[e-drug] Should drug companies test their own drugs?

e-drug
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E-DRUG: Should drug companies test their own drugs?
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[An important question raised by the BMJ editor: should drug companies be allowed to test their own drugs, or should we get independent review? Copied as fair use. WB]

BMJ 2006;333 (8 July), doi:10.1136/bmj.333.7558.0-f

Can we tame the monster?

What can we learn from the New England Journal of Medicine's correction last week of its study on rofecoxib (BMJ 2006;333: 12, 1 Jul)? The simple message is that increased cardiovascular risks were visible as early as four months into treatment, rather than the 18 months that Merck had claimed. But rofecoxib was withdrawn two years ago, so why all the fuss?

Well, reputations are at stake. The journal wants to show that it had made no mistakes in peer reviewing the study. And Merck, having already incurred financial loss, needs to protect its share price. But the stand-off between journal and drug company is just one symptom of a wider disease: an overpowerful, under-regulated drug industry and a research establishment and publishing industry in its thrall.

Between the interests of the public and the commercial interests of drug companies stand two potential safeguards-journal peer review and drug regulation. The pressures on journals to publish drug industry trials include the need for newsworthy content and revenues from reprint sales. These pressures are intensifying, and recent examples of selective reporting and data manipulation have made clear that peer review in its current form is unequal to the task. Writing in PLoS Clinical Trials (2006;1: e6)[CrossRef] in May, Richard Smith and Ian Roberts proposed a different model for disseminating the results of clinical trials. Protocols and analyses would be prespecified and posted for discussion, and full datasets would be uploaded on completion of the trial. The role of journals would be limited to providing commentaries. Is this feasible? Is it the answer?

Drug regulators too seem unequal to their task. Critics focus on their close relationship with industry; their lack of transparency; their lack of systematic post marketing surveillance; and an emphasis on efficacy over patient safety, which favours industry. In this week's BMJ, David Healy examines how the regulators failed to highlight the risks of selective serotonin reuptake inhibitors in depression (p 92). The US Food and Drug Administration has taken steps to reform, but critics want more. Writing in the New England Journal of Medicine, Wayne Ray and colleagues call for the establishment of three independent centres in charge of drug approval, postmarketing studies, and drug information (2006;354: 194-5)[Free Full Text]. As for the UK Medicines and Healthcare Products Regulatory Agency, it is seen by many as unaccountable, slow, and lacking the necessary expertise. It too needs urgent review and reform.

I suggest a more radical solution. As with most good ideas, it is not mine alone. Marcia Angell (personal communication) and Des Spence (BMJ 2006;332: 1155-6, 13 May (copied below) have also had it, but here is my version. Drug companies should not be allowed to evaluate their own products. To get their products licensed they would contribute to a central pot for independent, publicly funded clinical trials. Is this feasible? Is it the answer?

Fiona Godlee, editor

(fgodlee@bmj.com)

BMJ 2006;332: 1155-6, 13 May
[Copied as fair use]

Research for profit
EDITOR�The stumbling block for clinical trials in both the developing and developed world is the same, enrolment.1 It is difficult to enrol patients into trials, and we rely on consent forms and the investigating doctor to protect patients.

Unknown to most patients, however, is the conflict of interest that exists at the time of enrolment. When I first started in general practice over 10 years ago I was asked to conduct pharmaceutical company research. The motivation to conduct this research was financial with the potential to earn �10 000 (14 500; $18 500) on top of NHS income. This is still common, especially in the most deprived areas of the United Kingdom. I conducted the research and enrolled 10 patients�I told patients that I was being paid but did not disclose the amount.

Later I was again asked to act as an investigator in another trial. On this occasion, however, I decided on complete transparency and disclosed the fee to the patients at the time of enrolment. I was unable to recruit any patients. So ended my involvement in research for profit.

