The patient go-between?
A quick response to:
Key opinion leaders: independent experts or drug representatives in
disguise? Ray Moynihan, visiting editor, BMJ
Ray Moynihan has started a very useful debate on the practice of
using KOLs to advance the interests of drug companies amongst the medical
community. A number of writers have contributed their point of view, but
only one is actually part of the patient community. As patients with
thalassaemia we have also been subjected to this phenomenon. We would like
therefore to provide some further points gained by our experiences from
the “other side of the fence” dealing with doctors of both types (KOLs and
non KOLs) as well as with drug companies.
Unlike other conditions, thalassaemia in the UK and other high income
countries, is rare and involves relatively small numbers of patients when
compared with say diabetes, heart disease and cancer. Being a rare red
cell condition means it is not able to attract a large volume of high
calibre doctors and scientists internationally, as they consider oncology
more challenging or more rewarding for their careers. This in turn results
in a small number of ‘senior experts’ being effectively in control of the
development of treatment.
Globally, approximately 43,000 children with thalassaemia beta major
are born annually, most in developing countries . Approximately 62% need
regular blood transfusion to survive, but only about 13% of them have
access to it. It is estimated that worldwide over 72,000 patients are
living on regular transfusions. Without iron chelation therapy they will
die from iron overload between 12 and 24 years of age . However less than
50% of transfused patients have access to any form of chelation therapy,
and probably only 10% (including the less than 1,000 patients in North
America) benefit from the full protocol . Consequently, two to four
thousand patients die annually from iron overload.
The drug company perspective
The iron chelating drug Desferrioxamine developed in 1964, although
not without its problems, was one of Ciba-Geigy’s top earners before it
merged into Novartis: a switch to a cheaper chelator, or one not produced
by Novartis, will obviously be unwelcome.
Deferiprone (L1) developed from 1987, to be accessible in the
developing world is a simple and potentially cheap oral iron chelator.
When in 1992 Ciba-Geigy (then the only firm interested in iron chelation)
was asked to support clinical trials, largely because of the hope
deferiprone offered for patients in developing countries, the commercial
interest of maintaining the monopoly of a lucrative product as well as
avoiding dilution of revenue resulted in the firm declining, in favour of
developing a proprietary oral chelator in the future.
The UK Thalassaemia Society supported the introduction of Deferirpone
for thalassaemia in the UK at a total cost of £750,000 ($1,480,000) until
Apotex started producing Deferiprone (as Ferriprox) for high resource
countries under orphan drug regulations and Cipla in India. Without
financial support for quality clinical trials, evidence would have to be
collected piecemeal by dedicated professionals: the thalassaemia community
seemed in for a bumpy ride – a prediction that has been amply fulfilled.
Just like any market share driven sector, there has been a continuous
and concerted effort to demote this new competitor.
“Uncertainties in the use of the drug that have arisen since 1998 are
largely due to failure of separation of scientific evidence of the
efficacy and side-effects of deferiprone from ethical issues arising from
the dispute that arose between Olivieri and Apotex” but also in the
disregard for the need to obtain objective clarification of the true
science behind this event. What this has succeeded in doing is to
propagate the Fear Uncertainty and Doubt (F.U.D.) that has been poisoning
the thalassaemia community for years . It is now clear that this has not
happened by chance.
Kimberly Elliot very clearly dispels any remaining myths about the
true role of the KOLs.
Although with such high fees realisable , even if we discount any
personal benefits to the KOLs, working in today’s cash-strapped medical or
academic departments, doctors will not simply flock to the embrace of drug
companies for payments made. These are only a crude and ineffective method
of obtaining influence. The true relationship between KOLs and drug
companies is far more complex, and the manipulation is subtle and elusive
to uncover as it relies on the fundamental weaknesses of human behaviour.
Doctors are just like all other human beings. Practicing medicine
puts them in a position to make life-and-death decisions for their
patients, but they are not necessarily God-like. Their professional
environments of hospitals, research departments and pharmaceutical
companies, all obey the laws of economics.
Then there is the personal aspect: doctors see patients in clinic,
unresolved medical problems push them to do research for which they need
grants and approval of their peers. They are thus able to publish papers
in peer reviewed journals and for this they need the approval of
“sponsors” and “senior experts” in the editorial process. Without this
approval, there are no grants, limited research, no publications, no
visibility, no career advancement and even potentially loss of tenure.
