[e-drug] Antidepressant paroxetine in spotlight with new report

e-drug
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E_DRUG: Antidepressant paroxetine in spotlight with new report
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Another reason why full access to clinical trial data is essential.
Last week the BMJ published a re-analysis of Study 329 concerning efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence.

Conclusion: "Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs. Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative. The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base."

Full story:
http://www.bmj.com/content/351/bmj.h4320

Hedwig Diekwisch
BUKO Pharma-Kampagne / Gesundheit und Dritte Welt e.V.
August-Bebel-Str. 62
33602 Bielefeld
Tel.: +49 (0)521 60550
Fax.: +49 (0)521 63789
www.bukopharma.de
Pharma-Kampagne bei Facebook
<https://www.facebook.com/pages/BUKO-Pharma-Kampagne/195866943847728&gt;

Unterstützen Sie die Pharma-Kampagne mit einer Spende (online oder per Überweisung)
Gesundheit und Dritte Welt e.V.
Konto: 105 627 - Sparkasse Bielefeld 480 501 61
Hedwig Diekwisch <hd@bukopharma.de>

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E-DRUG: Antidepressant paroxetine in spotlight with new report(2)
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Thanks Hedwig

I am one of the authors: [Melissa Raven, postdoctoral fellow3], along with Joanna Le Noury, research psychologist1, John M Nardo, retired clinical assistant professor2, David Healy, professor1, Jon Jureidini, clinical professor3, , Catalin Tufanaru, research associate4, Elia Abi-Jaoude, staff psychiatrist5

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
http://www.bmj.com/content/351/bmj.h4320

There's also a commentary by Peter Doshi:
No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility
http://www.bmj.com/content/351/bmj.h4629

The commentary begins:
A major reanalysis just published in The BMJ of tens of thousands of pages of original trial documents from GlaxoSmithKline’s infamous Study 329, has concluded that the antidepressant paroxetine is neither safe nor effective in adolescents with depression.1 This conclusion, drawn by independent researchers, is in direct contrast to that of the trial’s original journal publication in 2001, which had proclaimed paroxetine “generally well tolerated and effective.”2 The new paper, published under the restoring invisible and abandoned trials (RIAT) initiative,3 has reignited calls for retraction of the original study, putting additional pressure on academic and professional institutions to publicly address the many allegations of wrongdoing.

and an editorial by David Henry and Tiffany Fitzpatrick:
Liberating the data from clinical trials
http://www.bmj.com/content/351/bmj.h4601

8 responses published so far (apparently there are others in the pipeline)
http://www.bmj.com/content/351/bmj.h4320/rapid-responses

Also Jon and I have an article in The Conversation:
Antidepressant trial's upended results show need for sharing all data
https://theconversation.com/antidepressant-trials-upended-results-show-need-for-sharing-all-data-47471

And Mickey has multiple blogs about the whole saga:
http://1boringoldman.com/index.php/2015/09/21/60048/

And there's a video:
Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence
https://www.youtube.com/watch?v=h0L78S_Ln9o

And lots of news coverage
http://study329.org/in-the-news/

We are emphasising that the implications go far beyond this particular trial and drug, but some of the coverage/responses are missing that point.

I usually just lurk on this list, but I will follow up with a separate email about my concerns about the pharma-funded Global Mental Health bandwagon, including the push for the inclusion of mental health as a UN sustainable development goal
http://www.bmj.com/content/349/bmj.g5189.long
For a rare critique, see
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4028926/

Cheers
Melissa

Melissa Raven
MPsych(Clin) MMedSci(ClinEpid) PhD
Psychiatric epidemiologist and policy analyst
Postdoctoral Fellow
Critical and Ethical Mental Health research group (CEMH)
Robinson Research Institute
University of Adelaide
55 King William Road, North Adelaide SA 5006, AUSTRALIA
"Melissa Raven" <melissa.raven@flinders.edu.au>

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E-DRUG Antidepressant paroxetine in spotlight with new report (3)
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Dear E-Drug Members,

Respectfully, and contrary to Hedwig Diekwisch post full clinical trial
data were not necessary to answer the question about the safety and
efficacy of paroxetine when used for depression in children and
adolescents. With great effort and expenditure of time the authors of the
Study 329 re-analysis only confirmed what has been recognized about the use
of this drug in pediatric populations for at least the last 17 years.

