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.

More Stories About the Fall of the FDA

Related, disturbing stories about how far the US Food and Drug Administration (FDA) has fallen have just come out.

Ketek Approval

We previously posted about the ill-fated clinical trial, study 3014, of the antibiotic telithromycin (Ketek) made by Sanofi-Aventis, run by Pharmaceutical Product Development Inc. (PPD). Problems with the trial included fabrication of data at one clinical site, and allegations of manipulation of data at another. The physician in charge of the first site was convicted of mail fraud, and the physician in charge of the second had his license suspended. Although the results of this trial were never published, it still crept into the clinical literature: it was cited in a review article in the New England Journal of Medicine. We also posted about how US Senator Charles Grassley, (Republican - Iowa), chair of the Senate Finance Committee, alleged that the FDA was covering up the process it used to approve Ketek.

Now the New York Times reported that Dr David Graham, now known as an internal FDA whistle-blower, and other FDA scientists challenged the initial approval of Ketek, to no avail. Graham wrote:

It’s as if every principle governing the review and approval of new drugs was abandoned or suspended where telithromycin is concerned.

The Times reported that four other agency officials, including Dr Charles Cooper, Dr David Ross, and Dr Rosemary Johann-Liang, "expressed serious reservations about Ketek."

Senator Grassley commented:

It’s no surprise to learn that the F.D.A. didn’t listen to Dr. Graham on the dangers of Ketek.

The F.D.A. has made it their business to discredit Dr. Graham and others who aren’t willing to cater to the drug companies.

FDA spokesperson Susan Bro countered, "Every issue or question raised during the Ketek review process and subsequently since approval has been rigorously reviewed by the nation’s best physicians, statisticians and epidemiologists both internal and external to the F.D.A."

Vioxx Aftermath

The Associated Press reported (here in USA Today) that Senator Grassley also "asked the inspector general at the Health and Human Services Department to probe whether the Food and Drug Administration and Merck acted in concert to call into question the safety findings made by Dr. David Graham, an FDA drug safety official." The report continued,

In a letter Wednesday, Grassley cited handwritten notes made by the Merck employee documenting an Oct. 13, 2004, conversation with the FDA official that suggests the two collaborated.
The FDA official mentioned an 'opportunity to get (the) message out' on Graham, a longtime employee of the agency, and provide journalists with a company critique of him, according to notes quoted in the letter.

'It is no secret that Dr. Graham was and is a critic of the FDA. However, that does not mean the FDA should scheme with drug sponsors to discredit its own employees,' Grassley said in the letter to Inspector General Daniel Levinson. The FDA, Grassley said, must maintain a 'clear, bright line between the regulated and the regulator.'

This time, FDA spokesperson Bro "had no comment."

Further details provided by AP were:

FDA e-mails seen by The Associated Press indicate that the agency shared in advance with Merck details about a presentation that Graham was to make in France in August 2004 about the dangers of Vioxx. The e-mails suggested that such a practice was commonplace.

Merck then issued a statement saying it stood by the safety of Vioxx. An FDA spokeswoman at the time said removing the drug was 'not on the table.'

The notes excerpted by Grassley indicate the FDA later went even further in helping Merck rebut Graham's work.

The FDA's Dr. Brian Harvey suggested to Merck's Dr. Ned Braunstein 'an official rebuttal on Graham,' according to the notes, which were admitted as evidence in a federal Vioxx trial.

Graham said he was 'quite shocked' to learn about Braunstein's notes.

FDA Employee Survey

The Baltimore Sun reported on a survey by the Union of Concerned Scientists of FDA scientists. The survey was sent to 5918 people, of whom 997 responded. The Sun reported that key findings were:

• "Fifteen percent of the 997 FDA scientists who answered the questionnaire said they were asked to keep information out of agency documents or alter their conclusions for nonscientific reasons."
• "Nearly one in three said the FDA doesn't routinely provide complete and accurate information to the public."
• "37 percent said the agency's leadership wasn't as committed to product safety as to approving products for sale."
• "Fifty-two percent said their job satisfaction had fallen the last few years, and 70 percent said the agency lacked the resources to carry out its mission."
• "two out of five scientists saying superiors didn't consistently stand behind staff whose "scientifically defensible positions" might have been politically controversial."
• "Eighty-one percent of respondents said the agency needed to strengthen its oversight of drugs after they go on sale."

