Key opinion leaders: independent experts or drug representatives in disguise?

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

The perception of appropriate interactions between doctors and pharma has changed dramatically during the past five years. Considerable scepticism surrounds the intent of industry and there are concerns regarding the vulnerability of doctors in the relationship.

Increasingly stringent guidelines have been introduced across Europe. Doctors are now cornered into making multiple conflict of interest statements and the nature and consequences of their relationships are regularly debated. This is one of the most contentious issues in healthcare. Impassioned views range from physicians who pledge to have no interaction with any industry professionals at all, through to others who feel that collaborations are essential to underpin scientific advances. Those opposed to pharma’s influence on medical professionals feel that financial gains from relationships may have a detrimental effect on or otherwise influence prescribing habits. Others feel that ethical issues are hindering the production of new or improved treatments that would benefit patients.

A point on which all agree is that both pharma and healthcare professionals need to focus on the shared-goal of improving human health. We appear to have lost sight of shared aspirations between medical and pharmaceutical professionals. It is in both parties’ interest to ensure that pharmaceutical products are safe, effective and useful and it is not credible to imply that healthcare professionals are easy victims to an industry that is readily able to fool them. Many European medical leaders who contributed to a recent year- long consultation called 'The INTEGRITY initiative' found it condescending that they would be viewed as being malleable to ‘marketing ploys’ and unable to conduct an ethical exchange with industry.

Despite some strong differences of opinion about interactions, those involved in the INTEGRITY consultation recognised that this is the critical time to consider how to establish and nourish balanced and authentic alliances between medical and pharmaceutical professionals.

This presents three core challenges:
1. Equipping the medical community with greater ‘promotional literacy’ so they are able to discern between clinical information and commercial embellishment more readily.
2. Encouraging all parties to adopt everyday ‘good relationship practice’ (GRP) as a protocol that reflects the spirit of all guidelines and limits potential for poor experiences to eclipse interactions of merit.
3. Ensuring that pharma and the medical community are more transparent about combining research, clinical and educational endeavours within a framework of professional networking.

It is true that the popular media are more likely to publish stories about drugs found to be unsafe or unsuitable, doctors who seem to have succumbed to financial incentives and reports that negative data have been withheld or played down. This no doubt fuels fears that interactions with the pharmaceutical industry are eroding medical professionalism. Yet, there are numerous examples where industry readily awards grants for scientific meetings that are important to the research community without expectation that promotional information will be included. However, the fact is that everyday actions of researchers in industry are not as newsworthy, neither is a pharma company announcing they have sponsored an educational conference.

It is in pharma’s best interest to research, develop and produce drugs that help healthcare professionals excel at their jobs. The industry must achieve this within a highly-regulated environment in which governments, trade associations, professional societies and individual company codes of practice are all in place to protect scientific values and medical integrity. Medical innovation may be hindered if we further limit the industry from interacting with healthcare. Medical professionals and industry researchers may find it equally frustrating if this limits their professional aspirations.

Pharma is often held responsible for the rising costs of healthcare. Companies are rewarded for the risks taken to develop products when a successful treatment reaches the market. Yet it is easy to ignore that products developed within pharma have consistently delivered improvements in human health for the past three decades. At worst, industry capitalises on our desire to live longer, healthier lives. As such, it is a victim of its own success in meeting our desires. When industry, physicians and academia collaborate, the proven most likely result is expediency in producing new treatments. The first step to recover the value of these relationships is to accept that both parties need to assume accountability for the transparency and outcomes of their collaborations.

One suggestion, to try to smooth this interaction and allay fears, is to include more teaching of pharmacy and drug development within medical training and as part of continuing medical education (CME). The pharmaceutical industry claims that 35 per cent of the estimated $9—14bn it spends each year on pharmaceutical marketing goes towards educational support. If pharma-sponsored CME is no longer allowed it may result in tomorrow’s doctors having to practice yesterday’s medicine.

There are three distinct improvements that can be made easily without bombarding either party with more stringent regulations.

1. Improving promotional literacy Industry and medical associations are currently working together to agree the content of programmes to improving promotional literacy among medics at student and post-graduate level. Key objectives will be to ensure that medical professionals:

-- Know how to disentangle commercial reasoning from clinical applicability

-- Can adequately judge the methodological qualities of clinical trials

-- Truly understand comparative outcome measures used in clinical trials

-- Are able to eliminate emotive and authoritative distortion to facilitate subjective assessment of data.

2. Adhering to GRP Despite nine sets of guidelines worldwide the INTEGRITY initiative suggested that many doctors are not consulting them regularly as part of everyday practice. This seems to reflect the belief that pharma is more likely to be punished for breaking the rules than healthcare professionals and therefore more likely to take control to make sure both parties act in a compliant manner.

Many doctors express the view that most of the guidelines focus too heavily on matters of hospitality, which they believe misrepresents their efforts to remain ethical and appropriate in their interactions with industry. There is also concern that guidelines written by industry are used in political competition between companies. Quite, simply, many doctors prefer to adhere to their personal code of integrity about interactions with industry. This is likely to change as legislation tightens to further restrict and regulate the actions of medical professionals.

A guide to good relationship practice has been drafted and will be validated in coming months. This will centre on three questions along the lines of:

1. Does the interaction or series of interactions, encourage scientific exchange of information or lead to an enhanced skill that will ultimately benefit the care of people living with disease and/or enhance the knowledge of those aspiring to help people to overcome, manage or better understand a medical condition?

2. Does this interaction require a minimal level of promotional literacy and contextual arbitration to guarantee it is an interaction of merit – be that in the form of a discussion, debate, exchange of experience, education/knowledge update, personal opinion or release of specific product information?

