialaudit.org.uk/58096-DH%20to%20WARK.htm

> > >

> > >

> > > section headed -

> > >

> > > Prozac and SSRIs for Children

> > >

> > >

> > >

> > >

> > >

> > > Prozac and SSRIs for Children

> > >

> > > Since I attended the SSRI review committee, the question of

the

> use

> > > of Prozac in children has come to the fore. Prozac is

apparently

> > > under review for children by MHRA at present and the impression

> > > stemming from correspondence that is in the public domain from

> > Lilly

> > > and from other regulators in Europe is that approval by MHRA is

> > > interestingly all but certain.

> > >

> > > I have had a chance to review a good deal of data on Prozac

> given

> > to

> > > children and wish to make the following comments to the

> committee,

> > > many of which will not come as any surprise to you.

> > >

> > > There have been four trials of Prozac in children who are

> > depressed.

> > > The first by Simeon et al 1990 showed no differentiation

between

> > > Prozac and placebo.

> > >

> > > The second by Emslie published in 1997 showed no

differentiation

> > > between Prozac and placebo on the primary outcome measure of

the

> > > study. This was a trial in which less than 100 children were

> > > selected from over 500 children screened. This trial also used

a

> > > placebo washout period to exclude placebo responders.

> > >

> > > The third trial was a most unusual trial. Emslie was again the

> > first

> > > author, and this trial was published in 2002. In addition to

> > > extensive screening to select patients likely to be responsive

to

> > > treatment, this trial had a placebo washout phase to exclude

> > placebo

> > > responders, as had the previous Prozac trials, but in addition

it

> > > had a further phase, which involved children randomised into

> Prozac

> > > arm of the trial being given a week of Prozac 10mg first with

an

> > > exclusion option for any children who appeared to respond

> adversely

> > > to Prozac. The trial proper started after this extraordinary

> > > manoeuvre.

> > >

> > > Even with this extraordinary step on the primary outcome

measure

> in

> > > the trial as indicated in FDA medical reviews of all of these

> > trials

> > > Prozac did not differentiate from placebo.

> > >

> > > The fourth trial you'll be aware of has recently been

published

> in

> > > JAMA with March as a first author, having first featured

in

> > the

> > > New York Times and elsewhere extolling the virtues of Prozac. I

> > > think rarely will the abstract of a major paper have been so

at

> > odds

> > > with the underlying raw data.

> > >

> > > I understand some of you in MHRA were watching the feed from

the

> > FDA

> > > paediatric advisory committee meeting. If that is the case

> > > presumably you will have seen Dr March present the data there

and

> > > heard him questioned. One of the most striking features of this

> > > interchange was that Dr March was forced to admit that

according

> to

> > > strict FDA criteria that Prozac in his trial had not been

shown

> to

> > > work either.

> > >

> > > The March group had manipulated the data in an interesting

> fashion,

> > > which involved searching for responders and non-responders on

> > scales

> > > such as the CDRS or the clinical global impression scales, and

> > > compared these. When this is done, the effect is to squeeze

> > patients

> > > into categories and under those circumstances Prozac can be

> shown

> > to

> > > be different from placebo but this squeezes the middle of the

> > > clinical population in a manner that is methodologically

> > > inappropriate. When the CDRS or other scales are used on a

> > > continuous variable basis, as per FDA requirements for

> > demonstrating

> > > efficacy, the differences between Prozac and placebo are not

> > > statistically significant. This point was recently brought out

> in a

> > > position piece by Newman in the NEJM.

> > >

> > > You will no doubt also be aware that the rate of suicidal acts

on

> > > Prozac in this latter trial is no less than the rate of

suicidal

> > > acts on other SSRIs, and is in fact substantially greater than

in

> > > most other SSRI trials.

> > >

> > > It would seem therefore that there is no more evidence of

> efficacy

> > > or for safety on Prozac than there is for other SSRIs, and

just

> as

> > > much evidence for harm.

> > >

> > > However it is also worth noting that there is some evidence for

> > > efficacy for Prozac, Seroxat/Paxil and Zoloft/Lustral for OCD,

> but

> > > at present it is difficult for any clinician to use an SSRI

for

> any

> > > child or teenager in the UK, owing to MHRA's handling of the

> issues

> > > thus far.

> > >

> > > For the record it's perhaps worth adding at this point that I

> don't

> > > agree that MHRA made the correct move in contraindicating

SSRIs

> in

> > > children. There is some evidence from trials in OCD and other

> > > anxiety disorders that some of these drugs can be effective.

