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.

More Drug Secrets: the Cymbalta/ Yantreve Case

Jeanne Lenzer has written a disturbing article in Slate about how the US Food and Drug Administration's (FDAs) rules about trade secrets may obscure information about adverse effects of drugs.
To summarize her findings.... Eli Lilly manufactures the selective serotonin reuptake inhibitor (SSRI) duloxetine under the brand name Cymbalta to treat depression in the US. However, Lilly also was developing the same compound, duloxetine, under the brand name Yantreve as a treatment of urinary stress incontinence.
During a trial of Yantreve, Traci Johnson, a young study participant who had no history of depression, committed suicide. An FDA investigation of her death was done, but could not determine whether it was due to the drug. Lilly later abandoned its testing of Yantreve as a treatment of depression.
Under current FDA procedures, data submitted to the FDA about drugs that are never marketed are considered "trade secrets," and cannot be revealed even under the Freedom of Information Act. The rationale, as described by Lenzer, is that "failed efforts at drug development need protection lest entrepreneurs suffer a competitive disadvantage when other companies aren't forced to expend the same time and money exploring dead ends." The FDA apparently applies this policy even when the withdrawn drug is chemically identical to other drugs on the market (and hence data about adverse effects of the withdrawn drug ought to apply to the same compound marketed under different names.)
Lenzer was able to obtain information, at least partially from anonymous sources, about suicides by patients in trials of Yantreve or Cymbalta that were not available publicly from the manufacturer or the FDA. Her anonymous sources also told her that "duloxetine causes suicidal tendencies in patients who took the drug for incontinence - and who were not depressed."
Only after Lenzer published an article in The Independent (UK) about the issue, did the FDA add information to its web-site that the rate of suicide attempts by patients taking duloxetine in trials of stress urinary incontinence was double that of patients taking placebo.
Lenzer's conclusion is worth quoting:

The use of trade-secret laws to conceal deaths and serious side effects linked to drugs has the obvious flaw of putting profits before public health. It also subverts the covenant between researchers and study volunteers. Subjects like Traci Johnson are told that even if they do not personally benefit from a new drug, the scientific knowledge gained from the study in which they've participated will benefit others. The volunteers should be told instead that scientists will learn about their experiences only if it's good news for the drug they're helping to test.

Please see our related posts on keeping drug trials secret here.

Using Drug Supply Contracts to Censor Negative Drug Utilization Review and Counter-Detailing

The Wall Street Journal reported (see summary here) how at least one drug company places restrictions on negative communications to physicians about its product in contracts that give discounted pricing to insurers and hospitals. In particular, Eli Lilly & Co offers its new anti-depressant Cymbalta ( duloxetine HCl) at a discount but with provisions that bar "negative D.U.R. (drug utilization review) correspondence to physicians," and "negative educational counterdetailing." Thus the hospital or insurer would be contractually prohibited from communicating with doctors in ways that might discourage them from prescribing the drug.
According to the Journal, Tarra Ryker, a Lilly spokeswoman, "says the Cymbalta contract isn't meant to stop communications that are 'backed up by clinical data' and 'presented in a fair and balanced manner.'" Her justification was that "there are a lot of things that are said to physicians and prescribers that in a lot of cases cannot be backed up with scientific evidence."
She also noted that Lilly has similar contract provisions in contracts to sell Symbyax (a combination of fluoxetine and olanzapine) and Zyprexa (olanzapine). Lilly's practices apparently are not unusual. A Pfizer spokesman, Jack Cox, said, that counterdetailing "language is probably in everyone's contracts."
I have previously posted about secrecy in health care (here). It may be that drug utilization review and counterdetailing are sometimes biased. But figuring that out should be up to physicians. And drug companies have plenty of opportunities to get their own messages to physicians. Impeding the free flow of information to physicians about drugs and other aspects of health care does their patients no favor.