Quintiles to More Heavily Directly Invest in the Drugs Which it Evaluates - But Not to Worry, Says an Expert?

The Associated Press just reported on the latest trend in commercially sponsored clinical research, direct investment by contract research organizations (CROs) in the development of specific drugs by particular pharmaceutical or biotechnology companies. Here is the background in the article:

Pharmaceutical companies previously did all their own research and testing and submitted the results to the Food and Drug Administration for approval to put a medication on the market.

Since the 1990s or so, Big Pharma has farmed out more and more of that testing to companies like Quintiles Transnational Corp., which grew quickly to meet the demand.

Now Quintiles is branching out...

Now Durham, N.C.-based Quintiles is the world's biggest contract research organization, and more than ever, it's using its deep pockets to entwine itself with the pharmaceutical companies, fronting them cash and services for a piece of the profits once a drug is approved.

Quintiles, which was created in 1982, upped the ante last month, saying it wants to invest even more in potential drugs as pharmaceutical companies grapple with the down economy. Quintiles is hoping its new investments will produce enormous payoffs in the future,....

Quintiles' decision to become more aggressive in taking investment risks comes at a time it's betting drug makers can use the resources it can offer, both cash and services.

'They're both currency for managing risk and having skin in the game,' said Ron Wooten, a Quintiles executive vice president who heads the company's capital investment group.

Controversy over creating the drug investment unit in 2000 was key in pushing Quintiles founder Dennis Gilling and several private-equity firms to buy out shareholders for $1.75 billion and take the company private again in 2003. Wall Street analysts complained they couldn't estimate what the drug investments were worth, prompting Gilling and others to decide the company's stock was undervalued.

The private company no longer publishes its profits. It claims revenues of about $3 billion a year. That's also about what Quintiles has invested in other drug companies.

Furthermore,

Quintiles appears to be uniquely positioned to both invest in and test potential medications. None of the half-dozen major shareholder-owned contract research organizations will have a drug-investment division after Wilmington, N.C.-based Pharmaceutical Product Development Inc. spins off its unit in a few months, Coldwell said.

The payoffs for the risk of developing a drug can be huge.

In 2002, Quintiles took a chance on Eli Lilly and Co.'s antidepressant Cymbalta. Quintiles said it invested $125 million in cash, then spent another $400 million on a sales force of more than 550 after the product launch. Cymbalta is now Lilly's second-biggest drug. Quintiles said it's brought in more than $700 million so far for a stream of royalties lasting to 2012.

Japan's Eisai Co. is hoping Quintiles' money and experience helps it double the number of potential treatments it can put through testing simultaneously

The article raised a concern that "the buffer between drug makers and testers are again blurred."

But not to worry.... Here is the response from Quintiles,

Wooten, the Quintiles executive, doesn't see his company's increased interest in bringing drugs to the market affecting its testing objectivity. Instead Quintiles is the outsider turning a hard eye on which pharmaceuticals will become profitable.

'It allows you to really get to the essence of the data that you're looking at instead of what you hope it says,' he said. There isn't 'the natural bias that you would have with your own babies.'

Furthermore, the AP reporter got reassurances from a noted academic expert in the area,

The FDA preserves the integrity of testing in a landscape already pockmarked with potential conflicts of interest that include company-sponsored academic research and investigators testing drugs while owning shares in companies that own the drug, said Kenneth Getz, a senior fellow at Tufts University's Center for the Study of Drug Development.

The FDA's view is that any company with a financial stake in a potential drug will face similar scrutiny from the agency.

'It's assumed,' FDA spokeswoman Karen Riley wrote in an e-mail, 'that drug/device/biologic companies who sponsor trials of pending products have a conflict because they will gain if the product is approved.'

Besides, pharmaceutical companies have navigated the tricky territory that comes with testing, Getz said. So have the companies like Quintiles that have taken on the outsourced work, he said.

'These potential conflicts of interest are ever-present, and the real question is how do companies manage these potential conflicts effectively,' he said. 'These are massive, massive companies that have thousands of staff that are not generally aware of a conflict of interest at a corporate level. They are paid to do a quality job that meets internal and regulatory guidelines or they are not going to keep their jobs.'

Here on Health Care Renewal, we have discussed how the conflicts of interest that are now pervasive in health care can adversely affect clinical care, teaching, and research.  We have looked at how clinical research sponsors, who have a vested interest in having the results favor the products and services they sell, may manipulate the design, implementation, analysis, and dissemination of research, and when all else fails, suppress unfavorable results.  We have also looked at problems with the ethics and quality of research done by contract research organizations, who are, after all, paid by companies again with vested interests in selling particular products or services.

Given all that, one may argue that having contract research organizations invest in particular drugs or devices which they are also evaluating through clinical research may not make things much worse.  However, at the least, it seems to me that it further obfuscates conflicts of interest that may lead to biased research results, dishonoring the patients who volunteered for the trials, and biasing the information on which patients and physicians make decisions.

Finally, I should note how Quintiles new investments in specific drugs was defended in the article.  The article quoted Quintiles executive vice president Ron Wooten suggesting that Quintiles might be able to be objective in making the original decision to invest in a drug. He conveniently did not address what might happen after the investment was made, when Quintiles was performing, analyzing, and reporting clinical research on a drug or device in which it had invested.

The article also quoted Kenneth Getz, the Senior Fellow at Tufts, who seemed unconcerned about the issue.  What the article did not mention is that the Tufts Center for the Study of Drug Development, at which Mr Getz is based,

receives unrestricted grants from pharmaceutical and biotechnology firms, as well as companies that provide related services to the research-based industry (e.g., contract research, consulting, and technology firms). These grants represent approximately 40% of Tufts CSDD’s operating expenses.

per the Center's web-site. Another page on the web-site lists Mr Getz's qualifications,

Kenneth A. Getz is a senior research fellow at the Tufts CSDD. Considered an expert on the investigative site and CRO markets, R& D management, ECT solutions adoption and clinical research volunteerism,....

Mr. Getz is the founder and chairman of CISCRP ....

He holds an MBA from the J.L. Kellogg Graduate School of Management at Northwestern University and a bachelor's degree, Phi Beta Kappa, from Brandeis University. Mr. Getz worked for over seven years in management consulting, where he assisted biopharmaceutical companies in planning and implementing drug development strategies. He is also the founder and former CEO of CenterWatch.

Note that Mr Getz seems to have no training in biomedical science, medicine, or health care.  Furthermore, CISCRP (the Center for Information and Study on Clinical Research Participation), has an advisory board (see their web-site here) that includes representatives of pharmaceutical companies (Vertex Pharmaceuticals, Biogen Idec, and Roche), and contract research organizations, (PPD Inc, and particularly, in this case, Quintiles). The vast list of the Center's "supporters" include a catalog of drug and biotechnology companies (including Abbott Vascular, Amgen, AstraZeneca, Biogen Idec, Daiichi Sankyo Pharmaceutical Development, Eli Lilly, Forest Laboratories, Genentech, Genzyme, GlaxoSmithKline, Janssen, Johnson and Johnson, Merck, Novo Nordisk, Novartis, Ortho-McNeil, Pfizer, Roche, Sankyo, Sanofi-Aventis, Serono, Shire, Takeda, and Wyeth), and contract research organizations, (including Covance, Parexel, PPDI, and notably again, Quintiles.)

So the other lesson from this bit of news is how the information the public, health care professionals, and policy makers  receive about health care policy is frequently shaped by people with horses in the race, but that such influences are rarely disclosed.  This article included an interview with a single apparently academic expert who provided reassurance that the conflicts of interest discussed in the article were not really so worrisome.  This expert, however, failed to disclose his own extensive, albeit somewhat indirect ties to a variety of corporations that might benefit from the conflicts discussed as the main topic of the article, including corporations that were directly involved in them (Quintiles and Eli Lilly).  Maybe because the reporter thought that the expert was unbiased, there was no attempt to find a contrasting opinion.

So I say again, again, again, health care professionals, policy  makers, and people in general need to be extremely skeptical of most of the apparently unbiased pronouncements made about medical and health care policy issues in the media.  It would be a small step toward a more transparent discussion if those who expressed opinions would also fully disclose in detail their relevant conflicts of interest.

Post Title → Quintiles to More Heavily Directly Invest in the Drugs Which it Evaluates - But Not to Worry, Says an Expert?

