The Institute of Medicine Releases Reports on Practice Guidelines and Systematic Reviews Which Generate Few Echoes

Two days ago, the prestigious US Institute of Medicine released two reports on important health care issues, clinical practice guidelines and systematic reviews.  Systematic reviews of the relevant clinical research have been advocated by evidence-based medicine proponents as the appropriate basis for clinical and policy decisions.  Clinical practice guidelines have been advocated by many health researchers, policy makers, and clinicians as the best way to encapsulate the evidence to inform clinical and policy decision making.  Both reports suggested series of standards for how systematic reviews and clinical practice guidelines should be developed. 

These topics are of general importance to clinicians, health services researchers, and health policy makers.  The Institute of Medicine, part of the US National Academy of Sciences, is one of the most authoritative sources of opinion on medicine and health care.  Therefore, one would think that these reports would have gotten wide notice, and would hardly required Health Care Renewal to create some echoes.

However, a Google News search today produced only six "hits" relevant to these reports, including the original press release.  All are in specialized medical/ health care news outlets.  None are in the national media, and none are from major medical/ professional journals or societies. 

Let me suggest a theory about why these two major reports have generated so few echoes so far.  Let me quote from the summary of the report on clinical practice guidelines:

Most guidelines used today suffer from shortcomings in development. Dubious trust in guidelines is the result of many factors, including failure to represent a variety of disciplines in guideline development groups, lack of transparency in how recommendations are derived and rated, and omission of a thorough external review process. To be trustworthy, clinical practice guidelines should:
• Be based on a systematic review of the existing evidence;
• Be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups;
• Consider important patient subgroups and patient preferences, as appropriate;
• Be based on an explicit and transparent process that minimizes distortions, biases, and conflicts of interest;
• Provide a clear explanation of the logical relationships between alternative care options and health outcomes, and provide ratings of both the quality of evidence and the strength of recommendations; and
• Be reconsidered and revised as appropriate when important new evidence warrants modifications of recommendations.
Additionally, as reflected in the committee’s standards for developing trustworthy clinical practice guidelines, guideline development groups optimally comprise members without conflict of interest. The committee recognizes that in some circumstances, a guideline development group may not be able to perform its work without members who have conflicts of interest—for example, relevant clinical specialists who receive a substantial portion of their incomes from services pertinent to the guideline. Therefore, the committee specifies that members of the guideline development group who have a conflict of interest should not represent more than a minority of the group.

So it seems that the report on clinical practice guidelines emphasized two issues highly relevant to Health Care Renewal, the need for transparency in guideline development, and the need to avoid conflicts of interest affecting the development process. The two first standards for guidelines are about transparency and minimization of conflicts of interest.  Similarly, the report on systematic reviews also included fairly tough standards to minimize conflicts of interest.

We on Health Care Renewal go on and on about the need to maximize transparency in health care, and particularly in health care leadership and governance, and about the need to disassemble the now pervasive web of conflicts of interest that has entangled health care.  However, as we know, these are not popular topics among the leadership of health care, which includes many individuals who have greatly benefited from lack of transparency and pervasive conflicts of interest.  We know these topics make these leaders, and many of those who report to, or work or associate with them very uncomfortable.

So unfortunately, I am not surprised that the two new and likely authoritative reports from the Institute of Medicine, despite that organization's prestige, have started off relatively anechoic.  It also unfortunately likely that they will remain relatively anechoic. 

In 2009, the IOM issued an authoritative report on conflicts of interest in medicine and health care which suggested fairly tough standards to decrease such conflicts and their influence (also see post here).  Since 2009, I just found 53 citations to that report in the medical literature using the ISI Web of Science, for a rate of 27/year.  In 1999, the IOM issued a report on medical errors, "To Err is Human."  Since then, it has received 1374 citations, a rate of 115/year. 

As we noted above, the topic of conflicts of interest seems to make the powers that be in health care very uncomfortable.  In contrast, "To Err is Human" was widely interpreted to mean that physicians make a lot of dangerous errors, and the best way to decrease them is to impose more controls by bureaucrats, managers, and executives (even if that was not its intent).  Thus, that report could be twisted to fit the talking points of the powers that be, and hence has been anything but anechoic.

So while Health Care Renewal is hardly a powerful tool for creating publicity, I thought we should try to get the word out about the new IOM reports on clinical practice guidelines and systematic reviews.  Every little bit helps.

Meanwhile, the deathly quiet reception these reports have gotten so far emphasizes the need to combat the anechoic effect.  As long as the powers that be can command billions of dollars to influence the health care conversation through their marketing, public relations, and lobbying departments, expect the discussion not to question what they do, and how they benefit from the status quo to the financial and health detriment of patients and the population.

We will not be able to truly reform health care until we can speak openly about what threatens health care values and what needs to be done about these threats.

The Institute of Medicine Releases Reports on Practice Guidelines and Systematic Reviews Which Generate Few Echoes

Two days ago, the prestigious US Institute of Medicine released two reports on important health care issues, clinical practice guidelines and systematic reviews.  Systematic reviews of the relevant clinical research have been advocated by evidence-based medicine proponents as the appropriate basis for clinical and policy decisions.  Clinical practice guidelines have been advocated by many health researchers, policy makers, and clinicians as the best way to encapsulate the evidence to inform clinical and policy decision making.  Both reports suggested series of standards for how systematic reviews and clinical practice guidelines should be developed. 

These topics are of general importance to clinicians, health services researchers, and health policy makers.  The Institute of Medicine, part of the US National Academy of Sciences, is one of the most authoritative sources of opinion on medicine and health care.  Therefore, one would think that these reports would have gotten wide notice, and would hardly required Health Care Renewal to create some echoes.

However, a Google News search today produced only six "hits" relevant to these reports, including the original press release.  All are in specialized medical/ health care news outlets.  None are in the national media, and none are from major medical/ professional journals or societies. 