The drug companies have become extremely adept and quite cynical at
when and how to use this situation by knowing at what stage to get
involved and with which doctors, in order to ensure a long term support
for their sales. As we have seen, even the allocation of clinical trials
for a new drug, apart from being a precious source of research grants, is
used in a highly selective way not only to have the best long term effect
but also to cement long term relationships with clinicians who in turn are
compelled to continue the company’s post-licensing marketing campaign, as
well as ensuring there is substantial conversion rates from the existing
to the new drug.
The recruitment and promotion of doctors by drug companies are
designed as an incentive towards a certain type of behaviour which is
being constantly monitored behind the scenes by the pharmaceutical
companies. It places the doctor in the paradoxical situation of always
having to prove that their opinion is unblemished.
As “invisible sales people” KOLs remain generally unknown by the
wider patient group, the end point of their salesmanship. In the small
international medical community of physicians treating thalassaemia, the
impact “senior specialists” acting as KOLs have on the lives of patients
can be very high indeed. Tactics similar to those applied for HIV, are
being practiced in iron chelation . The interaction and influence of KOLs
in many of the instruments of medical debate, as quite correctly
mentioned, does not solely result in the amount of prescriptions written
by them or others. They can also be very effective in exploiting
unresolved issues, raising doubts, fostering a climate of uncertainty and
fear of alternative treatments under the guise of scientific evidence
which is used quite selectively. The term “evidence based” is frequently
wheeled out to bolster this opinion-based science. They are oblivious to
the damage they cause to science, patients that potentially could benefit
from alternatives and ultimately to their own credibility.
We know very well that the boundary between genuine expertise and
salesmanship is often invisible and can be easily transgressed. The irony
in the Canadian case is that the clinician who initially appeared to be
the patients’ champion, in a battle with a drug company, through the
influential allies the controversy attracted, became the reason for the
patients of the US, Canada and elsewhere to be denied an additional
available drug, by contrast with their European counterparts. According to
Savulescu, the tragedy is that this controversy is still ongoing. The real
tragedy however is the still unmeasured cost in terms of patient lives.
In light of the above there should really be a moral debate within
society.
The patient perspective.
Chronic conditions require a long-standing partnership between
patient and doctor, based on trust, mutual respect, understanding and
agreed collaboration. Partnership has proven to have the best healthcare
outcomes.
Today’s patients are able to follow their doctors in lectures,
conferences, and debates and observe bias. They can see when the doctors’
opinion is not evidence based but opinion based. The opinions are those of
KOLs who may treat few patients themselves if any, yet tell other doctors
what to do. Although most doctors are risk averse professionals and not
innovators when no alternatives exist there may be an absolute need to
take. But what if these risks are continuously exaggerated? The influence
of drug companies can create anxiety, insecurity, and lack of trust
between doctors and patients and loss of integrity. If doctors are made to
feel uncertain they will avoid giving the treatment they think
appropriate. Fear Uncertainty and Doubt (FUD) harm patients in many ways;
they fear they are misinformed, feel uncertain about their future and come
to doubt the judgement and motivation of those they have entrusted with
their health and safety. It also prevents choice. Instead of living their
life with confidence they are filled with of anxiety. Continuous anxiety
due to doctors behaving badly is bad science, bad medicine and a nightmare
to live with. Observing FUD being actively propagated by vested interests
is terribly disillusioning for the patient.
The patients’ interests lie in removing the FUD and gaining clear
messages. Patients are also able to participate in the debate and have a
substantial contribution to make. They need to be heard because this
concerns their own lives.
If we see doctors behaving under commercial influences, sending
conflicting messages and creating or maintaining uncertainty due to
competing interests we can understand that all aspects of patient care are
open to manipulation. This is truly a very insidious problem of modern
healthcare and there has been no satisfactory answer from the point of
view of the patient. Increased scrutiny or disclosure will never be
sufficient as it can never reach the root of the problem.
Quite obviously the most important issue beyond that of the public
interest is when these relationships become so pervasive as to produce
Guidelines that are not manifestly objective then it becomes a patient
safety issue. In that sense it is a truly invisible, unquantifiable and
unaccountable threat.