Sham Studies and the Commercial IRBs that Approve Them, and Sham IRBs and the Government Department that Registers Them

We have occasionally posted about the activities of for-profit contract research organizations (CROs). These are commercial entities that conduct human research, including clinical trials for pharmaceutical, biotechnology and device companies. More clinical research is being done by such CROs rather than by academic investigators. CROs seem to operate under the radar of most physicians, academics, and policy makers, but sometimes stories surface that raise questions about them.

For example, we discussed the trials by SFBC International (now PharmaNet Development Group) in Miami that enrolled immigrants, often undocumented, under questionable circumstances and in Montreal that resulted in the transmission of active tuberculosis (see post here and links backward); and the trial by Parexel International in London that put most of its subjects in intensive care (see post here, with links backward). Last year, as we discussed here, two articles questioning the ethics of research done under the auspices of CRO appeared in two major medical journals.

In academia, human research is supposed to be overseen by institutional review boards (IRBs). Research done by CROs is also supposed to be overseen by IRBs, but the IRBs that do so are often also commercial. Despite concern that commercial IRBs may be tempted to lower their standards to get more business, commercial IRBs have flown even lower under the radar than have CROs. However, last week, a story appeared about how a "sting operation" tested one commercial IRB with amazing results. Here are excerpts from the article by Alicia Mundy in the Wall Street Journal,

The sting, detailed at a House Energy and Commerce Committee hearing Thursday, involved the creation of a fictitious company and a fake medical device, a surgical adhesive gel. The sham firm then applied to three for-profit oversight groups -- called institutional review boards, or IRBs -- for approval to begin a clinical trial using their adhesive on human subjects.

Two IRBs contacted by the GAO's sting operators -- Argus IRB of Arizona and Fox IRB of Illinois -- rejected the Adhesiabloc proposal because of unanswered safety questions.

'We realized it was a terrible risk for the patient … It is the worst thing I have ever seen,' an Argus IRB reviewer said, according to a slide shown at the hearing.

Coast IRB LLC of Colorado Springs, Colo., did approve a study for the fictitious adhesive gel, 'Adhesiabloc.'

The GAO also ran an experiment to see if the US Department of Health and Human Services (DHHS)would register a truly dubious commercial IRB

The committee, working with the Government Accountability Office, Congress's investigatory arm, named the CEO of the fake IRB Truper Dawg, after a staffer's three-legged dog, now deceased. Other fake names included 'April Phuls' and 'Timothy Wittless,' which lawmakers said should have signaled irregularities to HHS. The department registered the IRB.

On one hand, these anecdotes suggest, along with the stories discussed above, that CROs and the commercial IRBs that are supposed to oversee them deserve further scrutiny. Beyond that, one wonders if it is good for society for human research, including experiments involving drugs and devices, to be done by commercial firms dependent for their income on the companies that make these drugs and devices, overseen by other commercial firms also dependent on these same companies. The fundamental conflict is embodied by Coast IRB's self-description:

as an advocate and a catalyst for an ever-stronger pharmaceutical industry, ethically and economically.

which also

recognizes the vital importance of our role in protecting individuals in all clinical studies and in continuously raising the bar on professional standards.

How can the company be an "advocate" for the industry while simultaneously protecting the people exposed to the industry's still experimental drugs?

See also comments on the GoozNews blog.

Post Title → Sham Studies and the Commercial IRBs that Approve Them, and Sham IRBs and the Government Department that Registers Them

The Perils of Contract Research Organizations Out-Sourcing Clinical Trials

The St Petersberg Times last week published an investigative series on the out-sourcing of clinical trials to India, which raised important questions about the quality of data they produce.

Mary K. Pendergast, a former FDA deputy commissioner, said identifying a dangerous product is difficult enough. It's considerably trickier to find fraudulent clinical trial data, which could lead to the approval of dangerous drugs years later.

'It's much more time-consuming and extraordinarily tedious,' said Pendergast, who plowed through such data when she was prosecuting doctors doing drug studies in the United States. 'It's especially hard if the trial is taking place in a different country.'

Particularly when that country has a reputation for cutting corners.

The article quoted a number of people familiar with the clinical trials scene in India who suggested that corners indeed were being cut.

Amar Jasani:

In the burgeoning clinical trial business, says Amar Jesani, a doctor and medical ethicist in Mumbai, every layer of oversight is compromised by cash, and independent monitoring is nonexistent. He has resigned from supposedly independent ethics committees that rubber-stamp drug companies' proposals and overrule any objections.

Dr Arun Bhatt:

Dr. Arun Bhatt is president of Clininvent, a contract research organization in Mumbai that is running 11 trials involving 1,000 patients. He worries that Indian doctors ignore patients' reactions to experimental medicines, missing critical clues about a drug's safety.

'Most sites are not used to recognizing serious adverse events, so they are underreported,' he said with an attitude of resignation. 'Either they don't recognize, don't realize or are afraid to report this information.'

Dr Nandini Kuman:

Dr. Nandini Kumar retired in June as deputy director general of the Indian Council of Medical Research, the equivalent of the U.S. National Institutes of Health. She now works as a consultant for the agency in New Delhi, teaching doctors how to run ethical trials. Kumar is stunned by their ignorance of internationally recognized standards for conducting drug studies.

Asked what aspect of good clinical practice most surprised her students, the gray-haired, sari-clad Kumar snapped, 'Everything.'

'There are efforts to put rules in place, but at the same time there are people who just want to get the extra dollars or perks like trips abroad from doing drug trials....'

Dr S P Kalantri:

Dr. S.P. Kalantri has conducted trials for global pharma at the government hospital in Sevagram, a small town in central India. But he said he has pulled back from doing the studies.

'It's difficult to explain the complexities of trials to study participants,' Kalantri said of the hospital's mostly poor, illiterate patients. 'I think many investigators tend to take their patients for a ride. And there's an abysmal lack of know-how about clinical research among investigators.'

Dr C M Gulhati:

Dr. C.M. Gulhati, editor of an Indian medical journal, Monthly Index of Medical Specialties, said authorities cannot cope with the tsunami of trials.

'India's drugs controller general's office is both understaffed and incompetent,' he said, citing a case where the agency claimed it reviewed an 800-page trial protocol in just five days. 'How is that even possible?'

Gulhati, who fights unbridled drug testing from a dim and cluttered office above a busy Delhi shopping plaza, reeled off a litany of troubled trials:

In 2003 in Hyderabad, an unregistered study of a heart attack drug that resulted in six deaths.

In 2004 in Delhi, a first-in-human trial of a new suturing device on 13 patients without regulators' approval.

Last year, India's decision to become the only nation to allow domestic drug maker Sun Pharmaceutical Industries to market the anticancer drug Letrozole for infertility in women despite the drug's originator, Novartis, warning that it may cause fetal harm and should be used only in postmenopausal women.

And in October in Bangalore, the death of a baby during the testing of a new Wyeth vaccine.

But doing trials in India, and other less-developed countries is far cheaper and faster than doing them in developed countries. Contract research organizations (CROs) have figured this out.

Contract research organizations keep tabs on trials with regular audits. Site management organizations put an extra set of eyes in the doctor's office. Both entities dangle promises of FDA-ready studies in half the time, at 30 to 60 percent the cost in the United States. The secret? Cheap help and fast patient recruiting.

Quintiles, the world's largest contract research organization, boasts of enrolling 50 patients with diabetes in one month in India and 204 infants for a vaccine study in three days, far faster than possible in the States. In a brochure, Quintiles sums up India's allure: 'It's practically a paradise for conducting clinical trials.'

In fact, on Quintiles current web-site is an offer related to Phase II and III trials for

Accelerated Start-up and Recruitment worldwide, through a global network of investigators that includes many in nontraditional regions with large clusters of patients and few competing trials.

We have noted before that the limited oversight of CROs, which are responsible for an increasing proportion of industry-funded trials of drugs and devices, makes possible poor quality work, hence unreliable data (see most recent post here and links backward). The threat to data integrity from too hasty, too profit driven clinical research done by CROs is the third of the three major threats to the integrity of the clinical research data base. The other two, which are discussed frequently on Health Care Renewal, are suppression of clinical research, and manipulation of research design, implementation, and analysis and dissemination.