Let me suggest a theory about why these two major reports have generated so few echoes so far.  Let me quote from the summary of the report on clinical practice guidelines:

Most guidelines used today suffer from shortcomings in development. Dubious trust in guidelines is the result of many factors, including failure to represent a variety of disciplines in guideline development groups, lack of transparency in how recommendations are derived and rated, and omission of a thorough external review process. To be trustworthy, clinical practice guidelines should:
• Be based on a systematic review of the existing evidence;
• Be developed by a knowledgeable, multidisciplinary panel of experts and representatives from key affected groups;
• Consider important patient subgroups and patient preferences, as appropriate;
• Be based on an explicit and transparent process that minimizes distortions, biases, and conflicts of interest;
• Provide a clear explanation of the logical relationships between alternative care options and health outcomes, and provide ratings of both the quality of evidence and the strength of recommendations; and
• Be reconsidered and revised as appropriate when important new evidence warrants modifications of recommendations.
Additionally, as reflected in the committee’s standards for developing trustworthy clinical practice guidelines, guideline development groups optimally comprise members without conflict of interest. The committee recognizes that in some circumstances, a guideline development group may not be able to perform its work without members who have conflicts of interest—for example, relevant clinical specialists who receive a substantial portion of their incomes from services pertinent to the guideline. Therefore, the committee specifies that members of the guideline development group who have a conflict of interest should not represent more than a minority of the group.

So it seems that the report on clinical practice guidelines emphasized two issues highly relevant to Health Care Renewal, the need for transparency in guideline development, and the need to avoid conflicts of interest affecting the development process. The two first standards for guidelines are about transparency and minimization of conflicts of interest.  Similarly, the report on systematic reviews also included fairly tough standards to minimize conflicts of interest.

We on Health Care Renewal go on and on about the need to maximize transparency in health care, and particularly in health care leadership and governance, and about the need to disassemble the now pervasive web of conflicts of interest that has entangled health care.  However, as we know, these are not popular topics among the leadership of health care, which includes many individuals who have greatly benefited from lack of transparency and pervasive conflicts of interest.  We know these topics make these leaders, and many of those who report to, or work or associate with them very uncomfortable.

So unfortunately, I am not surprised that the two new and likely authoritative reports from the Institute of Medicine, despite that organization's prestige, have started off relatively anechoic.  It also unfortunately likely that they will remain relatively anechoic. 

In 2009, the IOM issued an authoritative report on conflicts of interest in medicine and health care which suggested fairly tough standards to decrease such conflicts and their influence (also see post here).  Since 2009, I just found 53 citations to that report in the medical literature using the ISI Web of Science, for a rate of 27/year.  In 1999, the IOM issued a report on medical errors, "To Err is Human."  Since then, it has received 1374 citations, a rate of 115/year. 

As we noted above, the topic of conflicts of interest seems to make the powers that be in health care very uncomfortable.  In contrast, "To Err is Human" was widely interpreted to mean that physicians make a lot of dangerous errors, and the best way to decrease them is to impose more controls by bureaucrats, managers, and executives (even if that was not its intent).  Thus, that report could be twisted to fit the talking points of the powers that be, and hence has been anything but anechoic.

So while Health Care Renewal is hardly a powerful tool for creating publicity, I thought we should try to get the word out about the new IOM reports on clinical practice guidelines and systematic reviews.  Every little bit helps.

Meanwhile, the deathly quiet reception these reports have gotten so far emphasizes the need to combat the anechoic effect.  As long as the powers that be can command billions of dollars to influence the health care conversation through their marketing, public relations, and lobbying departments, expect the discussion not to question what they do, and how they benefit from the status quo to the financial and health detriment of patients and the population.

We will not be able to truly reform health care until we can speak openly about what threatens health care values and what needs to be done about these threats.

Key Opinion Leader Services Companies: the Creation of Useful Idiots and Usefully Idiotic Organizations

In researching the conflicts of interest of the University of California "36," I stumbled upon a fascinating corner of the pharmaceutical/ biotechnology/ medical device marketing universe, the companies that find and manage key opinion leaders (KOLs), also known as "thought leaders."  Reviewing their own marketing materials reveals how KOLs truly are health care corporate marketing's useful idiots.

I found three companies which seem entirely devoted to the adoption, care and feeding of KOLs, plus numerous companies, including some medical education and communication companies (MECCs) that provide KOL-related products and services.  I will first describe the companies briefly, then draw upon their marketing materials to underline what KOLs are really about.

Leadership in Medicine Inc

This is the company I found first, because one of its directors is a member of the UC 36, the group of top university leaders who threatened to sue the university to increase their already generous pensions.

Leadership in Medicine Inc's web-site describes its reason for being thus:

IF YOU NEED TO KNOW who are the most prominent, admired, and influential actors in healthcare, how they are interconnected, and why, you need our expertise.

Given how vastly complex are the relationships among providers, researchers, and other significant actors in healthcare, it is vital to focus on key opinion leaders (KOLs) at local, regional, and global levels, and to understand the ties among them.

Its clients are:

Over 80 client companies
* All of the top 15 largest pharmaceuticals
* 8 of the 10 largest biotechs
* 5 of the 10 largest medical device companies

A graphic on its "experience" page listed the following companies: Baxter, Wyeth, Lilly, Roche, Gilead, GlaxoSmithKline, Pfizer, Abbott Laboratories, Genzyme, Bristol-Myers-Squibb, Medtronic, Johnson and Johnson, Genentech, and Covidien.

KOL LLC

Company description:

As our name implies, we are a company devoted to providing Key Opinion Leader software and Key Opinion Leader Management services for pharmaceutical, biotechnology and device companies.

The company's graphic client list included: Cephalon, Scios, Novartis, Schering-Plough King Pharmaceuticals, Pfizer, Genentech, Reliant Pharmaceuticals, McNeil (division of Johnson and Johnson, Jazz Pharmaceuticals, Endo Pharmaceuticals, Cytogen, Health Products Research, Shire, Reckitt Benckiser, Protein Design Labs, and Odyssey Pharmaceuticals.

Thought Leader Select

The relevant parts of the company description:

Thought Leader Select is a Chapel Hill, NC-based private research and consulting firm serving the biopharmaceutical and healthcare industries.

and

We serve these industries and the medical community at large by assessing medical experts (known as 'thought leaders' and 'key opinion leaders')....

Perusal of the materials used by these companies, and other companies which market KOL or thought leader related services makes the nature of the relationship between KOLs and commercial health care firms, and the purpose of employing KOLs clear.