One also has to remember that although the majority of doctors of
both camps are able to access the available channels of information and
debate, such as journals like the BMJ, patients are mostly not in this
privileged position and do not gain the background knowledge that the
medical profession enjoy. Their only source of information is from their
own doctors. Unfortunately in some cases they not only remain the silent
majority but are also misinformed by the one person they place their trust
in.
Although as Juan Gérvas, says KOLs obtain their credit from
peer review journals and other conferences and publications, they should
never forget that primarily their careers, and societal status and power
are conferred by the patients. Thalassaemia patients have a substantial
interest in this debate and have been participating through their articles
in this and other journals 6, They deserve more credibility and
consideration.
The ‘chameleon-like’ behaviour of interchangeable interests and
allegiances of KOLs are not compatible with Science and Integrity.
Compromising them is not acceptable and should not be forced to cohabit
with commercial interests.
However, patients have proved that they can react appropriately
against unacceptable sources of bias and misinformation, by selecting and
working with the true experts, as against ostensibly “independent experts”
to produce robust, unchallengeable and objective guidelines.
The UK Thalassaemia Society in 2005 created a true partnership of
patients and doctors, in order to publish their own Standards for the
Clinical Care of Children and Adults with Thalassaemia in the UK .
Ensuring no drug firm involvement, with extensive peer review, updated
regularly, and showing a commitment for objectivity, a true collaboration
of this kind may be the key to satisfactory resolution of this mess. The
UK Thalassaemia Society Standards have now become the model for other
patient associations in other countries.
Spiers makes a valuable distinction. There is indeed an invisible
boundary. Whenever a KOL decides to “change mode” it will be in stealth
and, by definition, under the disguise of “acting as an expert”. The
professional integrity of an independent is forever compromised and the
trust of the patient is betrayed. The doctor patient-relationship has
failed. As a result, their role as “independent experts” is purely aimed
at making their messages more acceptable and credible by lesser experts.
To those doctors we can only suggest to listen to and investigate the
claims from all with an open mind, questioning the veracity of the
scientific evidence presented before acting on any existing treatment.
This process is invisible to the patients, so we solely rely on the
doctors’ integrity.
In the new era of “expert patients” it is time the pharmaceutical
industry realise that the use of KOLs is counterproductive and start
changing their approach by focusing more on patients and their
representatives rather than turning scientists into salesmen.
Doctors are and should be the true and genuine gatekeepers between
the drug company and the patient. Are doctors able to accept this new
partnership?
Dr. Christos Sotirelis - UK Thalassaemia Society Vice President, â
thalassaemia major patient
George Constantinou - UK Thalassaemia Society Treasurer, Thalassaemia
International Federation Secretary, â thalassaemia major patient
Note: The opinions expressed here do not represent the views of the
UK Thalassaemia Society or of the Thalassaemia International Federation,
but solely these of the authors of this article.
Moynihan R. Key opinion leaders: independent experts or drug
representatives in disguise? Brit.Med.J. 2008;336:1402-3.
Angastiniotis M, Modell B. Global epidemiology of hemoglobin
disorders. Annals of the New York Academy of Sciences 1998;850:251-269.
Modell B, Berdoukas V. The clinical approach to thalassaemia. Grune
and Stratton, New York and London. 1984.
Guidelines for the clinical management of thalassaemia. Thalassaemia
International Federation. 2000.
A. Victor Hoffbrand,, Response to Savulescu Editorial. RE:
Deferiprone BMJ 2004;328:369-1. (Rapid response 19 March 2004 )
George Constantinou, The disappearing patient. BMJ 2004; 328:369-1.
(Rapid response 13 March 2004)
Key Opinion Leaders Average $25,000 to $50,000 in Annual Advising
Fees; http://www.reuters.com/article/pressRelease/idUS175983+24-Jan-
2008+MW20080124; Thu Jan 24, 2008, accessed 06/07/2008 14:17.
Joseph A Sonnabend, KOLs – Devils or Angels? ; BMJ 2008; 336: 1402-
1403 (Rapid response 25 June 2008)
Savulescu J. Thalassaemia major: the murky story of deferiprone. BMJ
2004;328:369-1.