In combination, they threaten the well-intentioned and idealistic goals of evidence-based medicine, to improve clinical care by basing decisions not only on knowledge of biology and the values of patients, but on critical review of the best available clinical evidence. But given that we have become increasingly skeptical, if not outright distrustful of the integrity of the evidence, the alternative ways of making clinical decisions, basing them on theoretical (but possibly incorrect) knowledge of biology, on authority, or on tradition to me are much worse.

Doctors and patients should be vehement about the need for carefully performed clinical trials free of manipulation meant to benefit vested interests, reported honestly even if their results offend vested interests.

Post Title → The Perils of Contract Research Organizations Out-Sourcing Clinical Trials

BLOGSCAN - "Academic" Contract Research Organizations - What Will They Think Of Next?

On the Hooked: Ethics, Medicine and Pharma blog, Dr Howard Brody discussed an article in the British Medical Journal by Jeanne Lenzer about the increasing role that contract research organizations (CROs) are taking in clinical research. Particularly enlightening were the discussions of academic CROs, a species not previously much in the limelight. It seems that medical schools, academic medical centers, and even schools of public health, stung by the loss of industry sponsored research to for-profit CROs, have spawned their own line of extra industry friendly affiliates. It seems not-for-profit academic medicine is getting less and less distinguishable from their for-profit benefactors.

Post Title → BLOGSCAN - "Academic" Contract Research Organizations - What Will They Think Of Next?

The Clinical Trials "Torture Economy"

Two recent commentaries in major medical journals on the same topic failed to get the recognition they deserved. Both were about exploitation of the poor in clinical research, usually in Phase I drug trials conducted by contract research organizations (CROs), supervised by for-profit institutional review boards (IRBs), and both paid by pharmaceutical, biotechnology or device companies.

The first article was by Carl Elliott and Roberto Abadie. [ Elliott C, Abadie R. Exploiting a research underclass in phase I clinical trials. N Engl J Med 2008; 358: 2316-7. Link here.] Per Elliott and Abadie, the context is:

Over the past decade, clinical trials have moved from universities to private testing sites, the pressure to recruit subjects quickly has intensified, and ethical oversight has been outsourced to for-profit institutional review boards (IRBs). Payment to subjects has escalated, creating 'shadow economies' in cities throughout North America and elsewhere.

The authors then cited several misadventures that we have discussed on Health Care Renewal: the trials by SFBC International (now PharmaNet Development Group) in Miami that enrolled immigrants, often undocumented, under questionable circumstances and in Montreal that resulted in the transmission of active tuberculosis (see post here and links backward); and the trial by Parexel International in London that put most of the subjects in intensive care (see post here, with links backward).

Elliott and Abadie concluded "there are good reasons to believe that poor subjects are being exploited," and cited several justifications for this belief:

• "Poor people are less likely than wealthier ones to get access to the drugs in question." This "appears to contravene article 19 of the Declaration of Helsinki, which states that medical research is ethically justified only if there is a reasonable chance that the population in which it is conducted will benefit from the results."
• "The U.S. oversight system is not well equipped to monitor a highly competitive, market-based, multinational research industry." The Office for Human Research Protection "has no jurisdiction over privately sponsored studies," the US Food and Drug Administration (FDA) has insufficient funds to monitor all but a tiny minority of trials. The institutional review boards (IRBs) that are supposed to supervise trials are ill-equipped to protect against the sort of abuses that are likely. Furthermore, for-profit IRBs that are dependent on research sponsors for repeat business may be loathe to upset the apple-cart.
• "Most sponsors apparently do not provide free care or treatment when subjects are injured."

Elliott and Abadie observed that most subjects in such trials see their participation as a job, rather than as a voluntary activity to promote science and human welfare. As the authors point out, if so, it is a poorly paid, risky job with few benefits and protections. Their conclusion is troubling,

The result is what one Philadelphia trial subject describes as 'a mild torture economy.' 'You are not being paid to do something,' he explains. 'You are being paid to endure.'

The only addition I can make is not only does the treatment of some patients in such trials appear inhumane, it amounts to bad science. Results from "professional trial subjects," who are likely to conceal characteristics which might have excluded them from this line of work, who may undergo one trial while still recovering from the effects of a previous, undisclosed trial, and who may be prone not to follow study protocols likely will not generalize to the patients who might actually be candidates for the drugs and devices assessed.

An editorial in the American Journal of Medicine was based on an article by Carl Elliott on the same topic published in the New Yorker. [Alpert JS. Dealing with ethical conflicts in clinical research. Am J Med 2008; 121: 457. Link here.]

His main conclusions were:

The ethical failure of such activities is obvious. The Nuremburg and Helsinki codes, developed following the human experimental atrocities of World War II, strongly advocate for voluntary participation on the part of research subjects. The substantial sums of money paid to the human 'guinea pigs' described by Elliott clearly obfuscate any volunteerism on the part of the individuals involved in these clinical experiments.

Lives saved and disease suffering lessened at the expense of individuals who are lured and perhaps even coerced into clinical trial participation cannot be allowed to continue in an open and equitable democracy. Clearly, the article by Elliott should be widely disseminated among academic and community physicians and governmental authorities. The topic should be openly discussed leading to corrective actions. Steps must be taken in the near future to protect the lives and the civil rights of individuals participating in clinical research studies.

Despite this call, I found no news coverage, and so far, no public discussion of any kind of the issues raised by these articles.

I hope that the charges that many current trials violate international ethical standards might get some peoples' attention, and maybe even inspire some action. I am not optimistic that anything will be done too hastily. After all, a lot of people are benefiting financially by the current scandalous status quo. They will not give up their ill-gotten gains gracefully. But this "mild torture economy" signals the approaching moral bankruptcy of our current health care system.

Post Title → The Clinical Trials "Torture Economy"

Who Do Pharmaceutical Companies Support to Run Clinical Trials?

On the Clinical Psychology and Psychiatry blog, this post discusses an amazing case of a psychiatrist who had his license suspended for giving genital herpes to two patients. Why is that amazing, or relevant to Health Care Renewal?

The psychiatrist also is known for enrolling patients in clinical trials sponsored by no less than 11 well-known pharmaceutical companies (AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Johnson & Johnson, Novartis, McNeil, Pfizer, and Shire) and working with no less than six well-known contract research organizations (I 3 Research, INC Research, Parexel, PPD Development, Quintiles, Rho Inc).

Apparently an FDA investigation of the (not so) good doctor also found he had "imprisoned" one patient, enrolled at least two patients in trials without informed consent, hospitalized patients in unlicensed facilities, and failed to record drug dosages in trials.

Yet, the psychiatrist seems to be regarded as something of a "thought leader," as he claims to be on the speakers bureaus of "Wyeth Pharmaceuticals, Pfizer Pharmaceuticals, Bristol Myers Squibb and others."

But of course, some have argued (e.g., see this post) that the physicians and researchers the pharmaceutical industry recruits as consultants, study investigators, and speakers are nothing but the "best and the brightest." Maybe not always...

Post Title → Who Do Pharmaceutical Companies Support to Run Clinical Trials?

Haunted Health Care: the Scope of Ghost Management

An important new article in PLoS Medicine expanded thinking about the involvement of pharmaceutical companies (and possibly other health care corporations) in the shaping of clinical research. [Sismondo S. Ghost management: how much of the medical literature is shaped behind the scenes by industry? PLoS Med 4(9): e286 doi:10.1371/journal.pmed.0040286]

Sismondo defined ghost management of medical research and publishing:

when pharmaceutical companies and their agents control or shape multiple steps in the research, analysis, writing, and publication of articles. Such articles are 'ghostly' because signs of their actual production are largely invisible—academic authors whose names appear at the tops of ghost-managed articles give corporate research a veneer of independence and credibility. They are 'managed' because those companies shape the eventual message conveyed by the article or by a suite of articles.

Sismondo thus went beyond the issue of ghost-writing, the contribution of unnamed authors who may be influenced, or hired, by pharmaceutical companies or other organizations with vested interests. (See recent post here.) He also went beyond the issue of how pharmaceutical companies and other research sponsors may attempt to influence the design and implementation of research studies, the analysis of their results, and/or how the results are reported. (See this post.)

As Sismondo noted,

It has been repeatedly and firmly established that pharmaceutical company funding strongly biases published results in favor of the company's products. Ghost management amplifies that bias, because when one set of commercial interests exerts influence at multiple stages of research, writing, and publication, it will shape the resulting article. In turn, bias affects medical opinion and practice, and ultimately, patients.