Responses were bi-partisan. Senator Barbara A Mikulsi (Democrat - Maryland) responded, "This agency has been politicized and degraded. Many FDA employees don't feel the FDA is doing enough to protect the public's health and are afraid to speak candidly about it." Senator Grassley responded that the FDA needs "major overhaul and a culture change at the highest levels." He also said it "needs to re-establish its relationship with its own scientists and distance itself from the drug industry. The FDA needs to get rid of its mindset that it's a facilitator for the drug industry and become regulator once again. The FDA's focus should be only on science and the public good."

Spokesperson Bro responded by criticizing the "scientific rigor" of the survey, and charging "This is a counterproductive exercise based on leading questions and innuendo. For centuries, science has depended on rigorous and disciplined processes to distill truth from exploration and debate -these principles above all others guide our daily work at the FDA on behalf of the American public health."

By the way, regarding technical issues about the survey: I agree that a response rate of less than 20% does raise concern about the generalizability of the results of the survey. However, given the content of the responses (and given the content of some written comments made on the sruvey), these results are still very disturbing. And I'm not sure on what Ms Bro's charge that the survey questions were "leading" was based.
Unfortunately, these stories make it even more imperative for doctors and patients to be extremely skeptical about what they are being told about pharmaceutical products, even by the formerly respected FDA.
These stories added together suggests that Senator Grassley's call for a complete overhaul of the FDA is on target. Unfortunately, the FDA, once regarded as a paragon of integrity (albeit one that may have been ponderous, bureaucratic, and sometimes inefficient), seems to have fallen into the same muck that too many other health care organizations, from hospitals to to managed care organizations to pharma and device manufacturers now occupy. Thus now doctors and patients must be extremely skeptical about nearly anything they hear about health care when it is said by someone who could possibly have vested interests other than improving patient care or the integrity of science.

We have a lot of overhauling and much-raking to do. Meanwhile, we have to work in a health care system in which doubt, ambiguity, and skepticism rule.

NOTE: See the takes on this by Pharma Gossip here, here, and here. See a related story by Dr Aubrey Blumsohn on the Scientific Misconduct blog here.

Senator "Smells a Coverup" About How FDA Approved Ketek

We previously posted about the ill-fated clinical trial, study 3014, of the antibiotic telithromycin (Ketek) made by Sanofi-Aventis, run by Pharmaceutical Product Development Inc. (PPD). Problems with the trial included fabrication of data at one clinical site, and allegations of manipulation of data at another. The physician in charge of the first site was convicted of mail fraud, and the physician in charge of the second had his license suspended. Although the results of this trial were never published, it still crept into the clinical literature: it was cited in a review article in the New England Journal of Medicine.

The Washington Post just reported on the failed efforts of US Senator Charles Grassley, (R-Iowa), Chair of the Senate Finance Committee, to get more information about how the US Food and Drug Administration (FDA) approved Ketek. The story is certainly colorful:

The agency acknowledges that there were major improprieties in a 25,000-patient clinical trial done for the drug's developer, Aventis. One person has gone to prison for fraud in connection with that trial, data from several other trial sites have been discarded because basic standards were not met, and the agency told the company it could not say anything about the trial results on its product label.

Nonetheless, the FDA allowed Aventis to use much of the data to support the company's contention that the drug is safe. It also allowed Aventis to present the data to an FDA advisory panel without telling its members of the widespread fraud allegations clouding the trial. Documents show that some FDA employees argued that the trial should have been discarded because of the company's inadequate oversight.