The greatest incentive for doctors to conduct research and enrol patients for pharmaceutical studies is financial, either directly or to their institution. This situation is not ethical. Patients agree to participate in trials for altruistic reasons and put trust in the professionalism of doctors. Ethics committees should recognise this and insist the exact amounts paid to doctors and hospitals be disclosed to patients. Perhaps it is time also that independent non-profit groups and charities oversee and organise clinical trials.

Money, medicine, and research is a heady and seductive cocktail but has the potential for excess, risk taking, and recriminations.

Des Spence, general practitioner
Glasgow G20 9DR destwo@yahoo.co.uk

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E-DRUG: Should drug companies test their own drugs? (3)
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Wilbert,

I agree with you that the BMJ editor's suggestion is very important. Rapid
responses can be read at:
http://bmj.bmjjournals.com/cgi/eletters/333/7558/0-f

It would be good to hear e-druggers' views on e-drug or as rapid responses
to the BMJ. Here is my rapid response:

A more comprehensive and achievable alternative
8 July 2006
     
The Angell Spence Godlee proposal to ban pharmaceutical manufacturers from
researching their products<1,2> has considerable merit. However, Healthy
Skepticism Inc advocates a more comprehensive alternative that will also
reduce the harm currently caused by misleading promotion, biased industry
funding of education and high drug prices. Our alternative is also more
politically achievable because implementation can be government revenue
neutral whilst securing long term competitive return on investment for the
pharmaceutical industry.

Pharmaceutical companies currently have four main functions: manufacturing,
research, promotion and education. Performance of those functions is
currently distorted by incentive systems that reward only activities that
increase sales of more expensive drugs regardless of the impact on health
care. We recommend that the four functions be paid for separately by
government agencies via iterative competitive public tender. This would
allow the relevant divisions and subcontractors of pharmaceutical companies
to compete with universities and non-profit non- government organisations
(NGOs) for funding to provide each function separately. Incentives can then
to be aligned to reward quality performance at each function separately. If
a company performed poorly, eg research fraud or misleading promotion, then
it would not get funding for that function in the next tender round. Drug
prices would no longer include a premium for research, promotion and
education. Consequently, drug companies would no longer fund those functions from drug sales. Lower prices would make drugs more cost-effective for larger numbers of people.

Our recommendations can be implemented quickly or slowly by gradually
reducing prices and transferring the savings to organisations that fund
research (eg UK Medical Research Council) education (eg medical schools and
royal colleges) and promotion (eg promotion provided by the Best Practice
Advocacy Centre, New Zealand). We also recommend improving both regulation
of the industry and education for health professionals about treatment
decision making.<3,4,5>

1. Godlee F. Can we tame the monster? BMJ 2006 July 8;333(7558):
2. Sweet M. Doctors and drug companies are locked in 'vicious circle'. BMJ
2004 Oct 30;329(7473):998
http://bmj.bmjjournals.com/cgi/content/full/329/7473/998
3. Mansfield PR. Healthy Skepticism about drug promotion: Memorandum for the UK House of Commons Health Committee Inquiry: The Influence of the
Pharmaceutical Industry. Healthy Skepticism International News 2004 Oct;
22(10-12)1 www.healthyskepticism.org/news/issue.php?id=6
4. Mansfield P, Rogers W, Jureidini J. Submission from Healthy Skepticism re RACP Ethical Guidelines. Healthy Skepticism International News 2005 Sep;
23(9)1 www.healthyskepticism.org/news/issue.php?id=15
5. Mansfield PR. Banning all drug promotion is the best option pending major reforms. J Bioethical Inquiry 2005;2(2):16-22

Competing interests: I have received funding from organisations that would
benefit from implementation of our recommendations including the many
universities, the Royal Australasian College of Physicians and the National
Health and Medical Research Council (Australia).

regards,

Peter

Dr Peter R Mansfield
GP
Director, Healthy Skepticism Inc. Countering misleading drug promotion.
www.healthyskepticism.org
peter@healthyskepticism.org
Research Fellow, Discipline of General Practice, University of Adelaide.
www.adelaide.edu.au/directory/peter.mansfield
peter.mansfield@adelaide.edu.au