Sismondo also attempted to estimate the prevalence of ghost management. This would have been predicted to be a difficult task, because,

it is not in the interests of writers, authors, or sponsors and their agents to reveal ghost management processes; hence a number of the published accounts of ghost management have stemmed from legal proceedings and investigative journalism.

So he set out to review existing evidence and find some new evidence.

First he noted the article by Healey and Cattall, based on documents produced during legal proceedings, that explained how Pfizer Inc ghost managed publications of multiple articles on the drug sertraline [Zoloft], producing 85 manuscripts, and accounting for an important part of the literature on this one drug. (See previous post here.)

An important contribution by Sismondo was what he called his "supply-side analysis."

A survey in 2001 identified 182 MECCs in the United States, up from 153 in 1998. A number specialize in producing, placing, and tracking journal articles, known in the trade as 'publication planning' or 'strategic communication planning.' While these firms hide details of their work—from potential critics and competitors—they also energetically promote themselves and their services.

I spent six hours searching web pages for MECCs offering publication planning or similar or overlapping services to the pharmaceutical industry, and found 23 (list available from the author). This is not an estimate of the number of such firms, but indicates how common they are. There may be many more firms providing publication planning, including some not uncovered in this search, and some not advertising these services on the Internet.

In a primer on publication planning, the director of one MECC defines the activity as: 'gaining product adoption and usage through the systematic, planned dissemination of key messages and data to appropriate target audiences at the optimum time using the most effective communication channels'.

Complete Healthcare Communications (CHC) claims on its banner that it 'has honed the systems and skills needed to develop the intellectual heart of pharmaceutical marketing—the publication plan. The result for your product? A continuum of awareness, interest, and prescriber confidence.'

CHC includes among its clients Pfizer, Sanofi-Aventis, Ortho Biotech, Wyeth, Schering-Plough, Shire, AstraZeneca, and other pharmaceutical companies.

Other agencies offer very similar services. As described in an article by three of its managers, the Medical Knowledge Group starts publication planning with a phase of exploring 'key messages' and 'author/journal options' before designing any publications to incorporate those messages

Another MECC, Envision Pharma, says that 'data generated from clinical trials programs are the most powerful marketing tools available to a pharmaceutical company.' Envision will work from early on in the process to ensure 'consistent message dissemination,' will plan and track the 'data dissemination plan,' and will produce 'scientifically accurate, commercially focused abstracts, posters, and primary and secondary publications'

Several of the publication planning firms identified are owned by major publishing houses. For example, Excerpta Medica is 'an Elsevier business' and writes that its 'relationship with Elsevier allows… access to editors and editorial boards who provide professional advice and deep opinion leader networks.'

Wolters Kluwer Health draws attention to its publisher Lippincott Williams & Wilkins, with 'nearly 275 periodicals and 1,500 books in more than 100 disciplines,' and to Ovid and its other medical information providers, emphasizing the links it can make between its different arms

Vertical integration is attractive in the industry as a whole: at least three of the world's largest advertising agencies own not only MECCs, but also CROs.

Ghost management of medical journal publications is clearly a substantial business, employing thousands of marketers, writers, and managers. It is large enough that the industry has established the International Publication Planning Association.

The conclusion is that

Given the amount of data that pharmaceutical companies control, the number of publication planning agencies that openly advertise on the Internet, the number of medical writers, the existence of two associations for publication planners, and meetings organized and reports written for them, we can conclude that ghost management is common.

Why is it so important?

Articles in medical journals have real effects upon physician prescribing behavior, which is why pharmaceutical companies invest so much in their publication. Journal articles are heavily used in detailing, to validate claims and rebut worries. Even independent of detailers, responsible physicians and medical researchers search the literature to gather evidence about the best treatments. Published scientific articles are the sources of medical information with the highest authority. Systematic reviews and meta-analyses almost all start with the published literature—so even fully independent reviews are influenced by ghostly activities.

It is clear that ghost management is a major part of the production of pseudoevidence-based medicine.

Sismondo's article is an important contribution to our knowledge of how research on human beings is manipulated into marketing and propaganda, if not outright disinformation. Such practices break the trust of research subjects who thought they were participating to advance science and medical care. Such practices mock physicians who think they are trying to make decisions based on clinical science. Such practices can harm patients who are subjected to tests and treatments based on hype and manipulation rather than unbiased data.

Sismondo ended with some suggestions for alleviating the problem, but noted,

There are no straightforward solutions, short of large changes to the nature of medical publishing and/or research, changes that would effectively sequester pharmaceutical company funding from research and publishing....

We have now said frequently that there are many reasons to think about whether organizations who have a vested interest having clinical research produce particular results should be banned from funding or other involvement in research on human beings. The probably pervasive practice of ghost management is another strong reason to consider this seemingly extreme step.

In the absence of such a drastic prohibition, all I could suggest is a much strengthened and more comprehensive disclosure policy. Many would now agree that all clinical trials should be registered. Such registration should include details of any involvement of pharmaceutical, biotechnology, device and similar companies in the design and implementation of the research, and the analysis and reporting of its results. Any involvement by contract research organizations, for-profit institutional review boards, medical education and communication companies, and the like should be disclosed in trial registration.

Furthermore, there should be full disclosure of all involvement by any of these organizations accompanying any publication or presentation of study results, including publications in peer-reviewed journals, abstract presentations, etc.

Furthermore, the penalties for concealing involvement of any of these organizations should be severe, all the way up to considering failing to disclose as potential criminal fraud.

Allowing ghost management to continue victimizes people who volunteer to participate in research, mocks physicians who try to base their clinical decisions on the best available evidence, and hurts patients.

Hat tip to the Medical Humanities Blog, and one of our corps of Health Care Renewal scouts.

Post Title → Haunted Health Care: the Scope of Ghost Management

BLOGSCAN - A "Quickie" Web-Site for Cymbalta

On PharmaLot, this post describes a web-site that suddenly appeared with favorable information about the drug Cymbalta (duloxetine, manufactured by Eli Lilly). Based on rumors that the site was run by NovaQuest, a subsidiary of contract research organization (CRO) Quintiles Transnational, blogger Ed Silverman sent an enquiry to NovaQuest. The response was that the site had been taken down, but did not address who put it up in the first place. Are such "quickie" unattributed web-sites the latest form of stealth marketing?

Post Title → BLOGSCAN - A "Quickie" Web-Site for Cymbalta

Yet Another Species of Health Care Conflicts of Interest: Contract Research Organizations Which Invest in Biotechnology Companies

The St. Petersburg (Florida) Times has an interesting story about the relationships between contract research organizations (CROs) and biotechnology and pharmaceutical companies.

Like many startup businesses, Accentia BioPharmaceuticals of Tampa was long on dreams but short on cash.

It held the license to an experimental sinus drug that looked like a potential blockbuster. But the company needed serious bucks to get the product to market.

Accentia found an investor in PPD Inc., a company that specializes in running the studies that must be conducted before regulators can approve a drug.

A year after recruiting PPD as an investor, Accentia went looking for someone to run the all-important trials proving the safety and effectiveness of its sinus drug.

Guess who got the job.

Now PPD is not only the second-biggest investor in Accentia, it also is handling the final preapproval studies of Accentia's new drug, SinuNase.

If the PPD-run trials result in the drug being approved by the Food and Drug Administration, financially strapped Accentia will be on its way to tapping a billion-dollar market of folks with chronic sinusitis. And PPD will get 14 percent of the royalties.

Is that a conflict of interest?

The FDA doesn't think so.

The agency requires doctors to disclose any financial interest in drugs they are testing on patients, but it doesn't even gather such information from companies like PPD.

Charged with protecting the public, the FDA gets most of its drug approval budget from pharmaceutical companies. Increasingly, those companies have been foisting off the drudgery of running drug trials onto companies like PPD, which are called contract research organizations.

But now, instead of just being paid to conduct a study, some CROs are taking a stake in a trial's success. This does not concern the FDA's senior adviser for clinical science, Dr. David LePay.

'We assume CROs have a financial interest in the compounds they're testing,' he said.

As proof the system is working, LePay noted how rarely the government finds fraud in clinical trials: 'We only find it in 1 to 2 percent of inspections.'

Others say those numbers prove something altogether different: that the regulators' focus is on approving, not challenging clinical studies.

'The FDA does not have the resources to inspect all clinical trial sites or even a major fraction of them,' said Dr. David Ross, who was with the agency's drug review office for a decade. 'And if you don't look for fraud, you won't find it.'