3. Is there any possibility that this interaction could be viewed as an inappropriate activity which could damage the perception of any of the participants’ intention and integrity to engage in a positive collaboration that furthers medical scientific understanding?

Ultimately, pharma and medical professionals are recognising that responsible leadership is no longer about influencing opinion but is instead about aligning aspirations and realising ambitions. Doctors want to champion patient needs and pharma wants to safeguard a positive presence in healthcare, committed to addressing these needs.

There is a public expectation that industry will reduce the amount of money spent on activities to engage the medical profession. This, together with legal limits on financial exchanges and a demand for more transparent associations, will accelerate the adoption of better practices and alignment of aspirations.

Pharma and the medical-scientific community are keen to address these challenges and make the necessary moves to improve interactions. The inaugural EU conference in September is the first positive forum in which this can start to move on from rhetoric to reality.

The Author Emma D’Arcy is leader of the INTEGRITY expert advisory panel.

Competing interests: Emma D'Arcy is an independent advisor to the medical community and the pharmaceutical industry about appropriate interactions.

We read with interest Ray Moynihan's piece about Key Opinion Leaders and would like to describe another "communication platform" the pharmaceutical industry use to influence the prescribing habits of doctors.

Whilst not strictly a condition of employment, many Deaneries promote doctors.net.uk and request that medical students and foundation programme doctors open email accounts with the company(1)(2)(3).

Accounts allow access to fora where doctors can discuss cases, resources including the Oxford Textbook of Medicine and CPD accredited online educational modules. But is it the service Deaneries should be promoting?

The company claims to be run "by doctors, for doctors". However, CEO Richard Adams "began his career as a medical representative for Wellcome" and Operations Director Paul Concannon has "22 years' experience in the pharmaceutical industry." The company receives funding from pharmaceutical companies who in return market their products to a selection of the 154,000 doctors who subscribe to the service.

The website describes their marketing methods (see doctors.net.uk/marketing). One campaign to "increase the depth of prescribing" utilised a "key opinion leader webcast". A "market development campaign" delivered "3,500 accredited disease education modules" to doctors. Colourful graphics demonstrate the significant effects their marketing campaigns have upon "knowledge", "prescribing" and "prescribing intentions".

It is known that contact with the pharmaceutical industry can adversely affect the prescribing habits of doctors. For example, three in four randomised controlled trials published in major journals are funded by pharmaceutical companies (BMJ 2003;326(7400): 1202-5) with sponsored trials four times more likely to find that therapies offer benefit (BMJ 2003; 326: 1167–1170). 80-95% of doctors regularly see drugs reps. Statements made by reps are often inaccurate, doctors do not pick up on these errors and errors almost always favour the product (JAMA 1995;273: 1296-1298). Physicians who rely on pharmaceutical companies for information are less likely to prescribe rationally (Soc Sci Med 1982; 16: 2017-23).

Whilst data needed to establish the magnitude of the effect online marketing has on prescribing practices is not freely available, pharmaceutical companies and doctors.net.uk apparently find this to be a profitable investment.

Deaneries are charged with turning graduates into competent doctors that prescribe drugs rationally on the basis of objective evidence.

It is therefore highly regrettable that they are encouraging medical students and doctors to have pharmaceutical company sponsored email addresses.

1. Doctors.net.uk official press release regarding deaneries www.doctors.org.uk/_datastore/pdf/deaneries.PDF

2. North Central Thames Foundation School registration form for final year medical students who have accepted foundation year posts has a doctors.net.uk email address as 'essential': http://www.ucl.ac.uk/medicalschool/nctfs/forms/Registration%20Form%20NCTFS%20 -%20entry%202008.pdf

This is reached through the page headed North Central Thames Foundation School NCTFS Requirements and Policies: http://www.ucl.ac.uk/medicalschool/nctfs/policies/

3. A Doctors.net.uk promotion sent to sucessful foundation programme applicants by the London deanery via NHS foundation application system website, a screeshot of the promotion is available online at http://i314.photobucket.com/albums/ll404/Sam_Jones_99/Doctorsnet.jpg

Competing interests: None declared

Both the pharmaceutical industry and health professionals must take responsibility for ensuring that their relationships remain ethical and professional (Key opinion leaders, 21 June 2008).

The activities of pharmaceutical companies are covered by the Association of the British Pharmaceutical Industry (ABPI) Code of Practice for the Pharmaceutical Industry which reflects and extends beyond UK law. Self regulation under the ABPI Code is supported by the Medicines and Healthcare products Regulatory Agency. Whilst the industry has a legitimate right to promote medicines to health professionals this has to be done responsibility within the robust self regulatory framework provided by the ABPI Code. The availability of accurate information is vital to the appropriate use of medicines.

The 2008 edition of the Code comes into effect on 1 July and for the first time has a separate clause setting out requirements for pharmaceutical companies employing health professionals as consultants. It includes the need for a written contract.

Transparency is a key requirement and under the newly introduced requirements companies are strongly encouraged to include in contracts an obligation that the health professional declares that they are a consultant to the company when relevant.

These newly introduced requirements come from The European Federation of Pharmaceutical Industries and Associations (EFPIA) Code on the Promotion of Prescription-Only Medicines to, and Interactions with, Healthcare Professionals. They have to be implemented by national associations throughout Europe by no later than 1 July 2008.

Pharmaceutical companies cannot use health professionals to present information/material that would be in breach of the Code if the company itself presented the same information.

Anyone with specific concerns about the activities of pharmaceutical companies should contact the Prescription Medicines Code of Practice Authority (PMCPA) which administers the Code at arm’s length from the ABPI. Copies of the 2008 Code together with advice and guidance are available at www.pmcpa.org.uk.

Competing interests: None declared