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[Interested e-druggers are encouraged to read the rapid responses to Fiona Goodlee's 'editor's choice': Can we tame the monster? in BMJ 8 July. http://bmj.bmjjournals.com/cgi/eletters/333/7558/0-f. Moderator]

Dear E-druggers,

This somewhat belated discussion is a sign that
the series of critical books which have been
published during the last three years (Angell,
Kassirer, Avorn, Robinson, Moynihan, Goozner, Law
and Bouma in Holland) have not missed their goal.
The serious accident in London has accelerated
the discussion. Anybody working in drug
registration during the transition CPMP-EMEA
could have predicted these problems. When EMEA
started its work registration guidelines
stipulated that all applications had to be
accompanied by a summary, to be written by "an
independent expert". Industry quite soon
complained that it was unable to fulfill the
request because they couldn't find such experts,
at least not enough of them. The CPMP then
acquiesced and left the writing of Summaries and
EPARs to "inside experts", i.e. to industry
employees. Even then it was quite obvious that a
scientist receiving his/her salary from industry
could never be fully independent. The amount of
data and the number of registration files has
since increased dramatically, making it
practically impossible for registration
authorities even to periodically check on the
veracity of the summaries. The sheer quantity of
data makes a critical assessment nearly
impossible. Re-analysing trial data may be quite
difficult, statistically complicated and time
consuming. But industry and gouverments have
gradually shortened time limits with disastrous
results and even EMEA and the FDA are seriously
understaffed. The "privatisation" of the
financial arrangements has seriously undermined
morale among the most highly qualified assessors.

Then: There is a critical difference between
adverse "non-pharmacological" - "toxic" or
"idiosyncratic" reactions - agranulocytosis,
contact eczema, acute renal failure, etc. - and
adverse reactions which are only a quantitative
increase of the incidence of normally occurring
diseases like myocardial infarction, hepatitis,
pancreatitis, gastrointestinal haemorrhage etc.
To define such events at an early stage as an
adverse reaction to a drug can be very difficult,
as the Vioxx affair has shown. Industry is quite
understandingly dragging its feet when it
suspects such problems, and registration
authorities might not be aware at all until it is too late.

As I discussed many years ago with Marcia Angell
journal editors are in a difficult position. In
the first place the great majority of trial
reports are boring to read and will put the
readers off. Nobody is happy to publish the N-th
megatrial on a me-too drug. Look at the columns
of The Lancet. Space in journals is limited and
if an author omits certain critical data or even
falsifies data or statistics there is nothing the
editor can do because the full trial data remain
confidential. A report may look elegant and very
complete, but nevertheless it may be
substantially different from the registration
file. But journal editors could be more critical
and refuse to publish data on drugs which show no
clinically relevant improvement in medical care
and outcome. Unfortunately some journals (don't
forget the publishers!!) can be bought.

Should industry no longer test its own drugs?
That means withdrawing funds and personnel from
normal health care, and who is going to pay? I
don't think this is the answer, but more
transparency and better supervision is a
preferable option. But with many others I would
like to advise gouverments to immediately
transfer the full financial and political
responsability of drug registration back to where
it belongs, i.e. the gouverment itself. As its is
now - to put it bluntly - it looks as if the
mafia is paying the salaries of the police.

Best regards,

Leo Offerhaus, Bussum, the Netherlands
Former member CPMP, former Vice-Chairman, Dutch
Committee on the Registration of Medicines
offerhausl@euronet.nl

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Leo,

It is possible to have contact eczema or acute renal failure without taking
a drug.