We should note that Pharmaceutical Product Development Inc (PPDI) was the CRO that ran a very questionable trial of the drug Ketek (see our most recent post here).

It turns out that PPDI's involvement with Accentia is not an isolated occurrence.

Most preapproval drug testing used to be done in academic institutions, directly under the control of the drug companies. Now most trials are performed in regular doctors' offices around the globe, and contract research organizations handle a major chunk of the work. As hired hands for the pharmaceutical industry, last year the companies generated some $15-billion in revenue.

Head and shoulders above the competition in terms of size are PPD and its chief rival, Quintiles Transnational Inc. Together their more than 25, 000 employees oversee thousands of clinical trials in more than 50 countries.

The two companies have distinguished themselves by offering clients a particularly attractive feature: money.

PPD, with $1.3-billion in revenue last year, has made four investments, including the one with Accentia. Through these "compound partnering" alliances, PPD said that last year it reaped $94-million in related clinical trial business. The company declined to comment for this story.

Quintiles, with $2-billion in revenue last year, started investing in up-and-coming drugs in 1999. Last year the investment division, called NovaQuest, teamed with a giant $5.8-billion venture fund to give it access to additional capital to invest. To date, NovaQuest has committed $2-billion to dozens of partnerships, including 26 deals with small biotechs.

Not surprisingly, CRO executives think that they can have such relationships without generating conflicts of interest.

Ron Wooten, the 49-year-old president of NovaQuest, said his company deals with the same potential conflicts of interest a drug company has when it oversees trials of compounds it owns.

'You manage that conflict by having fire walls around all information and strict confidentiality across all functions,' he said. 'Nobody on my staff talks to operations about there being higher stakes in a program when we have an investment. That never happens.'

But not all agree.

Arthur Caplan, professor of bioethics at the University of Pennsylvania, said federal regulators need to pay more attention to contract research organizations. Even if they don't invest in a drug under review, the companies have an incentive to get patients enrolled and tests completed fast, he said. Timely, trouble-free trials are the ticket to the next contract.

'CROs stay in business by hitting the numbers,' Caplan said.

And when a trial monitor has a financial interest in a drug study's outcome, as PPD does with SinuNase: 'That's a big ethical no-no,' Caplan said. 'They should never be reviewing anything in which they have a direct financial interest.'

Furthermore,

Dr. Marcia Angell, senior lecturer at Harvard Medical School, doesn't buy it. She said having drug companies or their proxies in charge of drug trials means the entire system is corrupt, 'from stem to stern.'

'It's a house of cards built on a fundamental conflict of interest,' said Angell, former editor of the New England Journal of Medicine and author of The Truth About the Drug Companies: How They Deceive Us and What to Do About It.

'The problem is that drug companies have inordinate influence over the evaluation of their own products. That, on the face of it, doesn't make sense.'

We have posted before about major problems with how CROs conduct research. Other than the story of how PPDI ran trials of Ketek, there were, for example, the disastrous trial of TGN 1412 run by Parexel International (see most recent blog post here), and the clinical trials by SFBC International (now Pharmanet) that infected multiple participants with tuberculosis (most recent blog post here).

The St Petersburg Times seems to have uncovered yet another species of conflict of interest affecting health care, and particularly affecting clinical research. In a way, this is akin to the conflicts that occur when academic researchers who are paid part time, usually as consultants or members of speakers' bureaus, by a given drug, biotechnology, or device company also conduct human research on that company's products. The concern is that their financial arrangements will influence how they design, carry out, and disseminate this research. The potential research biases induced by such arrangements ought to be clearly disclosed to the humans who volunteer to participate as research subjects.

Similarly, the potential research biases induced when a contract research organization has an ownership interest in the drug, biotechnology, or device company whose products it is supposedly dispassionately evaluating ought to be clearly disclosed to the human subjects of such research.

Finally, this is a reminder that patients and physicians ought to be highly skeptical about the results of clinical research carried out by people and organizations which may have financial relationships with the companies that produce the products their research is supposed to to evaluate.

And it is another reminder that for the good of research subjects, of clinical science, and of patients in general, we ought to consider how to make sure that all human research is done by people who do not have conflicts of interest, especially those that link the researchers to the manufacturers of the products or the providers of the services their research is meant to evaluate.

Post Title → Yet Another Species of Health Care Conflicts of Interest: Contract Research Organizations Which Invest in Biotechnology Companies

Updates on Commercially Sponsored Drug Research: "A Morally Flimsy Foundation to Advance Medical Knowledge"

There are new developments in several stories we have been following about commercially sponsored drug research done on human subjects.

Studies on Ketek (Telithromycin) Done by Pharmaceutical Product Development for Sanofi-Aventis

We recently discussed how results of study of Ketek (Telithromycin) done by Pharmaceutical Product Development for Sanofi-Aventis may have been affected by misconduct, including one conviction for fraud, by some of the physicians paid to enroll patients. Although the results of this trial were never published, they have been cited in the clinical literature.

Now Reuters has reported that Sanofi-Aventis is in talks with the US Food and Drug Administration (FDA) about strengthening the warning label on the drug. A report from PharmaLive said that US Senator Charles Grassley (R-Iowa), chair of the Senate Finance Committee, is pressing the FDA for more information on how it handled the approval of Ketek. The letter said,

the Committee continues to investigate the extremely troubling allegations related to , among other things, the approval and post-market [sic] surveillance of telithromycin (Ketek) by the Food and Drug Administartion. One of the most troubling allegations is that the FDA approved Ketek with full knowledge that some of the clinical safety data supporting its approval was beset by systemic data integrity problems. While the FDA takes its time negotiating with Sanofi-Aventis to decide what drug risk information the public should know, it is completely mystifying why a fraudulant clinical trial is reference in safety information on the FDA's web-site.

The Disastrous Trial of TGN 1412 Done by Parexel for TeGenero

We have previously posted, most recently here and here, about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill. We had previously noted allegations that there was reason to think prior to this trial that TGN 1412 would pose risks to human subjects.

The BBC interviewed several experts who also felt that TGN 1412 should have been regarded as a risky drug from the outset. For example, it quoted Dr David Glover, "it may be that it [the adverse effect] was unpredicted by the tests that were done. I believe from the basic science it was predictable." Professor David Winter, of the Laboratory of Molecular Biology in Cambridge said that "those testing TGN 1412 may have been lulled into a false sense of security by the fact that it did not seem to harm monkeys - but it was wrong to make too many assumptions based on animal experiments." In response, TeGenero "said it was an 'oversimplification' to suggest that the side effects could have been predicted in advance."

Multiple Clinical Trials Done by SFBC International

We have posted before about the troubles of contract research firm SFBC International We started by posting about allegations that private, for-profit clinical research firms, including SFBC International, supervised by for-profit institutional review boards (IRBs), were doing sloppy and shoddy work. We then noted allegations that SFBC International had tried to threaten or intimidate research subjects who talked to reporters about such poor research practices. Furthermore, we discussed how a review commissioned by the company found that a top executive, Jerry Seifer, SFBC International's Vice President for Legal Affairs, threatened participants in clinical studies who had talked to the press with deportation. Seifer, it turns out, had been the subject of past regulatory sanctions by federal regulators. In addition, study participants in a trial of an immunosuppressant drug carried out by the firm's Canadian subsidiary, SFBC Anapharm, acquired tuberculosis after exposure to another participant with active disease, despite their complaints to Anapharm staff. More recently, we noted that Seifer had resigned, and the company's stock price had fallen. Finally, we noted allegations that 20 people, including trial participants and staff at SFBC International's Montreal facility acquired latent tuberculosis after exposure during trials.

Per Bloomberg News, SFBC International just announced it will shut down its facility in Florida that was the location of allegedly sloppy and shoddy research practices noted above. In fact, the Miami-Dade County Unsafe Structures Board gave the company 60 days to "file a permit to demolish its Miami facility.... The company said it would appeal the ruling and may file [for] an injunction." Bloomberg quoted Kenneth Goodman, Director of the University of Miami's bioethics program, who had toured the Miami area facility,

This is going to send a signal through the entire drug industry that human-subject protection is not a nicety or a courtesy, but a bold-faced moral and legal requirement.
What I saw was a research mill where vulnerable poor and uneducated people were being enticed into taking medical risks to make a living. That's a morally flimsy foundation to advance medical knowledge.