KOLs are Employed by Marketing Departments to do Marketing

The best example comes from a description of a KOL information technology application sold by Nagarro:

A web-based application was developed by Nagarro to help the marketing department of a global pharmaceutical company exploit Key Opinion Leader (KOL) information in order to promote products and remain ahead of its competition.

Problem Description

In today s fast-paced competitive environment, pharmaceutical companies cannot solely rely on superior products to succeed. Well organized marketing departments help sales departments reach goals and give companies an edge over competition, but without access to valuable resources, like KOLs, they are ineffective. KOLs influence the medical community and ultimately the end users of pharmaceutical products.

Pharmaceutical companies that are able to identify and work with KOLs will be better positioned to compete....

Benefits

[include]
Creation of market intelligence from highly specialized and customizable reports containing previously unavailable aggregate data....

Ability to group KOLs by product knowledge and associations in order to better promote products

Ability to maximize ROI from KOL related events

Enhanced sales and marketing productivity through streamlining of complex multi-source information

That makes it crystal clear that marketers use KOLs to market, to sell products. While at times KOLs might actually be used to advise health care corporations about clinical or scientific issues, that is hardly their major point. KOLs are almost always hired to market by marketing departments.

In case someone might argue that this is only one example, let us look at materials from the other companies.

KOL LLC described the usefulness of KOLs thus:

Everyone recognizes the value of opinion leaders (OL), or thought leaders. While national level OLs may not write many prescriptions they influence thousands of prescribers and hence prescriptions through their research, lectures, publications and their participation on advisory boards, committees, editorial boards, professional societies and guidelines/consensus document development. Regional level OLs are often involved in state societies or legislative initiatives in addition to their speaking and publications. While local level OLs may not publish, they provide advice to local colleagues and may speak at grand rounds. And who are the ‘rising stars’ in your therapeutic area?

It is imperative that you know the OLs in your market at a national, regional and local influence level as well as those ‘rising stars’.

This is a bit more indirect, but it is clear that the goal is to "influence prescribers" to prescribe, not provide scientific or clinical advice to the company.

Leadership in Medicine Inc's materials also continually emphasized the point of KOLs is to influence, for example, they boasted of pioneering analyses "to assess paths of influence in healthcare," developed a particular tool called "Centrality Ranking" to "provide fine-grained ratings of KOLs' influence," and claimed to "have identified, profiled, and mapped the influence of tens of thousands of individual KOLs...." The clear implication is that KOLs' influence is the central consideration, and what else is this influence good for other than to sell products, and perhaps advocate for corporations in general?

When KOLs are Involved, Many Activities that Appear to be Educational or Scientific Really Are For Marketing

Strikingly, KOL LLC claimed its role in guideline development:

Guidelines produced by national societies are optimal, but often can be a slow, painful and expensive process to develop. KOL, L.L.C. can provide a faster alternative. We have experience convening a panel of experts in a therapeutic area. We serve a project management role to ensure the timelines and deliverables are met. We have access to a medical writing team of 25 healthcare professionals who can write the initial drafts, as our experience tells us it is easier for experts to edit, than to write from scratch.

There has been growing realization that guidelines may be biased by commercial sponsorship and by the participation by individuals with conflicts of interest. The KOL LLC marketing materials suggest, however, that guidelines have become purpose-built marketing vehicles through the participation of selected KOLs with allegiances to drug, device and biotechnology companies. As an aside, note that guideline-development services includes the participation of a team of ghost-writers who will write the first drafts, a function that naive academics might have thought should be that of clinical and scientific experts.

For another example, KOL LLC asserted it could manage "investigator meetings," :

We’ll help you better plan to maximize the communication of the trial results through targeted abstracts, posters, publications and lectures.

so

Due to the time constraints placed on Clinical Research Departments, many times ‘research mills’ are selected as the trial sites. This is fine, but who is going to publish the results and stand up and present the results at national, regional and local meetings. We can provide you advice and counsel about how to involve your KOLs effectively, while maintaining your aggressive timelines.

The goal of KOL management here is for the company to control how the research is disseminated. Note also the cynical view of "research mills," which likely refers to contract research organizations. Do we really think that CROs are used by commercial firms because they do better research?

Key Leading Organizations

A bonus from reading through the offerings on KOL management was to discover another related business that has not been subject of polite conversation before. Leadership in Medicine Inc put it this way:

Equally essential is recognizing the roles played by key leading organizations (KLOs) such as medical institutions, payers, professional organizations, patient groups, government entities, and journals in structuring KOL activities and relationships, since those are the stages on which KOLs perform.

Key Leading Organizations (KLOs) apparently include influential organizations, e.g., academic medical institutions, medical societies, and patient advocacy groups that can be deliberately turned into organizations of useful idiots for marketing purposes. Note that we and others have discussed how institutional conflicts of interest and conflicts of interest affecting leaders of of such organizations can lead to bias in favor of commercial interests. But what Leadership in Medicine Inc has written suggests that such organizations can be deliberately taken over to function as industry's fellow travelers.

Similarly, Thought Leader Select advertised services to manage organizations to support "thought leadership":

Through Centers, all of our research and assessment skills culminate in our evaluation of universities, influential clinics, and research foundations for a holistic approach to thought leadership in the medical community. With centers of excellence assessments we take a drill-down approach, starting at the academic medical centers, then moving into affiliated hospitals and clinics....

Summary

Industry spokespeople and key opinion leaders tout themselves as clinical, educational, and/or scientific experts chosen for their expertise to advance medicine, science and public health.  There are documented instances (e.g., see posts here and here) in which defectors from marketing departments of commercial health care corporations described KOLs as salespeople who could be more influential hidden within their professional or academic cloaks.  Even some physicians paid to be speakers on behalf of pharmaceutical corporations have acknowledged their role as salespeople in fancy dress (see post here).  There are cases of documents revealed by discovery in legal actions that show how companies planned organized stealth marketing efforts for drugs that included activities by KOLs (e.g., see post here about marketing of Lexapro, and here about Neurontin).

However, the marketing materials used by KOL service companies (for lack of a better name) show that KOLs are largely meant to be stealth marketers, and hired for that purpose, that KOLs participate as marketers in the sorts of activities that to the naive appear to be educational or scientific, and that marketers try to recruit whole organizations, such as medical schools, research organizations, medical societies, and patient advocacy groups as disguised sales organizations.