The US Food and Drug Administration (US FDA) approval package dated 1998,
posted free of charge on agency's web site, found that paroxetine had not
been shown to be safe and effective in pediatric populations.[1] This
information was available to the public three years before the original
publication of Study 329.[2] The professional product label for paroxetine
has been required to contain a box warning, the strongest type of safety
alert the US FDA can require, that the drug is not approved for use in
pediatric patients since the mid-2000s.[3]

The use of paroxetine for depression in children and adolescents is an
unapproved (off label) use that was disapproved.

More disturbing than the results of the Study 329 re-analysis is the
continued prescribing of drugs, such as paroxetine, in populations in which
there is no evidence at the level of rigorous regulatory scrutiny that the
drug is beneficial. This leaves patients with only the possibility of
harm. Prescribers must recognize that the phrase 'safe and effective' has
two meanings. One is the common usage that can be used in conclusions of
medical journal articles with impunity and the other is the regulatory
meaning that requires rigorous review of the evidence submitted to support
the approval of or use of a drug in a specific population.

Any positive impact on patient safety from the re-analysis of Study 329
trial 14 years after the original study was published is questionable. A
lesson that should be learned from the Study 329 tale is that patient drug
safety may be better served by promoting and placing the information from
regulatory summary documents in the hands of patients and their parents.

Additional comments about the Study 329 re-analysis have been posted on the
Patient Drug News web site at www.patientdrugnews.com.

References
1. Dubitsky GM. Food and Drug Administration Review and Evaluation of
Paroxetine Controlled Released Tablets, July 17, 1998. At
http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20-936_Paxil_medr_P1.pdf.
Accessed August 24, 2015.

2. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the
treatment of adolescent major depression: a randomized, controlled trial. J
Am Acad Child Adolesc Psychiatry Jul 2001;40(7):762-772.

3. Apotex Corp. Professional Product Label: Paxil CR (Paroxetine), July
12, 2015. At
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=483bd97f-c4d0-4e23-aaa8-6334f4471e0c.
Accessed August 24, 2015.

Best regards,

Larry
Larry D. Sasich, PharmD, MPH, FASHP
1201 North Shore Blvd East #802
Burlington, Ontario L7S 1Z5
Canada
Cell: 705-491-0609
E-Mail: larry.sasich@gmail.com

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E-DRUG Antidepressant paroxetine in spotlight with new report (4)
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With great respect and contrary to Larry Sasich, he has missed the many
points behind the Study 329 report.

First, FDA had to be told by outsiders to look under the emotional lability
rock while appraising the submission of paroxetine for pediatric use. Even
then they missed many of the suicidal events. As regards efficacy they
agreed with what they had been previously told by GSK - that Study 329 did
not show efficacy but agree to approve paroxetine for pediatric use and
agreed that it would not be helpful to mention the existence of negative
studies in the labeling.

Study 329 gave rise to a controversy about suicidality when it became clear
that the medical reviewer of the issue was gagged by FDA leading to
Congressional Hearings on the matter of the gagging.

What can we conclude? That all FDA reviews are vetted and reviewers
self-censor so that no-one is being told the truth. That in the absence of
access to the underlying data most journal articles on the results of RCTs
and FDA reviews must be assumed to be compromised as Study 329 was as there
is nothing in Study 329 that suggests this was anything other than standard
industry practice.

David Healy

David Healy
Professor of Psychiatry
Hergest Unit
Bangor Wales LL57 2PW
United Kingdom
T 44-1248-384453
C 447771897792
E david.healy54@googlemail.com
E David.Healy@rxisk.org

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E-DRUG: Antidepressant paroxetine in spotlight with new report (5)
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Regarding David Healy's comments. Hopefully, all can agree on several
points. First, paroxetine has never been approved for use in children and
adolescents. Second, the US FDA refused to approve paroxetine for major
depression in children and adolescents. Third, this information has been
publicly available free of charge on the Internet for years, primarily in
US FDA summary documents and professional product labeling.

Note, approval packages are rigorous analyses of data submitted by manufacturers to
support the approval of a new drug.