Grassley has pressed to speak with an agent in the FDA's Division of Scientific Investigations who, he said, 'is key to understanding what the FDA did when it became clear that the safety study required by the FDA in order to approve the drug was fraudulent and faulty. Did FDA managers turn a blind eye and let the drug maker off too easy, or did the FDA do the right thing?'

In reply, FDA spokeswoman Susan Bro said: 'We would like to do whatever we can to help [Grassley] fulfill his constitutional duty as well as ours to the American people. However, we will not compromise an ongoing investigation.'

After months of trying to get firsthand information from a government official familiar with a controversial new antibiotic, Sen. Charles E. Grassley (R-Iowa) marched into the Department of Health and Human Services headquarters yesterday asserting his congressional right to receive the data.

After a brief meeting with senior HHS and Food and Drug Administration officials, Grassley departed empty-handed and angry.

'This is extraordinary for me,' the senior Republican said outside the headquarters. 'I haven't had to go to an agency like this since 1983 to get information I requested.'

'I smell a coverup.'

'I'm tired of the runaround,' he said after leaving the HHS headquarters. He said that he told the agencies' officials that 'I know it's probably not your intent to protect companies, to cover for companies.'

'But I said that every time that you stand in the way of information getting out that ought to be public, that's the impression you give the American people.'

It is noteworthy how this story has evolved. Originally, it seemed to be about sloppily supervised research whose unpublished results still had influence. Now the story seems to be morphing into one that includes allegations of government cover-ups of information about how questionable commercially sponsored clinical research may be. The moral is that patients and physicians need to be extremely skeptical about the results of commercially sponsored clinical research.

As we have said before, doctors and patients ought to base choices of tests or treatments on honestly done, honestly reported clinical research. Depending on poorly executed or misleadingly reported research will lead to bad decisions and bad outcomes. Furthermore, failure to honestly report the results of clinical research betrays the trust of the human volunteers who willingly participated in the research partly to help add to scientific knowledge and improve clinical care.

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."

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.

California Nightmares - More Troubles at UC, and Big Conflicts of Interest at UCSD

It is getting hard to keep up with all the stories about the University of California (UC) system, most about the lavish pay and perks given to its top managers, and the rising tide of editorial criticism of the huge university. At the same time, UC-Irvine has been accused of mismanaging its liver, bone marrow, and kidney transplant programs, and of hiring a resident after his father gave the hospital a large contribution (see most recent post here).

Here are the latest additions to this on-going saga:

Undisclosed Severance Packages - The San Francisco Chronicle found that many University of California managers have received previously undisclosed severance packages even after they voluntarily resigned. "While the program was approved by regents, details about the individual payments and who received them have never been publicly reported." Although the program is only supposed to be open to executives without simultaneous faculty appointments, or those hired before 1996, the University seems to have made various exceptions. For example, UC- Santa Cruz Chancellor Denice Denton is on this plan, although she is not a faculty member and was hired after 1996. Denton is well known for receiving one particularly striking perk: the University constructed a $30,000 run for her dogs at her executive mansion (see the Modesto Bee). Also, "In another case, UC quietly worked out a similar severance arrangement for a dean who was not eligible for the program, UCSF's David Kessler. Many UC managers have received severance packages, including some from Health Sciences, and some were from UC-Irvine.

No Confidence Vote at UC-Davis - The San Francisco Chronicle also reported on a petition calling for no-confidence vote in the Chancellor of UC-Davis, Larry Vanderhoef, in the Academic Senate. This was inspired by Vanderhoef's agreement to give former Vice Chancellor Celeste Rose a settlement that included $205,000 yearly for two years without any work responsibilities after Vanderhoef's attempt to fire Ms Rose, and her complaints of gender and racial discrimination. Simultaneously, in another setback for UC-Davis, its medical center has lost its designation as a magnet hospital for nursing excellence (per the Sacramento Bee).