This goes beyond the problem of bias of physicians, or individual health professionals due to their financial relationships.  It goes beyond the problem of bias of organizations due to their sources of financial support or the financial relationships of their leaders.  It looks like there has been a massive campaign by health care corporate marketers to make useful idiots out of possibly a majority of medical academics and academic, professional, and supposedly patient-centered organizations.  This appears to be a massive, cynical effort to hollow out our once respected health care institutions and professionals in the service of marketing.

A final word to any individuals reading this who are paid by corporate marketers to be KOLs.  If you think that you are paid for educational or scientific purposes, you likely have been made into a chump.  The people who did this to you were likely not acting in your best interests, or those of society, but to cynically market their product and increase their own earnings.  If you doubt this, look at the materials cited above.  You really don't want to continue being chumps, do you?

Key Opinion Leader Services Companies: the Creation of Useful Idiots and Usefully Idiotic Organizations

In researching the conflicts of interest of the University of California "36," I stumbled upon a fascinating corner of the pharmaceutical/ biotechnology/ medical device marketing universe, the companies that find and manage key opinion leaders (KOLs), also known as "thought leaders."  Reviewing their own marketing materials reveals how KOLs truly are health care corporate marketing's useful idiots.

I found three companies which seem entirely devoted to the adoption, care and feeding of KOLs, plus numerous companies, including some medical education and communication companies (MECCs) that provide KOL-related products and services.  I will first describe the companies briefly, then draw upon their marketing materials to underline what KOLs are really about.

Leadership in Medicine Inc

This is the company I found first, because one of its directors is a member of the UC 36, the group of top university leaders who threatened to sue the university to increase their already generous pensions.

Leadership in Medicine Inc's web-site describes its reason for being thus:

IF YOU NEED TO KNOW who are the most prominent, admired, and influential actors in healthcare, how they are interconnected, and why, you need our expertise.

Given how vastly complex are the relationships among providers, researchers, and other significant actors in healthcare, it is vital to focus on key opinion leaders (KOLs) at local, regional, and global levels, and to understand the ties among them.

Its clients are:

Over 80 client companies
* All of the top 15 largest pharmaceuticals
* 8 of the 10 largest biotechs
* 5 of the 10 largest medical device companies

A graphic on its "experience" page listed the following companies: Baxter, Wyeth, Lilly, Roche, Gilead, GlaxoSmithKline, Pfizer, Abbott Laboratories, Genzyme, Bristol-Myers-Squibb, Medtronic, Johnson and Johnson, Genentech, and Covidien.

KOL LLC

Company description:

As our name implies, we are a company devoted to providing Key Opinion Leader software and Key Opinion Leader Management services for pharmaceutical, biotechnology and device companies.

The company's graphic client list included: Cephalon, Scios, Novartis, Schering-Plough King Pharmaceuticals, Pfizer, Genentech, Reliant Pharmaceuticals, McNeil (division of Johnson and Johnson, Jazz Pharmaceuticals, Endo Pharmaceuticals, Cytogen, Health Products Research, Shire, Reckitt Benckiser, Protein Design Labs, and Odyssey Pharmaceuticals.

Thought Leader Select

The relevant parts of the company description:

Thought Leader Select is a Chapel Hill, NC-based private research and consulting firm serving the biopharmaceutical and healthcare industries.

and

We serve these industries and the medical community at large by assessing medical experts (known as 'thought leaders' and 'key opinion leaders')....

Perusal of the materials used by these companies, and other companies which market KOL or thought leader related services makes the nature of the relationship between KOLs and commercial health care firms, and the purpose of employing KOLs clear.

KOLs are Employed by Marketing Departments to do Marketing

The best example comes from a description of a KOL information technology application sold by Nagarro:

A web-based application was developed by Nagarro to help the marketing department of a global pharmaceutical company exploit Key Opinion Leader (KOL) information in order to promote products and remain ahead of its competition.

Problem Description

In today s fast-paced competitive environment, pharmaceutical companies cannot solely rely on superior products to succeed. Well organized marketing departments help sales departments reach goals and give companies an edge over competition, but without access to valuable resources, like KOLs, they are ineffective. KOLs influence the medical community and ultimately the end users of pharmaceutical products.

Pharmaceutical companies that are able to identify and work with KOLs will be better positioned to compete....

Benefits

[include]
Creation of market intelligence from highly specialized and customizable reports containing previously unavailable aggregate data....

Ability to group KOLs by product knowledge and associations in order to better promote products

Ability to maximize ROI from KOL related events

Enhanced sales and marketing productivity through streamlining of complex multi-source information

That makes it crystal clear that marketers use KOLs to market, to sell products. While at times KOLs might actually be used to advise health care corporations about clinical or scientific issues, that is hardly their major point. KOLs are almost always hired to market by marketing departments.

In case someone might argue that this is only one example, let us look at materials from the other companies.

KOL LLC described the usefulness of KOLs thus:

Everyone recognizes the value of opinion leaders (OL), or thought leaders. While national level OLs may not write many prescriptions they influence thousands of prescribers and hence prescriptions through their research, lectures, publications and their participation on advisory boards, committees, editorial boards, professional societies and guidelines/consensus document development. Regional level OLs are often involved in state societies or legislative initiatives in addition to their speaking and publications. While local level OLs may not publish, they provide advice to local colleagues and may speak at grand rounds. And who are the ‘rising stars’ in your therapeutic area?

It is imperative that you know the OLs in your market at a national, regional and local influence level as well as those ‘rising stars’.

This is a bit more indirect, but it is clear that the goal is to "influence prescribers" to prescribe, not provide scientific or clinical advice to the company.

Leadership in Medicine Inc's materials also continually emphasized the point of KOLs is to influence, for example, they boasted of pioneering analyses "to assess paths of influence in healthcare," developed a particular tool called "Centrality Ranking" to "provide fine-grained ratings of KOLs' influence," and claimed to "have identified, profiled, and mapped the influence of tens of thousands of individual KOLs...." The clear implication is that KOLs' influence is the central consideration, and what else is this influence good for other than to sell products, and perhaps advocate for corporations in general?