Vioxx should not have been approved until there was adequate evidence that
it was no worse than other NSAIDs for at least one group of patients. The
VIGOR trial data showed equal efficacy and an overall increased rate of
serious adverse events so Vioxx should have been withdrawn then. However
because of industry control and groupthink the key findings were not given
the attention they deserved. Refusal to approve Vioxx until there was
adequate evidence that it was no worse would have provided an incentive for
studies in people at high risk of GI adverse effects and low risk of
cardiovascular disease for whom Vioxx may be superior.

I don't understand your distinction between the two types of adverse event.
I think there is a continuum between adverse events that are easy to link to a drug because they are clear cut, immediate and/or unlikely to have another cause at one end of a spectrum with events at the other end of the spectrum that are subtle, delayed and/or could have another cause so it is difficult to distinguish the signal from the noise.

A more important point is that publicly funded and accountable drug
regulation is not enough. We also need publicly funded and accountable
research, manufacturing, education and promotion. Healthy Skepticism's
proposals for redesigning the incentives for those 4 activities are
summarised in my rapid response at:
http://bmj.bmjjournals.com/cgi/eletters/333/7558/0-f

Even that is not enough. Healthy Skepticism's full reform agenda includes:

1. improve decision making by improving education for health professionals
and the public
2. redesign incentives for drug companies
3. redesign incentives for health professionals
4. improve regulation of drug companies
5. improve regulation of health professionals

See:
Mansfield P, Rogers W, Jureidini J. Submission from Healthy Skepticism re
RACP Ethical Guidelines. Healthy Skepticism International News 2005 Sep;
23(9)1 www.healthyskepticism.org/news/issue.php?id=15

regards,

Peter

Dr Peter R Mansfield
GP
Director, Healthy Skepticism Inc. Countering misleading drug promotion.
www.healthyskepticism.org
peter@healthyskepticism.org
Research Fellow, Discipline of General Practice, University of Adelaide.
www.adelaide.edu.au/directory/peter.mansfield
peter.mansfield@adelaide.edu.au

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Dear friends,

   We all know what can be achieved in a research environment that is
   well regulated and monitored, where the process is above suspicion or
   bias. We all know that the outcome of that process would, if passed by
   an independent body, a useful product to the public, as well as a
   profitable product for the researchers and the drug company. That
   is the platform we have. If we argue that this platform necessarily
   needs to change in order to remove bias from drug companies, external
   clinical researchers, etc, then we should be prepared to discuss the
   consequences that change in platform might bring.

   The fact remains that as part of their research and drug development,
   drug companies are expected to test their own drugs. What we are
   asking is whether we can trust industry to self- regulate that
   process. But as long as drug companies are required to do clinical
   trials, the potential for self- serving will be there; as long as
   assistance from external researchers (eg, GPs) is used, the potential
   for bias will be there, especially when money is involved.

   For reasons that have been pointed out by Leo Offerhaus, it may be a
   tall order to suggest that internal processes and research processes
   should be audited by an external, independent body, other than
   the drug company itself. Besides usual factors, how would that
   arrangement address preserving intellectual property, confidentiality,
   etc?

   Since there is no regulation about what incentive pay should be made
   to (for example, GPs and) others participating as external
   research/clinical trials parties, regulating this area might be easy
   and probably acceptable by all. Secondly, regulating the research
   process, the information that is reported, etc, can also be
   established or where these exist, could be strengthened

   If we agree that the role of these regulatory bodies is to look after
   public health and safety, then governments have a duty to ensure these
   agencies are empowered to carry out that mandate. I believe that most
   developed countries have sufficient research and clinical trial
   arrangements and provisions, but these need to be supported in respect
   to enforcement. If the regulators role is to be robust, then these
   bodies need priority support by governments at all times. Alternative
   arrangements such as full or semi- privatisation of this regulatory
   function is a recipe for disaster, as we are now witnessing.

   Regards,

   Bonnie
   Bonface Fundafunda PhD, MBA, B.Pharm(Hon)
   Hartmannsvej 16,
   Kgs.Lyngby
   2800 Denmark
bcfunda@hotmail.com