The

> > key

> > > issue is that the treatment should come with the proper

warnings

> > for

> > > both adult and paediatric populations.

> > >

> > > My suspicion is that, as MHRA rarely if ever do anything

without

> > > some consultation with the market authorisation holders, it

> > appeared

> > > to be a better bet to the market authorisation holders to have

> the

> > > drugs contraindicated in children, given that so few children

in

> > the

> > > UK were having these drugs, rather than to have appropriate

> > warnings

> > > placed on the treatment, as such warnings might impact on the

> adult

> > > market. But contra-indicating SSRIs and other antidepressants

is

> > the

> > > move that seems to have set up the current quandary MHRA are

in,

> > > which appears to have all but required a licensing of Prozac

for

> > > children.

> > >

> > > If Prozac is licensed for children, it is also worth noting

that

> > > there are other features of Prozac use in children that are of

> > > concern. The FDA reviews of this drug make it clear that

children

> > > taking Prozac failed to grow at the rate that children taking

> > > placebo grew. The FDA asked Lilly to undertake follow-up

studies

> of

> > > this effect, but as far as I know the company have not done

so.

> No

> > > doubt MHRA will have noticed this problem in the trial data

> also.

> > If

> > > you do intend to license Prozac, it would be good to know that

> the

> > > issue of growth has been investigated properly.

> > >

> > > There is a further potential hazard of Prozac that FDA could

not

> > > have been aware of when they reviewed the drug, but which MHRA

> have

> > > a chance to familiarise themselves with. In April of this year

> the

> > > US Department of Health and Human Services, National Toxicology

> > > Programme, issued a Centre for the Evaluation of Risks to Human

> > > Reproduction Report that focused on Fluoxetine – NTP CERHR

Expert

> > > Panel Report on the reproductive and developmental toxicity of

> > > Fluoxetine. In this it is made clear that in male animals

tested

> > > Prozac leads to testicular shrinkage of approximately 25%. The

> use

> > > of this drug in men generally must therefore be of some

concern.

> > The

> > > use of this drug in pubertal boys would seem distinctly

> > problematic.

[Guest guest]

http://www.seroxatusergroup.org.uk/images/_38329933_davidhealy315.jpg

> > >

> > >

> > > Professor Healy advises the MHRA that Prozac leads to

> > > testicular shrinkage of approximately 25%.

> > >

> > >

> > > Can be found at

> > >

> > >

> > > http://www.socialaudit.org.uk/58096-DH%20to%20WARK.htm

> > >

> > >

> > > section headed -

> > >

> > > Prozac and SSRIs for Children

> > >

> > >

> > >

> > >

> > >

> > > Prozac and SSRIs for Children

> > >

> > > Since I attended the SSRI review committee, the question of

the

> use

> > > of Prozac in children has come to the fore. Prozac is

apparently

> > > under review for children by MHRA at present and the impression

> > > stemming from correspondence that is in the public domain from

> > Lilly

> > > and from other regulators in Europe is that approval by MHRA is

> > > interestingly all but certain.

> > >

> > > I have had a chance to review a good deal of data on Prozac

> given

> > to

> > > children and wish to make the following comments to the

> committee,

> > > many of which will not come as any surprise to you.

> > >

> > > There have been four trials of Prozac in children who are

> > depressed.

> > > The first by Simeon et al 1990 showed no differentiation

between

> > > Prozac and placebo.

> > >

> > > The second by Emslie published in 1997 showed no

differentiation

> > > between Prozac and placebo on the primary outcome measure of

the

> > > study. This was a trial in which less than 100 children were

> > > selected from over 500 children screened. This trial also used

a

> > > placebo washout period to exclude placebo responders.

> > >

> > > The third trial was a most unusual trial. Emslie was again the

> > first

> > > author, and this trial was published in 2002. In addition to

> > > extensive screening to select patients likely to be responsive

to

> > > treatment, this trial had a placebo washout phase to exclude

> > placebo

> > > responders, as had the previous Prozac trials, but in addition

it

> > > had a further phase, which involved children randomised into

> Prozac

> > > arm of the trial being given a week of Prozac 10mg first with

an

> > > exclusion option for any children who appeared to respond

> adversely

> > > to Prozac. The trial proper started after this extraordinary

> > > manoeuvre.

> > >

> > > Even with this extraordinary step on the primary outcome

measure

> in

> > > the trial as indicated in FDA medical reviews of all of these

> > trials

> > > Prozac did not differentiate from placebo.