When KOLs are Involved, Many Activities that Appear to be Educational or Scientific Really Are For Marketing

Strikingly, KOL LLC claimed its role in guideline development:

Guidelines produced by national societies are optimal, but often can be a slow, painful and expensive process to develop. KOL, L.L.C. can provide a faster alternative. We have experience convening a panel of experts in a therapeutic area. We serve a project management role to ensure the timelines and deliverables are met. We have access to a medical writing team of 25 healthcare professionals who can write the initial drafts, as our experience tells us it is easier for experts to edit, than to write from scratch.

There has been growing realization that guidelines may be biased by commercial sponsorship and by the participation by individuals with conflicts of interest. The KOL LLC marketing materials suggest, however, that guidelines have become purpose-built marketing vehicles through the participation of selected KOLs with allegiances to drug, device and biotechnology companies. As an aside, note that guideline-development services includes the participation of a team of ghost-writers who will write the first drafts, a function that naive academics might have thought should be that of clinical and scientific experts.

For another example, KOL LLC asserted it could manage "investigator meetings," :

We’ll help you better plan to maximize the communication of the trial results through targeted abstracts, posters, publications and lectures.

so

Due to the time constraints placed on Clinical Research Departments, many times ‘research mills’ are selected as the trial sites. This is fine, but who is going to publish the results and stand up and present the results at national, regional and local meetings. We can provide you advice and counsel about how to involve your KOLs effectively, while maintaining your aggressive timelines.

The goal of KOL management here is for the company to control how the research is disseminated. Note also the cynical view of "research mills," which likely refers to contract research organizations. Do we really think that CROs are used by commercial firms because they do better research?

Key Leading Organizations

A bonus from reading through the offerings on KOL management was to discover another related business that has not been subject of polite conversation before. Leadership in Medicine Inc put it this way:

Equally essential is recognizing the roles played by key leading organizations (KLOs) such as medical institutions, payers, professional organizations, patient groups, government entities, and journals in structuring KOL activities and relationships, since those are the stages on which KOLs perform.

Key Leading Organizations (KLOs) apparently include influential organizations, e.g., academic medical institutions, medical societies, and patient advocacy groups that can be deliberately turned into organizations of useful idiots for marketing purposes. Note that we and others have discussed how institutional conflicts of interest and conflicts of interest affecting leaders of of such organizations can lead to bias in favor of commercial interests. But what Leadership in Medicine Inc has written suggests that such organizations can be deliberately taken over to function as industry's fellow travelers.

Similarly, Thought Leader Select advertised services to manage organizations to support "thought leadership":

Through Centers, all of our research and assessment skills culminate in our evaluation of universities, influential clinics, and research foundations for a holistic approach to thought leadership in the medical community. With centers of excellence assessments we take a drill-down approach, starting at the academic medical centers, then moving into affiliated hospitals and clinics....

Summary

Industry spokespeople and key opinion leaders tout themselves as clinical, educational, and/or scientific experts chosen for their expertise to advance medicine, science and public health.  There are documented instances (e.g., see posts here and here) in which defectors from marketing departments of commercial health care corporations described KOLs as salespeople who could be more influential hidden within their professional or academic cloaks.  Even some physicians paid to be speakers on behalf of pharmaceutical corporations have acknowledged their role as salespeople in fancy dress (see post here).  There are cases of documents revealed by discovery in legal actions that show how companies planned organized stealth marketing efforts for drugs that included activities by KOLs (e.g., see post here about marketing of Lexapro, and here about Neurontin).

However, the marketing materials used by KOL service companies (for lack of a better name) show that KOLs are largely meant to be stealth marketers, and hired for that purpose, that KOLs participate as marketers in the sorts of activities that to the naive appear to be educational or scientific, and that marketers try to recruit whole organizations, such as medical schools, research organizations, medical societies, and patient advocacy groups as disguised sales organizations.

This goes beyond the problem of bias of physicians, or individual health professionals due to their financial relationships.  It goes beyond the problem of bias of organizations due to their sources of financial support or the financial relationships of their leaders.  It looks like there has been a massive campaign by health care corporate marketers to make useful idiots out of possibly a majority of medical academics and academic, professional, and supposedly patient-centered organizations.  This appears to be a massive, cynical effort to hollow out our once respected health care institutions and professionals in the service of marketing.

A final word to any individuals reading this who are paid by corporate marketers to be KOLs.  If you think that you are paid for educational or scientific purposes, you likely have been made into a chump.  The people who did this to you were likely not acting in your best interests, or those of society, but to cynically market their product and increase their own earnings.  If you doubt this, look at the materials cited above.  You really don't want to continue being chumps, do you?

High Costs and Poor Outcomes - A Lesson About the Suppression of Research

Last week, blogger Alison Bass was one of the few to comment on a new article on the risks of antidepressant medications published electronically last week by the British Medical Journal.[1] The article adds to the clinical evidence about these specific drugs. However, it also should remind us about why our health care costs seem to continue to inflate disproportionate to any improvements in health care outcomes.

Background - Why Don't Doctors Diagnose and Treat Depression According to the Evidence?

Here is the background. Since the early 1990s, based on numerous published clinical trials that showed that the newer (mainly SSRI, that is, selective serotonin reuptake inhibitor) antidepressants seemed to be quite safe and effective, authoritative guidelines have urged physicians to screen patients for depression, and have a low threshold for beginning treatment, particularly with these then new drugs. (For example, see the 1993 AHCPR guidelines,[2] and the Ambulatory Care Quality Alliance Recommended Starter Set[3].) Such guidelines targeted primary care physicians as well as psychiatrists. As a primary care physician, I often felt guilty that I didn't screen all patients, including those who did not outwardly appear depressed, for depression, and was reluctant to be the primary prescriber of antidepressants for depressed patients. I was not alone. There was evidence that many primary care physicians failed to follow these apparently evidence-based guidelines.