If one agrees with the above four points, then the debate must center on
how to protect patients and their families in the short term from being
prescribed drugs for off-label uses that have been disapproved in a time
frame that is much shorter than the Study 329 re-analysis provides. Time
and effort should be expended on promoting the contents of FDA documents
and professional product labels directly to the public as the public has
both a need and right to this information.

There is nothing new in manufacturers trying to expand the size of markets
using the medical literature. The 'publication strategy' to increase the
market share for gabapentin was designed to circumvent the FDA's drug
approval process is an example from recent history. Economically this was
a very successful tactic.

The negative paroxetine trials for use in the pediatric population for
depression are mentioned in the drug's professional product label. True,
they are not fully described but this does not prevent researchers and
prescribers from accessing the US FDA documents.

The US FDA reviewer did question the companies rational for coding adverse
drug reactions. But these adverse drug reactions have been in paroxetine's
professional labeling for years, including a box warning.

Congressional hearings were held on paroxetine. But, they were held. A
criticism of the US Congress has been the failure to hold regular oversight
hearings on FDA approvals and withdrawals as were done in the 1970s.

There is difficulty in understanding that the FDA reviewer self censored.
He found that the drug was not effective for depression in pediatric
populations. This agrees with the Study 329 re-analysis.

Dr. Healy's statement that 'FDA reviews must be assumed to be compromised
as Study 329 was' is remarkable. The Study 329 re-analysis group has
apparently confirmed an FDA compromised review.

A final question for Dr. Healy. How does the public determine who is
a legitimate independent third party that should review clinical trials?

Best,

Larry

Larry D. Sasich, PharmD, MPH, FASHP
1201 North Shore Blvd East #802
Burlington, Ontario L7S 1Z5
Canada
Cell: 705-491-0609
E-Mail: larry.sasich@gmail.com

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E-DRUG: Antidepressant paroxetine in spotlight with new report (6)
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[Thank you very much for the serious attention you have given this important thread. It has been well covered now. BS Moderator]

Response to Larry Sasich

There is a good deal in Dr Sasich's email that I and all readers of these
posts can agree with but there are a number of points that recent events
have shed further light on..

First, FDA wrote an approvable letter for Paxil despite 3 negative trials
in MDD in children and no positive trials. This is available on
Study329.org.

Second, one might quibble they didn't in fact approve pediatric Paxil but
in fact they approved pediatric Prozac a short while before even though the
evidence for efficacy was no better than for Paxil and the evidence for
harms has been as concealed - See Hogberg G, Antonuccio D, Healy D
(2015). Suicidal
Risk from TADS Study Was Higher than it First Appeared. Int J Risk &
Safety in Medicine 27, 85-91. DOI 10.3233/JRS-150645

Third in a later analysis of the 329 data done under a public spotlight,
FDA got the number of suicidal events significantly wrong. FDA review
manufacturers submissions - they do not review or analyze the data or on
the rare occasions they do they commonly get it wrong.

In the case of the Risperdal submission now also hitting the headlines, the
FDA reviewer noted in passing a large number of suicidal events after
Risperdal withdrawal but dismissed these because we know antipsychotics
don't cause a withdrawal syndrome. This was the response of a bureaucrat
who simply didn't know the literature. Antipsychotics were well known
since the 1960s to have a significant withdrawal syndrome.

The bigger issue is this. The fact that FDA might not have approved Paxil
is publicly available, is not the issue. I should not have to trust Marty
Keller and colleagues writing the original Study 329. No one on this list
should have to trust me. None of us should have to trust FDA. If we have
to trust we are talking about religion rather than science. Science means
we can check. And as things stand we can check the results of no clinical
trials that industry runs.

Dr Sasich asks how does the public determine who is a legitimate third
party to review clinical trials? Make the data publicly available and this
problem is transformed. The public will still be faced as Dr Sasich has
outlined with an academic apparatus co-opted to help market drugs but FDA
offer no help in this respect - they were happy to sit there having been
told by GSK that Study 329 was a negative study and still say nothing about
an article sitting in the public domain then being vigorously built into
all guidelines on the treatment of children that claimed the drug worked
well and was safe.

David Healy
--
David Healy
Professor of Psychiatry
Hergest Unit
Bangor Wales LL57 2PW
United Kingdom
T 44-1248-384453
C 447771897792
E david.healy54@googlemail.com