Juan Gérvas, Experts and female health BMJ 2008; 336: 1402-1403
(Rapid response 22 Jun 2008)
Constantinou C, Melides S, Modell B. The Olivieri case (letter). New
England Journal of Medicine 2003;348:860-1.
Competing interests:
None declared
Competing interests:
No competing interests
15 July 2008
Christos Sotirelis
UK Thalassaemia Society Vice President, â thalassaemia major patient
Rapid Response:
The patient go-between?
The patient go-between? A quick response to: Key opinion leaders: independent experts or drug representatives in disguise? Ray Moynihan, visiting editor, BMJ
Ray Moynihan has started a very useful debate on the practice of using KOLs to advance the interests of drug companies amongst the medical community. A number of writers have contributed their point of view, but only one is actually part of the patient community. As patients with thalassaemia we have also been subjected to this phenomenon. We would like therefore to provide some further points gained by our experiences from the “other side of the fence” dealing with doctors of both types (KOLs and non KOLs) as well as with drug companies.
Unlike other conditions, thalassaemia in the UK and other high income countries, is rare and involves relatively small numbers of patients when compared with say diabetes, heart disease and cancer. Being a rare red cell condition means it is not able to attract a large volume of high calibre doctors and scientists internationally, as they consider oncology more challenging or more rewarding for their careers. This in turn results in a small number of ‘senior experts’ being effectively in control of the development of treatment.
Globally, approximately 43,000 children with thalassaemia beta major are born annually, most in developing countries . Approximately 62% need regular blood transfusion to survive, but only about 13% of them have access to it. It is estimated that worldwide over 72,000 patients are living on regular transfusions. Without iron chelation therapy they will die from iron overload between 12 and 24 years of age . However less than 50% of transfused patients have access to any form of chelation therapy, and probably only 10% (including the less than 1,000 patients in North America) benefit from the full protocol . Consequently, two to four thousand patients die annually from iron overload.
The drug company perspective
The iron chelating drug Desferrioxamine developed in 1964, although not without its problems, was one of Ciba-Geigy’s top earners before it merged into Novartis: a switch to a cheaper chelator, or one not produced by Novartis, will obviously be unwelcome.
Deferiprone (L1) developed from 1987, to be accessible in the developing world is a simple and potentially cheap oral iron chelator. When in 1992 Ciba-Geigy (then the only firm interested in iron chelation) was asked to support clinical trials, largely because of the hope deferiprone offered for patients in developing countries, the commercial interest of maintaining the monopoly of a lucrative product as well as avoiding dilution of revenue resulted in the firm declining, in favour of developing a proprietary oral chelator in the future.
The UK Thalassaemia Society supported the introduction of Deferirpone for thalassaemia in the UK at a total cost of £750,000 ($1,480,000) until Apotex started producing Deferiprone (as Ferriprox) for high resource countries under orphan drug regulations and Cipla in India. Without financial support for quality clinical trials, evidence would have to be collected piecemeal by dedicated professionals: the thalassaemia community seemed in for a bumpy ride – a prediction that has been amply fulfilled.
Just like any market share driven sector, there has been a continuous and concerted effort to demote this new competitor.
“Uncertainties in the use of the drug that have arisen since 1998 are largely due to failure of separation of scientific evidence of the efficacy and side-effects of deferiprone from ethical issues arising from the dispute that arose between Olivieri and Apotex” but also in the disregard for the need to obtain objective clarification of the true science behind this event. What this has succeeded in doing is to propagate the Fear Uncertainty and Doubt (F.U.D.) that has been poisoning the thalassaemia community for years . It is now clear that this has not happened by chance.
Kimberly Elliot very clearly dispels any remaining myths about the true role of the KOLs.
Although with such high fees realisable , even if we discount any personal benefits to the KOLs, working in today’s cash-strapped medical or academic departments, doctors will not simply flock to the embrace of drug companies for payments made. These are only a crude and ineffective method of obtaining influence. The true relationship between KOLs and drug companies is far more complex, and the manipulation is subtle and elusive to uncover as it relies on the fundamental weaknesses of human behaviour.
Doctors are just like all other human beings. Practicing medicine puts them in a position to make life-and-death decisions for their patients, but they are not necessarily God-like. Their professional environments of hospitals, research departments and pharmaceutical companies, all obey the laws of economics.