Suspicions that SSRIs Were Not as Effective or Safe as Thought

However, in 2004, internal documents from one drug company (Glaxo Smith Kline), published by the Canadian Medical Association Journal, suggested that the company had suppressed a study which failed to show its SSRI was effective for adolescent patients.[4] Also, then New York state attorney general Elliot Spitzer sued the company alleging it had suppressed such data.[5] Considerable anecdotal information thereafter came to light suggesting that drug companies may have suppressed data from clinical research (that is, studies done on patients, not in the laboratory) which tended to show the drugs were less effective, or more dangerous than previously thought. Many began to suspect that the drugs increased the risk of suicidal thoughts or behavior, even though one would think that if they were effective in treating depression, they should decrease such risks.

How Does Uncovering Suppressed Trials Change the Evidence About the Benefits and Harms of SSRIs?

Then, an analysis of trials of SSRIs given to adolescent patients, which included unpublished as well as published trials, did show they increased the risk of suicide.[6] But what about adult patients?

In 2008, Erick Turner and colleagues published a meta-analysis that included numerous trials of SSRIs and other antidepressants given to adult patients that had never been published, but whose results had been submitted to the US Food and Drug Administration (FDA).[7] When those trials were included in the analysis, the drugs seemed less effective than was previously believed.

The new meta-analyis by Stone et al[1] suggested how adding evidence from the suppressed trials improves our knowledge about the possible harms of these drugs. Stone et al specifically addressed whether the drugs increased the risk of suicidal thoughts or actions for adult patients. It was based on data from 372 trials that included 99,231 patients. "Most of the studies were unpublished; those that had been published in some form seldom contained information concerning suicidality in the publication." Its main result was that SSRI drugs approximately doubled the risk of suicidal behavior for patients less than 25 years old, but decreased the risk for older patients.

Suppressing Trials Distorted the Evidence-Base

Thus, the combined results of several meta-analyses suggests that SSRIs are neither as safe nor as effective for adult patients as they were previously touted to be. The drugs used to appear to be more safe and effective because the drug companies that sponsored (paid for) clinical trials of their own products suppressed the publication of studies whose results did not show their products in a favorable light. The guidelines once thought to be so authoritative are probably much to enthusiastic about the use of drugs to treat depression. It may be that those physicians who resisted pressure from these guidelines and other efforts by would-be quality improvers to diagnose more depressed patients and treat them with SSRIs weren't so dumb.

Health Policy Implications

The recently published meta-analysis of the risk of suicidal ideation or behavior due to SSRIs for adult patients[1] adds not just to the clinical evidence about the treatment of depression, but to the evidence that suppression of research by those with vested interests in its results may not be rare. There is no reason to think that suppression of research about other medical interventions used for other clinical problems does not occur just as often.

This underscores why we as a society should not have handed over control of how new drugs and devices are evaluated to the companies that stand to profit by selling them. The apparent benefits and safety of most drugs and devices brought to the market in recent years may have been exaggerated by the ability of the corporations who sponsored the research to suppress those studies that were least favorable to their products. Thus, it is very likely that doctors have over prescribed newer (and more expensive) drugs and devices based on erroneous beliefs about their safety and effectiveness, beliefs supported by an evidence base which was distorted by suppression of studies whose results did not show the results their commercial sponsors wanted to see. Furthermore, we have likely collectively paid too much for these drugs and devices based on these same erroneous beliefs. Thus, the distortion of the clinical evidence base caused by putting the makers of medical products in charge of their evaluation has likely led to increased costs and worse outcomes for patients.

Health care reformers serious about wanting to improve patient outcomes and reduce costs ought to be at the forefront of a movement to make clinical research more honest. All clinical trials completed and submitted to government regulators ought to be published in some form, so that the data they contain is available to guide clinical decisions. Going forward, all studies should be published in some form in a timely manner to prevent future research suppression. There ought to be better regulation of research sponsored, and de facto run by companies who have vested interests in the results being favorable to their products. It would not be unreasonable to prevent companies with such vested interests from running or otherwise directly influencing clinical research meant to evaluate their own products.

But here in the States, we are probably too diverted by yelling at each other about whether a "public option" is vital or nefarious to worry about such issues.. Meanwhile, expect our health care to continue to get more expensive, less accessible, and less good for patients.

ADDENDUM (25 August, 2009) - Also, see the comments by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma Blog

References

1. Stone M, Laughren T, Jones ML et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Brit Med J 2009; 339: b2880. Link here.
2. Depression Guideline Panel. Depression in Primary Care: Volume 2 - Treatment of Major Depression. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1993. Link here.
3. Ambulatory Care Quality Alliance. Recommended Starter Set: Clinical Performance Measures for Ambulatory Care. http://www.ahrq.gov/qual/aqastart.htm
4. Kondro W. Drug company experts advised staff to withhold data about SSRI use in children. Can Med Assoc J 2004; 170: 783. Link here.
5. Wadman M. Sptizer sues drug giant for deceiving doctors. Nature 2004; 429: 589. Link here.
6. Hammad T, Laughren T, Racoosin JA. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry 2006;63:332-9. Link here.
7. Turner EH, Matthews AM, Linardatos E et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252-260. Link here.

Guidelines in Whose Interest? - the Withdrawal of the Children's Medication Algorithm Project (CMAP) Guidelines

In 2006, we posted about striking allegations that guidelines used in the state of Texas and elsewhere for management of adult psychiatric patients, the Texas Medication Algorithm Project, (TMAP) were influenced by payments by pharmaceutical companies to the state, and to the people developing the guidelines.

Now the Dallas Morning News has reported that a parallel set of guidelines for the management of pediatric psychiatric patients has been put on hold amid more allegations that these too have been so influenced.

A state mental health plan naming the preferred psychiatric drugs for children has been quietly put on hold over fears drug companies may have given researchers consulting contracts, speakers fees or other perks to help get their products on the list.

The Children's Medication Algorithm Project, or CMAP, was supposed to determine which psychiatric drugs were most effective for children and in what order they should be tried at state-funded mental health centers. In April, high-ranking state health officials gave researchers the go-ahead to roll out the guidelines.

A month later, the officials delayed the protocol, after Texas Attorney General Greg Abbott's office objected to it.

At most, the suspension indicates that state investigators fear fraud has occurred. At the least, it reflects nationwide unease with potential conflicts of interest between leading medical researchers and the pharmaceutical firms that fund much of their work.