> > >

> > > The fourth trial you'll be aware of has recently been

published

> in

> > > JAMA with March as a first author, having first featured

in

> > the

> > > New York Times and elsewhere extolling the virtues of Prozac. I

> > > think rarely will the abstract of a major paper have been so

at

> > odds

> > > with the underlying raw data.

> > >

> > > I understand some of you in MHRA were watching the feed from

the

> > FDA

> > > paediatric advisory committee meeting. If that is the case

> > > presumably you will have seen Dr March present the data there

and

> > > heard him questioned. One of the most striking features of this

> > > interchange was that Dr March was forced to admit that

according

> to

> > > strict FDA criteria that Prozac in his trial had not been

shown

> to

> > > work either.

> > >

> > > The March group had manipulated the data in an interesting

> fashion,

> > > which involved searching for responders and non-responders on

> > scales

> > > such as the CDRS or the clinical global impression scales, and

> > > compared these. When this is done, the effect is to squeeze

> > patients

> > > into categories and under those circumstances Prozac can be

> shown

> > to

> > > be different from placebo but this squeezes the middle of the

> > > clinical population in a manner that is methodologically

> > > inappropriate. When the CDRS or other scales are used on a

> > > continuous variable basis, as per FDA requirements for

> > demonstrating

> > > efficacy, the differences between Prozac and placebo are not

> > > statistically significant. This point was recently brought out

> in a

> > > position piece by Newman in the NEJM.

> > >

> > > You will no doubt also be aware that the rate of suicidal acts

on

> > > Prozac in this latter trial is no less than the rate of

suicidal

> > > acts on other SSRIs, and is in fact substantially greater than

in

> > > most other SSRI trials.

> > >

> > > It would seem therefore that there is no more evidence of

> efficacy

> > > or for safety on Prozac than there is for other SSRIs, and

just

> as

> > > much evidence for harm.

> > >

> > > However it is also worth noting that there is some evidence for

> > > efficacy for Prozac, Seroxat/Paxil and Zoloft/Lustral for OCD,

> but

> > > at present it is difficult for any clinician to use an SSRI

for

> any

> > > child or teenager in the UK, owing to MHRA's handling of the

> issues

> > > thus far.

> > >

> > > For the record it's perhaps worth adding at this point that I

> don't

> > > agree that MHRA made the correct move in contraindicating

SSRIs

> in

> > > children. There is some evidence from trials in OCD and other

> > > anxiety disorders that some of these drugs can be effective.

The

> > key

> > > issue is that the treatment should come with the proper

warnings

> > for

> > > both adult and paediatric populations.

> > >

> > > My suspicion is that, as MHRA rarely if ever do anything

without

> > > some consultation with the market authorisation holders, it

> > appeared

> > > to be a better bet to the market authorisation holders to have

> the

> > > drugs contraindicated in children, given that so few children

in

> > the

> > > UK were having these drugs, rather than to have appropriate

> > warnings

> > > placed on the treatment, as such warnings might impact on the

> adult

> > > market. But contra-indicating SSRIs and other antidepressants

is

> > the

> > > move that seems to have set up the current quandary MHRA are

in,

> > > which appears to have all but required a licensing of Prozac

for

> > > children.

> > >

> > > If Prozac is licensed for children, it is also worth noting

that

> > > there are other features of Prozac use in children that are of

> > > concern. The FDA reviews of this drug make it clear that

children

> > > taking Prozac failed to grow at the rate that children taking

> > > placebo grew. The FDA asked Lilly to undertake follow-up

studies

> of

> > > this effect, but as far as I know the company have not done

so.

> No

> > > doubt MHRA will have noticed this problem in the trial data

> also.

> > If

> > > you do intend to license Prozac, it would be good to know that

> the

> > > issue of growth has been investigated properly.

> > >

> > > There is a further potential hazard of Prozac that FDA could

not

> > > have been aware of when they reviewed the drug, but which MHRA

> have

> > > a chance to familiarise themselves with. In April of this year

> the

> > > US Department of Health and Human Services, National Toxicology

> > > Programme, issued a Centre for the Evaluation of Risks to Human

> > > Reproduction Report that focused on Fluoxetine – NTP CERHR

Expert

> > > Panel Report on the reproductive and developmental toxicity of

> > > Fluoxetine. In this it is made clear that in male animals

tested

> > > Prozac leads to testicular shrinkage of approximately 25%. The

> use

> > > of this drug in men generally must therefore be of some

concern.

> > The

> > > use of this drug in pubertal boys would seem distinctly

> > problematic.