Then there is the personal aspect: doctors see patients in clinic, unresolved medical problems push them to do research for which they need grants and approval of their peers. They are thus able to publish papers in peer reviewed journals and for this they need the approval of “sponsors” and “senior experts” in the editorial process. Without this approval, there are no grants, limited research, no publications, no visibility, no career advancement and even potentially loss of tenure.
The drug companies have become extremely adept and quite cynical at when and how to use this situation by knowing at what stage to get involved and with which doctors, in order to ensure a long term support for their sales. As we have seen, even the allocation of clinical trials for a new drug, apart from being a precious source of research grants, is used in a highly selective way not only to have the best long term effect but also to cement long term relationships with clinicians who in turn are compelled to continue the company’s post-licensing marketing campaign, as well as ensuring there is substantial conversion rates from the existing to the new drug.
The recruitment and promotion of doctors by drug companies are designed as an incentive towards a certain type of behaviour which is being constantly monitored behind the scenes by the pharmaceutical companies. It places the doctor in the paradoxical situation of always having to prove that their opinion is unblemished.
As “invisible sales people” KOLs remain generally unknown by the wider patient group, the end point of their salesmanship. In the small international medical community of physicians treating thalassaemia, the impact “senior specialists” acting as KOLs have on the lives of patients can be very high indeed. Tactics similar to those applied for HIV, are being practiced in iron chelation . The interaction and influence of KOLs in many of the instruments of medical debate, as quite correctly mentioned, does not solely result in the amount of prescriptions written by them or others. They can also be very effective in exploiting unresolved issues, raising doubts, fostering a climate of uncertainty and fear of alternative treatments under the guise of scientific evidence which is used quite selectively. The term “evidence based” is frequently wheeled out to bolster this opinion-based science. They are oblivious to the damage they cause to science, patients that potentially could benefit from alternatives and ultimately to their own credibility.
We know very well that the boundary between genuine expertise and salesmanship is often invisible and can be easily transgressed. The irony in the Canadian case is that the clinician who initially appeared to be the patients’ champion, in a battle with a drug company, through the influential allies the controversy attracted, became the reason for the patients of the US, Canada and elsewhere to be denied an additional available drug, by contrast with their European counterparts. According to Savulescu, the tragedy is that this controversy is still ongoing. The real tragedy however is the still unmeasured cost in terms of patient lives. In light of the above there should really be a moral debate within society.
The patient perspective.
Chronic conditions require a long-standing partnership between patient and doctor, based on trust, mutual respect, understanding and agreed collaboration. Partnership has proven to have the best healthcare outcomes.
Today’s patients are able to follow their doctors in lectures, conferences, and debates and observe bias. They can see when the doctors’ opinion is not evidence based but opinion based. The opinions are those of KOLs who may treat few patients themselves if any, yet tell other doctors what to do. Although most doctors are risk averse professionals and not innovators when no alternatives exist there may be an absolute need to take. But what if these risks are continuously exaggerated? The influence of drug companies can create anxiety, insecurity, and lack of trust between doctors and patients and loss of integrity. If doctors are made to feel uncertain they will avoid giving the treatment they think appropriate. Fear Uncertainty and Doubt (FUD) harm patients in many ways; they fear they are misinformed, feel uncertain about their future and come to doubt the judgement and motivation of those they have entrusted with their health and safety. It also prevents choice. Instead of living their life with confidence they are filled with of anxiety. Continuous anxiety due to doctors behaving badly is bad science, bad medicine and a nightmare to live with. Observing FUD being actively propagated by vested interests is terribly disillusioning for the patient.
The patients’ interests lie in removing the FUD and gaining clear messages. Patients are also able to participate in the debate and have a substantial contribution to make. They need to be heard because this concerns their own lives.
If we see doctors behaving under commercial influences, sending conflicting messages and creating or maintaining uncertainty due to competing interests we can understand that all aspects of patient care are open to manipulation. This is truly a very insidious problem of modern healthcare and there has been no satisfactory answer from the point of view of the patient. Increased scrutiny or disclosure will never be sufficient as it can never reach the root of the problem.
Quite obviously the most important issue beyond that of the public interest is when these relationships become so pervasive as to produce Guidelines that are not manifestly objective then it becomes a patient safety issue. In that sense it is a truly invisible, unquantifiable and unaccountable threat.