Publicly, officials say it's because the state is suing a pharmaceutical company alleged to have used false advertising and improper influence to get its drugs on Texas' now-mandatory adult protocol, the Texas Medication Algorithm Project.

Privately, individuals with knowledge of the case – who spoke only on condition of anonymity because of the pending litigation – say the attorney general's investigation of possible fraud in the adult protocol has spread to the children's version.

At least four of CMAP's key developers – all affiliated with the University of Texas system, and all of them published child psychiatry experts – have received research funding from drug companies, or have been consultants and speakers for several different pharmaceutical firms, according to their own published papers and financial disclosure forms filed with the university. Drugs made by some of these manufacturers appear in the children's drug protocol.

The doctors say there's no room for improper influence when their reputations are at stake. If the drugs weren't effective, they wouldn't endorse them – and the research they conducted to craft CMAP wouldn't have been published in prestigious medical journals.

Dr. Graham Emslie, a UT-Southwestern psychiatry expert, said he never once witnessed improper influence from drug companies while he helped conduct CMAP research.

The news article listed four CMAP researchers and their financial relationships with pharmaceutical companies.

DR. M. LYNN CRISMON: The CMAP project director who heads UT-Austin's College of Pharmacy has received research funding or consulting dollars from at least 10 different drug companies, according to his published studies, including Eli Lilly, Janssen, and Pfizer. He said he could not comment on CMAP or the lawsuit.

DR. GRAHAM EMSLIE: The UT-Southwestern Department of Psychiatry researcher has consulted for several different drug companies, including GlaxoSmithKline and Pfizer. He has received research grants from at least three drug companies, including Eli Lilly and Forest Laboratories. University financial disclosure forms, where these drug companies are listed, report income in broad ranges. They indicate he may have made up to $125,000 from drug companies since 2004. He said the CMAP protocol was about evidence-based medicine, 'not the [drug] the most recent representative told me about.'

DR. STEVEN PLISZKA: The UT Health Science Center in San Antonio scientist has received research funding from Cephalon and AstraZeneca and has served as a consultant and speaker for McNeil and Shire. University financial disclosure forms, where these drug companies are listed, indicate he has made at least $130,000 in drug company speakers fees and consulting contracts since 2002. Dr. Pliszka said he didn't know CMAP had been delayed until a reporter asked about it. 'For any physician, the bottom line is, does their patient get better,' he said.

DR. CARROLL HUGHES: The UT-Southwestern's Department of Psychiatry doctor has received research funding from GlaxoSmithKline. University financial disclosure forms also indicate he was once an ad-hoc consultant for BioBehavioral Diagnostics, which designs equipment to test for behavioral disorders, and was awarded shares of company stock. He declined to comment.

Here we go again. I would note that the article included examples of the now familiar protests by a academic physicians with substantial financial relationships with pharmaceutical or device companies that such relationships have no effect on their judgments or decisions. But the psychological evidence suggests that the influence of conflicts of interest may not act at the conscious level. Furthermore, as Joe Collier observed [Collier J. The price of independence. Br Med J 2006; 332: 1447-9], "people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult."

Furthermore, there is increasing evidence, (see this recent post, for example), that pharmaceutical and device companies cultivate "key opinion leaders" primarily to help them with marketing their products, and that they may be selected for their willingness to endorse these products as much as for their experience or intellectual prowess. It is the KOLs who generally get the consulting fees and speakers' honoraria. (Some academics may actually be consulted for specific technical or clinical expertise. But note that in this article, as is often the case, the consultants and paid speakers did not explain what they were paid to do, other than to market the payers' products.)

As I just said, --- there is a growing and ever more pervasive web of financial ties among academic medicine and commercial firms that make drugs and devices and provide various health care services. The resulting conflicts of interest suggest patients, physicians and policy-makers should be ever more skeptical about seemingly authoritative medical research, and medical education, practice guidelines, and health care policy based on this research.To make better decisions for individual patients, and better policies for populations, people, patients, physicians and policy-makers at least need clearer and more detailed information about all conflicts that may affect the evidence and opinions that influence their decisions. But might it not be simpler and ultimately better for people, patients, physicians and policy-makers to eliminate some of these conflicts so that we can begin to believe that researchers and academics are paid only to take care of patients, and create and disseminate new knowledge?

See also this post on PharmaLot.

More Questions About Conflicts of Interest and "Surviving Sepsis"

Two years ago, we posted about questions whether the "Surviving Sepsis" campaign was driven by marketing as well as science. Then, we discussed a commentary in the New England Journal of Medicine which asserted that the campaign was part of an effort by Eli Lilly & Co to market Xigris (recombinant human activated protein C, or rhAPC, also known as drotrecogin alfa [activated]) for the treatment of sepsis.(1)

The Wall Street Journal just published an article questioning another aspect of that campaign. In 2001 a clinical trial in the New England Journal of Medicine by Rivers et al reported favorable results for early goal-directed therapy in the treatment of sepsis.(2) This therapy incorporated continuous monitoring of oxygen in the blood using a special central venous catheter capable of measuring oxygen saturation. The WSJ article first raised concerns that some of the patients initially entered into the study were excluded after randomization.

The medical-journal article analyzed 263. But it also said that 288 patients were 'evaluated,' of whom 25 'were excluded or did not consent to participate.'

Dr. Rivers, in an April interview describing how he proceeded, said 'all 288 are randomized' -- that is, placed into either the standard-therapy group or the other group -- 'and then some are excluded because they're not considered severe septic shock.'

But once patients are randomly placed in a group, they must be included in a final analysis, according to a fundamental principle of medical research. Twenty-five were not, the medical-journal article makes clear.

Further muddying the waters, Dr. Rivers, despite having said all 288 patients were 'randomized," stated in a later email that 'there were absolutely no patients pulled out before the analysis.'

The result appears to be a lack of clarity about exactly how this seminal study was done.

Hospital statisticians who worked on it had concerns about the data and recalculated the results with all 288 patients, according to people familiar with the events. When they did, these people say, the death-rate gap wasn't statistically significant.

Statisticians were especially concerned when they noticed that a relatively high proportion of the other 25 -- those not included in the final analysis -- were either conventional-therapy patients who survived or patients on aggressive therapy who died, say the people familiar with the events.