Summary

The cases of the Ketek trial, the TGN 1412 trial, and various trials done by SFBC International have rarely been juxtaposed, except on Health Care Renewal. However, their juxtaposition suggests

• Physicians and patients should be extremely skeptical of the results of drug research carried out by contract research organizations sponsored by pharmaceutical companies, since the design and implementation of such studies may not be what they seem. Other evidence that commercial research sponsors may manipulate the design of studies, the analysis of their data, and the dissemination of their results should only add to this skepticism (see most recent post here).
• People should be extremely wary about signing up as subjects for such trials, since their risks may be worse than they realize
• We ought to rethink the social desirability of the current relatively unregulated system of having human clinical research sponsored by commercial firms with interests in their results.

We are clearly on a "morally flimsy foundation to advance medial knowledge."

Post Title → Updates on Commercially Sponsored Drug Research: "A Morally Flimsy Foundation to Advance Medical Knowledge"

The Saga of Study 3014 and the Safety of Telithromycin

An article in the Wall Street Journal by Anna Wilde Matthews (subscription not required to access article) raises questions about the integrity of the clinical research evidence about the antibiotic telithromyci (Ketek) made by Sanofi-Aventis.

Background

Telithromycin is a ketolide, a molecular modification of erythromycin with some similarity to macrolide antibiotics. In the US, it is approved by the Food and Drug Administration (FDA) for treatment of outpatient upper respiratory infections and pneumonia.

A brisk review of the drug is found in this editorial in the Annals of Internal Medicine: Turner M, Corey GR, Abrutyn E. Telithromycin. Ann Intern Med, Mar 2006; 144: 447 - 448. This editorial notes concerns about the liver toxicity of the drug, based in part on a case report of three patients in the same issue ( Clay KD , Hanson JS, Pope SD, et al. Severe Hepatotoxicity of Telithromycin: Three Case Reports and Literature Review. Ann Intern Med, Mar 2006; 144: 415 - 420.). One patient required a liver transplant, and one died. The case report also noted that Sanofi-Aventis reported seven cases of hepatitis or hepatocellular damage in patients taking telithromycin in data from Phase III trials. Also, the FDA received ten post-marketing surveillance reports of serious liver problems in patients taking the antibiotic, and often, other drugs.

The Wall Street Journal Article

The article focused on a large randomized controlled trial, study 3014, initiated by Aventis (to become Sanofi-Aventis) in 2001. According to the WSJ article, "Aventis first sought permission to sell Ketek in the U.S. in March 2000. Fifteen months later the FDA refused to approve it." So, "Aventis originally undertook study 3014 in 2001 at the request of the FDA, which was worried about liver damage, blurry vision and other possible side effects from Ketek after reviewing the company's earlier trials." Then, "Aventis hired a contractor called Pharmaceutical Product Development Inc. (PPD), which specializes in coordinating clinical trials." The study was designed to enroll patients with respiratory infection seen in the offices of 1824 primary care physicians. Patients were randomized to telithromycin or amoxicillin/clavulanate potassium (Augmentin).

Problems were soon discovered at study sites that enrolled the most patients.

• The study eventually enrolled 407 patients from the office of Dr Maria "Anne" Kirkman Campbell. Her practice "attracted patients by advertising weight-control treatments." By January, 2002 she was enrolling "30 new people a day." Minutes from a PPD study management meeting stated that someone was a "little uncomfortable" with the site, which required "additional monitoring." In February, 2002, Nadine Grethe, "an Aventis manager overseeing the study," got an email from PPD warning of problems at the site with lack of "proper diagnosis of an appropriate medical condition" for study patients, and that medical charts were "very limited," and laboratory test results "suspiciously similar." A statistical analysis by Aventis failed to indicate problems with the data. "When Aventis turned in the results of study 3014 to the FDA on July 24, 2002, they included 407 patients from Dr. Campbell. At this point, 'Aventis did not alert the Agency to any problems....'" Yet when an FDA inspector examined Dr Campbell's office in the fall of 2002, chosen simply because of the volume of patients enrolled there, problems found included "patients [who] said they hadn't gotten any medication," patients "who were allegedly being treated fro weight loss, and not respiratory infections," and some who "were family members and friends of Dr. Campbell." Later, "Sanofi-Aventis says it was only after the government investigation that it discovered Dr. Campbell was fabricating data." Dr. Campbell eventually plead "guilty of one count of mail fraud in March, 2004 and was sentenced to four years and nine months in federal prision."
• The site with the third greatest number of patients, 214, was that od Dr. Egisto Salerno. His "medical license was on probation during the study." "Aventis told the FDA in December 2002 that it didn't know Dr. Salerno was on probation." An FDA inspection found "use of white-out on some study documents." Seven weeks after ending study enrollment, "police found Dr. Salerno with cocaine in his underwear and a loaded handgun," and he eventually surrendered his medical license, and plead guilty to a misdemeanor, which was later expunged after community service and drug counseling.

However, "when a committee of outside adviers to the FDA met early in 2003 to weigh a recommendation on Ketek, agency officials didn't mention the problems turned up by its inspections. The FDA's Dr. [Janice] Soreth and Dr. Jenkins say revealing the suspicions might have biased the decision and impaired the investigation. The committee voted to recommend Ketek's approval. Two weeks later the FDA rejected the recommendations. It asked Aventis for more documents on study 3014 and potential side effects overseas. Aventis complied. But the FDA ultimately decided the study was so flawed that the data couldn't be trusted." After considerable internal debate, "the FDA formally approved Ketek on April 1, 2004...." "FDA officials said they believed the original Aventis data submitted in 2000, plus the data from smaller studies and the drug's safety record oversea, justified approval."

The WSJ article noted that study 3014 was cited in an "article in the New England Journal that suggested Ketek is as safe as other antibiotics. Five of the six authors of that article disclosed that they received consulting fees from Sanofi-Aventis, and the sixth was an Aventis employee at the time of the study." The article mentioned in the WSJ appears to be this report of a randomized controlled trial of talithromycin versus placebo for patients with acute asthma ( Johnston SL, Blasi F, Black PN, Martin RJ, Farrell DJ, Nieman RB, the TELICAST Investigators. The Effect of Telithromycin in Acute Exacerbations of Asthma. N Engl J Med 2006; 354:1589-1600.) In apparent reference to safety information derived from study 3014, Johnston et al concluded, "among patients with normal liver aminotransferase levels at entry, the incidence of elevations of at least three times the upper limit of normal after treatment was similar among patients receiving telithromycin and drugs used for comparison."

The WSJ quoted US Senator Charles Grassley (R-Iowa, and Chair of the Senate Finance Committee), "the Ketek allegations appear to be as serious as anything I've seen so far." Additionally, US Representatives Edward Markey (D-Massachusetts), and Henry Waxman (D-California) are separately investigating. Rep. Waxman said he is "deeply disturbed," and that Aventis "failed to disclose to FDA grave flaws in a key safety study."

Summary

At best, this appears to be yet another story about a drug trial that was poorly executed by a contract research organization, and not rigorously supervised by a pharmaceutical company. We have previously discussed apparently sloppy work by other contract research organizations (see post here). Furthermore, results from this poorly executed trial seem to have been used to suggest that telithromycin is relatively safe, even though the integrity of the data provided by this trial is questionable.

The story of study 3014 appears to be yet another cautionary tale about how the clinical evidence that physicians and patients rely upon to make clinical decisions must be regarded with skepticism. Our skepticism about particular research studies needs to be extended not just to the usual considerations of study design, the nature of the data collected, and the appropriateness of the statistical analysis. We must now be skeptical about the details of the study execution, particularly when the study has been done by a contract research organization, and worry about problems that may go beyond just honest mistakes.

Post Title → The Saga of Study 3014 and the Safety of Telithromycin

The TGN 1412 Trial "Raises a Number of Big Red Flags"

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG. All six healthy volunteers who got the antibody soon became critically ill (see our most recently here). The International Herald Tribune has done some investigative reporting on this trial.

First, the Tribune confirmed that TeGenero, the manufacturer of TGN 1412, was aware prior to the trial of the possibility that subjects might undergo "cytokine release syndrome" after taking the drug. This syndrome had apparently been observed in some animal testing, although the species of primates tested did not manifest the syndrome. TeGenero, however, felt that this reaction was "not expected," in the human trial.