One also has to remember that although the majority of doctors of both camps are able to access the available channels of information and debate, such as journals like the BMJ, patients are mostly not in this privileged position and do not gain the background knowledge that the medical profession enjoy. Their only source of information is from their own doctors. Unfortunately in some cases they not only remain the silent majority but are also misinformed by the one person they place their trust in.
Although as Juan Gérvas, says KOLs obtain their credit from peer review journals and other conferences and publications, they should never forget that primarily their careers, and societal status and power are conferred by the patients. Thalassaemia patients have a substantial interest in this debate and have been participating through their articles in this and other journals 6, They deserve more credibility and consideration.
The ‘chameleon-like’ behaviour of interchangeable interests and allegiances of KOLs are not compatible with Science and Integrity. Compromising them is not acceptable and should not be forced to cohabit with commercial interests.
However, patients have proved that they can react appropriately against unacceptable sources of bias and misinformation, by selecting and working with the true experts, as against ostensibly “independent experts” to produce robust, unchallengeable and objective guidelines.
The UK Thalassaemia Society in 2005 created a true partnership of patients and doctors, in order to publish their own Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK . Ensuring no drug firm involvement, with extensive peer review, updated regularly, and showing a commitment for objectivity, a true collaboration of this kind may be the key to satisfactory resolution of this mess. The UK Thalassaemia Society Standards have now become the model for other patient associations in other countries.
Spiers makes a valuable distinction. There is indeed an invisible boundary. Whenever a KOL decides to “change mode” it will be in stealth and, by definition, under the disguise of “acting as an expert”. The professional integrity of an independent is forever compromised and the trust of the patient is betrayed. The doctor patient-relationship has failed. As a result, their role as “independent experts” is purely aimed at making their messages more acceptable and credible by lesser experts. To those doctors we can only suggest to listen to and investigate the claims from all with an open mind, questioning the veracity of the scientific evidence presented before acting on any existing treatment. This process is invisible to the patients, so we solely rely on the doctors’ integrity.
In the new era of “expert patients” it is time the pharmaceutical industry realise that the use of KOLs is counterproductive and start changing their approach by focusing more on patients and their representatives rather than turning scientists into salesmen.
Doctors are and should be the true and genuine gatekeepers between the drug company and the patient. Are doctors able to accept this new partnership?
Dr. Christos Sotirelis - UK Thalassaemia Society Vice President, â thalassaemia major patient
George Constantinou - UK Thalassaemia Society Treasurer, Thalassaemia International Federation Secretary, â thalassaemia major patient
Note: The opinions expressed here do not represent the views of the UK Thalassaemia Society or of the Thalassaemia International Federation, but solely these of the authors of this article.
Moynihan R. Key opinion leaders: independent experts or drug representatives in disguise? Brit.Med.J. 2008;336:1402-3.
Angastiniotis M, Modell B. Global epidemiology of hemoglobin disorders. Annals of the New York Academy of Sciences 1998;850:251-269.
Modell B, Berdoukas V. The clinical approach to thalassaemia. Grune and Stratton, New York and London. 1984.
Guidelines for the clinical management of thalassaemia. Thalassaemia International Federation. 2000.
A. Victor Hoffbrand,, Response to Savulescu Editorial. RE: Deferiprone BMJ 2004;328:369-1. (Rapid response 19 March 2004 )
George Constantinou, The disappearing patient. BMJ 2004; 328:369-1. (Rapid response 13 March 2004)
Key Opinion Leaders Average $25,000 to $50,000 in Annual Advising Fees; http://www.reuters.com/article/pressRelease/idUS175983+24-Jan- 2008+MW20080124; Thu Jan 24, 2008, accessed 06/07/2008 14:17.
Joseph A Sonnabend, KOLs – Devils or Angels? ; BMJ 2008; 336: 1402- 1403 (Rapid response 25 June 2008)
Savulescu J. Thalassaemia major: the murky story of deferiprone. BMJ 2004;328:369-1.
Juan Gérvas, Experts and female health BMJ 2008; 336: 1402-1403 (Rapid response 22 Jun 2008)
Constantinou C, Melides S, Modell B. The Olivieri case (letter). New England Journal of Medicine 2003;348:860-1.
Competing interests: None declared
Competing interests: No competing interests