In 2005, a medical resident at Henry Ford doing follow-up research complained to senior hospital officials about the data in Dr. Rivers's study. The hospital convened a panel of inquiry, which concluded the issues had been satisfactorily resolved, hospital officials say.

The panel did a 'thorough investigation' and 'unanimously supported the conclusions,' the hospital said, adding that Dr. Rivers is 'an outstanding clinical investigator whom we support.'

The hospital declined to make the panel's report available. The medical resident who complained, Michael Donnino, declined to discuss the issue of the other 25 patients not included in the final analysis.

Dr. Rivers said that 'randomization was valid,' that 'all patients enrolled in the [early goal-directed therapy] study were appropriately selected, randomized and examined statistically,' and that 'there are no scientific integrity issues in the study.'

I should note that ideally randomized controlled trials should account for all patients randomized, and attribute their results to the group in which they were randomized, even if they did not complete the treatment to which they were randomized. Eliminating patients after randomization could bias the results of analysis, especially if patients particularly likely to have good or bad outcomes were selectively eliminated from one group or the other. The WSJ article raises questions about the occurrence of such bias, but does not prove it occurred.

Further complicating things, the WSJ article suggested that the authors of the article also had undisclosed conflicts of interest.

At the time the study at Henry Ford Hospital was published, in late 2001, the hospital was the owner of patents on the catheter used in the new treatment. Dr. Rivers had transferred the rights to the institution.

The New England Journal of Medicine didn't mention the patents when publishing the study. According to its editor, its policy at the time was to ask only whether an investigator had financial ties to companies involved, and Dr. Rivers said, correctly, that he had none.

Since the publication, catheter maker Edwards Lifesciences has made various payments to Dr. Rivers and his hospital. Such arrangements aren't unusual in medicine, but their existence can raise doubts about findings.

Dr. Rivers and the hospital over the years have received at least $404,000 from Edwards, the Irvine, Calif., company says.

For instance, Edwards paid $150,000 between 2001 and 2003 to Henry Ford Hospital for what Edwards terms 'nonexclusive patent rights [and] ongoing research' into blood oxygen and the mechanism of shock. Dr. Rivers, in an interview, described this as 'money I've gotten from the catheter...all for research.'

In addition, Edwards said, it has paid Dr. Rivers $158,000 to make speeches about his research, $20,000 to reimburse him for patent legal fees, $36,000 in reimbursed expenses and $40,000 in consulting fees.

Edwards Lifesciences said medical evidence has 'demonstrated that early goal-directed therapy yields significant reductions in sepsis-related mortality, lower organ failure rates and/or reduced health-care costs, particularly due to reduced stays.' In recent articles he has written, Dr. Rivers has disclosed receiving support from Edwards.

Also, Edwards Lifesciences was, along with Eli Lilly, a major sponsor of the Surviving Sepsis campaign.

In 2002, critical-care doctors from several specialties joined together to recommend treatments, calling themselves the Surviving Sepsis Campaign. Leading it were R. Phillip Dellinger of Cooper University Hospital in Camden, N.J., and Mitchell M. Levy of Brown University Medical School. Both, plus four others in the group, received consulting fees, honoraria or research-grant support from catheter maker Edwards.

Edwards helped pay for overseas meetings of the group in 2002 and 2004, which cost $861,000 in all. Surviving Sepsis endorsed Dr. Rivers's protocol as well as a drug made by another funder of the conferences, Eli Lilly & Co. Edwards said such support is 'routinely given to advance science and treatments for the benefit of patients.'

Finally, Dr Rivers also has also recently disclosed that he has been receiving money from Eli Lilly, for example, in a 2006 article, "Dr. Rivers has done consultant work for Biosite, Inc., Chiron, the Lilly Corporation, and Edwards Lifesciences over the last year."(3)

So, for an interval summary, recent guidelines promulgated by the "Surviving Sepsis" campaign include fairly enthusiastic endorsements for use of Xigris, made by Eli Lilly & Co, and early goal directed therapy, which requires use of a specific catheter made by Edwards Lifesciences (and other companies). These guidelines were based on research sponsored by these two companies which the guidelines touted as more definitive than it now appears to be. Furthermore, there is a web of financial links, that now appears increasingly complex, tying together these two companies, some researchers involved in these studies, their institutions, and the guideline writing process. These apparent conflicts of interest have raised questions about the integrity of the research on which the guidelines were based, and bias influencing the writing and deployment of the guidelines.

So it is becoming more difficult to determine the extent that marketing considerations influenced the "Surviving Sepsis" campaign, and some of the medical research on which its guidelines were based. Thus, the issue of how best to manage sepsis, already a complex one, now becomes more complex and less clear.

The larger lessons, again, are that there is a growing and ever more pervasive web of financial ties among academic medicine and commercial firms that make drugs and devices and provide various health care services. The resulting conflicts of interest suggest patients, physicians and policy-makers should be ever more skeptical about seemingly authoritative medical research, and medical education, practice guidelines, and health care policy based on this research.

To make better decisions for individual patients, and better policies for populations, people, patients, physicians and policy-makers at least need clearer and more detailed information about all conflicts that may affect the evidence and opinions that influence their decisions. But might it not be simpler and ultimately better for people, patients, physicians and policy-makers to eliminate some of these conflicts so that we can begin to believe that researchers and academics are paid only to take care of patients, and create and disseminate new knowledge?


References

1. Eichacker PQ, Natanson C, Danner RL. Surviving sepsis - practice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med 2006; 335: 1640-1642. Link here.

2. Rivers E, Nguyen B, Havstad S et al for the Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-1377. Link here.

3. Rivers EP. Early goal-directed therapy in severe sepsis and septic shock: converting science to reality. Chest 2006;129:217-218. Link here.

BLOGSCAN - Guidelines for Aprotinin

On the GoozNews blog, anonymous blogger "PM" discussed a set of guidelines written last year on the prevention of operative bleeding. The guidelines endorsed aprotinin to reduce bleeding despite concerns raised in a 2006 New England Journal of Medicine article. Subsequently, several studies showing increased risks of mortality for patients receiving the drug, and it is now off the market. PM wondered whether these guidelines enthusiasm related to the financial ties that a majority of authors reported with Bayer, the company that made aprotinin?