The Tribune interviewed a survivor of the trial, who stated:

• He believed "he was participating in a fairly standard trial of a painkiller like ibuprofen, for arthritis."
• He said that "the novelty of TGN 1412 never came up in upbeat pre-trial briefing, adding: "I had no idea it altered the immune system.'"
• "At Parexel's orientation meeting there was little time to read the study's 11-page consent form before signing, Rob O. said. Headaches and bruising were listed as potential side effects, as well as the possibility of a severe allergy. But that risk was downplayed."
• Once the trial was underway, the investigators continued to dose subjects even after the first subjects had started to experience adverse effects. "About the time Rob. O's infusion started, at 9:10 am, the first patient had actually passed out in the adjacent room...." charged one of the subjects' attorneys.
• Since the trial, "the companies [TeGenero and Parexel] have been unwilling to meet with the trial subjects or provide more data...."

The Tribune quoted Dr Michael Ehrenstein of University College London, who said that human research on TGN 1412 was "a high risk strategy." Michael Goodyear, described as an oncologist and medical ethicist at Dalhousie University, Halifax, Nova Scotia, Canada, said that the conduct of the trial "raises a number of big red flags."
Nonetheless, Dr Ezekiel Emanuel, Chief of Clinical Bioethics at the US National Institutes of Health (NIH) , said "This is a terrible tragic event but so far I don't see any clear ethical problems." (Note that Emanuel formerly expressed indignation when the NIH made conflict of interest rules more stringent, so that his secretary would no longer be allowed to keep stock holdings in health care companies worth more than US $15,000, as noted in this post.)
In my humble opinion, this newspaper article raises further serious questions about whether research subjects were adequately informed about the nature of the trial and its possible risks, and why the investigators continued to administer the drug after the first subjects had begun to experience adverse effects.
Hopefully, further investigations will afford more transparency, and will lead to improved conduct of trials that put the interests of patients ahead of the imperative to "speed your product through clinical development." (The latter phrase is currently a promise made by Parexel on its web-site.)

Post Title → The TGN 1412 Trial "Raises a Number of Big Red Flags"

A Report Leaves Many Questions About TGN 1412 Unanswered

We previously posted about the disastrous trial, implemented by Parexel International , of a new monoclonal antibody designated TGN 1412, manufactured by TeGenero AG,. All six healthy volunteers who got the antibody soon became critically ill.

Our first post noted that little was known about how the trial was designed, and about who had reviewed the ethical aspects of its protocol. A later post summarized questions posed in a BMJ editorial, including how were research subjects recruited and motivated, what were they told about possible risks, why were healthy volunteers rather than patients recruited, and why were all patients given the drug simultaneously? The BMJ editorial, a Lancet editorial, and our first post all called for more openness and transparency in drug research.

Now the UK Medicines and Healthcare Products Regulatory Agency has issued an interim report. (See news articles in the Times [UK], Nature, and the Boston Globe.) Basically, the MHRA "ruled out contamination, overdose, and procedural problems," as per the Globe. But it revealed nothing more about the trial protocol, nor how it was reviewed. For example, the Globe stated that "Parexel spokeswoman Jill Baker said that she couldn't comment on the design of the trial, but it had been approved by health authories and reviewed by an ethics committee in Britain." None of the other news accounts provided any other answers to the questions above.

The main conclusion of the report was that "the drug TGN 1412 caused an unprecedented and unexpected reaction that did not occur in tests on animals," per the Times. This seems to be stating the obvious. The questions remain whether this unprecedented and severe adverse drug reaction could somehow have been anticipated by perusal of animal testing data or understanding of the science behind development of the drug; or whether the adverse drug reaction could have been reduced by a differently designed or implemented trial?

The Telegraph reported that a lawyer for two of the trial participants is not happy. Ms Ann Alexander said "the MHRA's report gives no detailed information about the pre-clinical trials, about which there has been conflicting information since the trial was suspended."

So there is still little transparency to this trial. We still do not know the results of testing the antibody in animals, the design of the trial protocol, the justification for aspects of the trial design, or who reviewed the ethical aspects of the protocol.

This sad case still illustrates how commercially sponsored pharmaceutical research often remains hidden behind the veils of trade secrecy and business confidentiality. If pharmaceutical companies really want patients and physicians to trust them more, they should start making their human research more transparent.

Post Title → A Report Leaves Many Questions About TGN 1412 Unanswered

More Questions, Few Answers About TGN 1412

The disastrous results of the phase I trial of TGN 1412 (see our most recent post here) has lead to a news article in the British Medical Journal, and opinion pieces in the BMJ and the Lancet.

None of these has important new answers. The Lancet editorial noted that the journal's request for the protocol of the trail was rebuffed by TeGenero, the manufacturer of the TGN 1412, and by the UK Medicines and Healthcare Regulatory Agency (MHRA) as "commercially sensitive."

The BMJ editorial listed the questions raised by this incident, which somewhat parallel the list of thing we did not know about the trial at the time of our first post on TGN 1412. The questions were:

• How were the volunteers recruited and motivated?
• How much accurate information, based on full risk analysis, do volunteers receive?
• How much money is too much, and when does money cloud the judgment needed to evaluate risks realistically?
• Why was the drug tested on healthy volunteers rather than patients?
• Why were all eight volunteers given the drug at the same time? [Actually, only six were given the drug, while two others got a placebo - Ed]
• What information did the ethical and regulatory bodies have before the trial?
• How much do regulatory and ethical bodies have to rely on information from investigators and sponsors, which may be subject to publication bias, rather than truly independent reviews?
• Finally, what does this trial tell us about the degree of transparency througout the process of developing new drugs?

The conclusion to the BMJ article,

This tragedy creates one more imperative for an open culture in medical research, a culture that many fear is increasingly losing its way.

and the conclusion of the Lancet article,

the fact that [dreadful events] ... have occured should lead to maximum transparency to reaffirm trust in clinical trials and their regulation.

mirror the conclusion of our first post about TGN 1412, "research subjects and future patients deserve complete transparency about the drug or device to be tested, and how the testing will be performed and supervised."
Maybe if enough people repeat this sentiment, it will actually have an effect on the increasingly opaque world of drug development and evaluation.

Post Title → More Questions, Few Answers About TGN 1412

An Update on the Tragic TGN 1412 Trial

Our most recent post on the lack of transparency in the trial run by Parexel of TGN 1412, a drug developed by TeGenero, which left all six participants in intensive care with multi-organ system failure, was here.

This trial has generated tremendous media attention. Thus, we now know a bit more about it, but still not much.

According to TeGenero's website, the drug TGN 1412 is a monoclonal antibody that targeted the CD28 receptor on T-lymphocytes. The drug is not meant to destroy T-lymphocytes, but rather to activate the CD28 receptor. According to TeGenero, the TGN 1412 leads to "pronounced T-cell activation and expansion." Thus, unlike some other monoclonal antibodies used to treat cancer, this drug was meant to change the settings, as it were, of the patient's immune system. This was thus a novel therapy, and hence one whose results might have been unpredictable.

Furthermore, the Times (UK) reported that before the trial was carried out, there may have been reasons to be concerned that this drug might have had adverse effects. The Times article quoted Angus Dalgleish, (who holds the Foundation Chair of Oncology at St. George's Medical School in London, but is also the Research Director for Onyvax, a company that also is developing cancer treatments based on immunology), "I would have told the people doing this trial [on TGN 1412] not to do it because the dangers were so great." He cited studies of a "similar drug," "They should have known they would get a meltdown because this drug was hitting exactly the same immune response pathways." (I have not yet been able to figure out precisely which studies he meant.) Furthermore, the Times quoted Jorg Schaaber, "a member of the German drug industry monitoring group Buko Pharma" (whose web-site is here, but appears to only be in German), that monoclonal antibodies like TGN 1412 carry "considerable risks." Finally, it quoted Michael Seed, a Senior Research Fellow at the William Harvey Institute at Barts and the London Hospital and the Queen Mary's School of Medicine and Dentistry, "The danger is that they are messing around with T regulator cells and we don't know what all the T regulator subsets do. Some will switch things on and some will switch things off."