Investigation into Incidents at UC-Irvine - The Los Angeles Times also reported that UC-Irvine will start scrutinizing all refusals of kidneys for transplant after media reports suggested that its medical center has had an unusually high rate of refusal and low rate of transplants (see our post here). Also, Medical School Dean Thomas C. Cesario announced that a panel of associate deans would review the case of a admittance into a special residency slot of a physician whose father made a large donation to the hospital. The Times noted that "Cesario approved the creation of the position and the selection .... [UC-Irvine spokeswoman Jennifer] Ward was unable to explain why Cesario was chosen to appoint the [investigative] panel [to investigate Cesario's own actions]."

But that's just the warm-up for today's main act....

Ten Corporate Boards for the UC - San Diego Chancellor'

UC - San Diego Chancellor Marye Anne Fox joined the legion of lavishly compensated UC executives when a report appeared that she received an undisclosed bonus of $248,000 when she was hired to compensate for a sabbatical she had not taken before she was hired.

On top of that, the San Diego Union-Tribune disclosed that Chancellor Fox serves on the board of directors of ten different for-profit and not-for-profit corporations. "In the past year, she received cash and stock worth at least $339,260 from her board memberships.... In addition, she receives more than 12,000 shares in stock options from the public companies annually. In the past 10 years since she began serving as a board director, Fox has accumulated stock and stock options worth more than $1 million." Fox's salary is $359,000, so it appears she collects more income from being on corporate boards than from being Chancellor. "Last year, Fox was expected to attend 50 corporate board and committee meetings." The Union-Tribune noted that "the average corporate board member devotes 191 hours annually in preparation time, travel and attendance on each board...." Based on that figure, membership in 10 boards would require 1910 hours a year, nearly 40 hours a week.

Furthermore, while Fox as Chancellor is responsible for the UC-San Diego School of Medicine and UCSD Medical Center, she sits on the boards of two for-profit health care corporations.

One is Boston Scientific Corp (some of whose travails were mentioned in this recent post). Boston Scientific is a major manufacturer of medical devices. Presumably, UC- San Diego medical center is a major user of such devices.

Chancellor Fox also sits on the board of Pharmaceutical Product Development Inc., which describes itself as "a leading global contract research organization providing discovery and development services, market development expertise and compound partnering programs. Our clients and partners include pharmaceutical, biotechnology, medical device, academic and government organizations."

Fox justified her board memberships thus, "the real benefit is the university's profile is enhanced by board service by chancellors and presidents." She also "said her experience as a director helps here management skills and provides important insights into private industry."

On the other hand, one UC- San Diego professor said "I would worry about whether she's either compromising her fiduciary responsiblities to the people of California or to the corporations and nonprofits she's serving."

In particular, in my humble opinion, having ultimate leadership responsibilities for a medical school and medical center, while also having ultimate fiduciary responsibilities for the management of a medical device company and a contract medical research company amounts to the biggest conflicts of interest I have ever seen.

This case illustrates why I am skeptical of the widely publicized approach to conflicts of interest recently published in JAMA by Brennan et al (see post here). Brennan and colleagues had zero tolerance for any financial relationships between physicians and drug and device companies. Their rationale was:

Social science research demonstrates that the impulse to reciprocate for even small gifts is a powerful influence on people's behavior. Individuals receiving gifts are often unable to remain objective; they reweigh information and choices in light of the gift

Brennan and colleagues were silent, however, about conflicts of interest affecting managers of health care organizations, yet authorized the managers of academic medical centers to enforce such zero tolerance on physician faculty.

If applied to UC -San Diego, this approach would authorize management to condemn a junior faculty member for accepting a coffee cup with a Boston Scientific logo, while the managers answered to a Chancellor who was a Director of Boston Scientific.

If even small gifts from a corporation have a powerful influence on behavior, what effect would one expect from being made a director of the corporation?

It seems hypocritical to have zero tolerance for trivial corporate gifts to medical school faculty, but infinite tolerance for lavishly remunerated, highly responsible corporate positions for university management.