Furthermore, newspaper reports hint at irregularities in how the trial was conducted. The Times (UK) article suggested that the fees paid volunteers were sufficient to be inducements, rather than just payments for time and expenses. It also alleged that in other trials, Parexel, the contract research organization conducting the TGN 1412 trial, used consent forms so long as to be unreadable, and "pressured" volunteers to sign the form with reading it, "because I felt like I was slowing everyone down." Also, it noted that some trial participants may have been professional research subjects, e.g., one, referred to as a "serial human guinea pig," had reportedly made 60,000 pounds sterling in four previous years from participating in drug trials.

An article in the Telegraph (UK) cited a review article on the effects of monoclonal antibodies to CD28 (Hunig T, Dennehy K. CD28 superagonists: Mode of action and therapeutic potential. Immunol Letters 2005; 100: 21-28 )which noted "massive expansion and functional activation of regulatory T-cells by in vivo treatment with CD28 superagonists," but also revealed gaps in current knowledge about what CD28 activation does, and then asked "does it even make sense to talk of informed consent when the experts themselves admit to sugh gaps in their knowledge?"

Thus, there are reasons to suspect that this trial had not been fully thought through, and that it it was not optimally implemented.

Once again, while hoping that six participants in this trial get better, I also hope this tragedy prompts a re-evaluation of our drug testing procedures, and particularly more transparency in all phases of the process.

Post Title → An Update on the Tragic TGN 1412 Trial

A Window on Human Research Done by Contract Research Organizations

The recent tragic and unprecedented results of a Phase I clinical trial of a monoclonal antibody known only as TGN 1412 provide a new window into the issues surrounding the now heavily commercialized world of drug testing.

The outcome of the TGN 1412 tests have received global attention. Briefly, TGN 1412 is a monoclonal antibody developed by the German company TeGenero AG. An initial test on six volunteers was arranged by Parexel International at their facility at Northwick Park Hospital in London, UK. Six volunteers received apparently the same initial dose of the drug, while two others received placebo. Within hours of receiving the drug, all six complained of fever, and severe pain in their heads. They apparently developed severe swelling of their heads and upper bodies, and then developed multi-organ system failure. All were rapidly admitted to the hospital's intensive care unit.

The particular symptom complex these patients suffered seems to be unprecedented. Previous instances in which everybody who received a new drug rapidly developed life-threatening illnesses are apparently unheard of.

The media have been doing their best to investigate what happened, while the UK Medical and Healthcare Products Regulatory Agency (MHPRA) suspended the trial and is also investigating. Based on newspaper reports available so far, though it is striking what is not known about this drug trial.

We know the company designation for the drug, and its general type (a monoclonal antibody, or protein developed to bind to a specific molecule), but nothing more specific. We do not know what the target molecule was for the antibody, the rationale for its potential therapeutic usefulness, or the results of its in vitro (test-tube) or animal testing. Some of the news reports suggested conflicting results of animal studies. For example, one report in the Times (UK) quoted the girl-friend of one of the trial subjects , "They [the drug company] said there was an oversensitivity in monkeys...." Furthermore, "a dog and some animals had died." But the Times also reported that the Chief Scientific Officer of TeGenero, Thomas Hanke, "refused at a press conference to say whether animals had died during earlier tests. 'There has been no issue on the safety of the drug oanimalsls. This is not relevant.'" In addition, Bloomberg News reported that the CEO of TeGenero, Benedikte Hatz, said "these events were completely unexpected and do not reflect the results we obtained from initial laboratory studies...." Finally, the Independent reported a claim by a lawyer for one of the research subjects that "there is confusion about whether the drug had been testsuccessfullylly and safely on animals before the tests on these volunteers."

We know very little about how the trial was designed. The Times reported "the trial protocol had been agreed with the MHPRA and was carried out 'according to strict ethical and regulatory requirements,' per Parexel. The MHPRA yesterday refused to give precise details, citing commercial confidentiality, and questions to Parexel went unanswered." Some reports suggested that all six volunteers got doses of the drug simultaneously. The Times noted that this practice was not condoned by a textbook it consulted, which instead suggested sequential dosing.

We do not know what sort of oversight or review this trial had received. The Bloomberg report quoted Parexel's claim that it uses "standardized procedures for testing a drug in humans for the first time, based on a protocol approved by ethics committees and regulatory authorities." What ethics committee approved this protocol is unclear.

We have previously posted about how clinical research on human subjects has become more and more an enterprise done by for-profit commercial contract research organizations, (like Parexel), and supervised (in the US, at least) by commercial institutional review boards (IRBs). We posted (go here and see links) about various questionable practices by US based commercial contract research organization SFBC International, which is now under investigation by a US Senate Committee and the US Security and Exchange Commission (SEC). Furthermore, a trial immunosuppressantresant drug carried out by SFBC International's Canadian subsidiary resulted in 20 patients and staff members contracting latent tuberculosis.

Current regulations of clinical research on humans in the US were developed in the days when most research was carried out and directed by faculty members at academic institutions. Now most research is funded by commercial firms, mainly drug and device companies. When such research is carried out in academic institutions, it is performed often under contracts that give considerable control to the commercial research sponsors, rather than to the faculty ostensibly principal investigators. Furthermore, most such research is now carried out by contract research organizations, under contract to the drug or device company, and supervised by commercial IRBs also paid by the commercial sponsor.

Human clinical research has profound health and safety implications both for its subjects, and for any patients who eventually take the drug or use the device under study. Given that, research subjects and future patients deserve complete transparency about the drug or device to be tested, and how the testing will be performed and supervised. Such transparency was obviously not in evidence in the trial of TGN 1412. We need to revise regulation of drug and device testing on human subjects to make it sufficient to protect research subjects and patients in the current era of globalized commercial research.

Post Title → A Window on Human Research Done by Contract Research Organizations

Consequences of SFBC International's Clinical Trials: 20 People Get Tuberculosis

We have posted before about the troubles of contract research firm SFBC International We started by posting about allegations that private, for-profit clinical research firms, including SFBC International, supervised by for-profit institutional review boards (IRBs), were doing sloppy and shoddy work. We then noted allegations that SFBC International had tried to threaten or intimidate research subjects who talked to reporters about such poor research practices. Furthermore, we discussed how a review commissioned by the company found that a top executive, Jerry Seifer, SFBC International's Vice President for Legal Affairs, threatened participants in clinical studies who had talked to the press with deportation. Seifer, it turns out, had been the subject of past regulatory sanctions by federal regulators. In addition, study participants in a trial of an immunosuppressant drug carried out by the firm's Canadian subsidiary, SFBC Anapharm, acquired tuberculosis after exposure to another participant with active disease, despite their complaints to Anapharm staff. Most recently, we noted that Seifer had resigned, and the company's stock price had fallen.

There is an update on the human consequences of SFBC International's (mis)management of clinical trials. 20 people have contracted latent tuberculosis after being exposed to a patient with active TB during a trial of an immunosuppressant agent at SFBC International's SFBC Anapharm Canadian testing facility, according to CTV. Bloomberg News noted that 11 were employees of the company, while the remainder were patients in the study. CTV suggested that all would have to undergo nine months of therapy (presumably to suppress their latent TB and lower the likelihood it would become active in the future.) An investigation by Health Canada is ongoing. Bloomberg news could not get officials of SFBC International nor of Isotechnika, which made the trial drug, to comment.

CTV interviewed Professor Trudo Lemmens of the University of Toronto, who summed up the major issues.

The pharmaceutical industries want to have drugs on the market and they want to have them on the market quickly.
So they contract research organizations to do the human subject research for them. These companies are paid for the outcome, which is to have the trials done as quickly as possible, and so they have significant financial incentives to recruit human subjects and research them very quickly.

Lemmens also noted that commercial ethics board may not do a good job policing such trials.

While many may be doing a good job, it's possible in the current regulatory system to shop for the most convenient, the fastest and the perhaps most lenient research ethics boards which imposes the least restrictions on your clinical trial.

In response to this case he suggested,

The current Quebec situation underscores the need for the creation of a watchdog to oversee the industry, as well as stronger federal and provincial regulations to establish guidelines and requirements for research ethics boards, Lemmens said.

It sounds like parallel solutions are needed in other countries.

Sadly, this case provides yet another reminder about how skeptical we must be about much of the clinical research now going on that is financed, and now often performed and supervised by loosely regulated corporations. And that is coming from a proud supporter of evidence-based medicine who has long advocated for clinical research, and who put my money where my mouth is by signing up as a trial subject. This sort of story really hurts.

Post Title → Consequences of SFBC International's Clinical Trials: 20 People Get Tuberculosis