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"

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

Some Consequences for SFBC International

We have posted frequently about the troubles of SFBC International, a for-profit clinical research firm.

Last month, we posted 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.

There have been some consequences for all this. The South Florida Business Journal reported that Seifer has resigned, although SFBC International gave no reason for his departure. Also, the Miami Herald reported that the company has hired investment banks "to explore strategic alternatives," which the newspaper suggested meant looking for buyers for the firm, whose stock price has dropped from $41 to $15.

Commercial research firms are carrying out an increasing proportion of clinical research. Doctors and patients depend on such research when making decisions about which tests and treatments to employ. Thus, the troubles of SFBC International, a major player in the commercial clinical research world, raise yet another set of worries about the integrity of clinical research.

However, although these troubles have attracted the attention of legislators and investors, they have caused few ripples in health care circles. The anechoic effect lives.

Post Title → Some Consequences for SFBC International

More Shoddy Work by Commercial Research Firm

Last month, we posted about allegations that private, for-profit clinical research firms, supervised by for-profit institutional review boards (IRBs), were doing sloppy and shoddy work. We then noted allegations that one such firm, SFBC International, had tried to threaten or intimidate research subjects who talked to reporters about such poor research practices.

SFBC International is now back in the spotlight.

On one hand, the Miami Herald reported that "outside counsels" hired by SFBC International to review its operations had partially exonerated their clients. Some of the "outside counsels'" arguments were:

• That the apparent conflict of interest raised because the wife of a Vice President of SFBC worked for one of its IRBs, was less serious because she did not vote on panels that reviewed SFBC studies. Replied Ken Goodman, of the bioethics program at the University of Miami, "this doesn't clear the arm's length test."
• Responding to allegations that SFBC International is a "recruiting mill" using "poor desparate people," the counsels said "our review revealed that SFBC requires valid Social Security or tax identification numbers, in order to ensure that its participants are legal United States residents."
• Responding to allegations that SFBC International's CEO threatened research participants who talked to the press with deportation, the counsels noted that it was really Jerry Seifer, SFBC International's Vice President for Legal Affairs, who said "Well, if you don't have your immigration, don't you know you can get deported?" "If you're illegal, immigration is down the street on 79th street." Also, "I have a friend in the INS and I can ask my friend and I can deport you guys." [The Miami Herald just reported that Seifer, who just bought a $15 million dollar house and a Rolls-Royce jointly with SFBC International chair Lisa Krinsky, settled charges by the US Federal Trade Commission that he misrepresented wireless cable TV licenses he was selling to consumers. He also was fined and subject to a cease and desist order by the Commodities Futures Trading Commission.]

Although SFBC International Lead Director Jack Levine said that this reporte exonerated the company, per Bloomberg news, it sounds to me like the counsels were just quibbling about the prior allegations.
Furthermore, Bloomberg News has just reported more evidence of shoddy, sloppy work done by SFBC International.
SFBC International's Canadian subsidiary, SFBC Anapharm Inc, was running a trial of an immunosuppressant drug, ISA 247, for Isotechnika Inc. At their Montreal test center, patients were to be confined to the center 24 hours a day for a total of 31 days, for which they would earn Canadian $6800, most to be paid after the full 31 days.
One patient, identified only as Moshen, was confined in a double room with a man from Haiti, whom Moshen described as "lethargic," and coughing up blood. Despite Moshen's multiple complaints to SFBC Anapharm Inc. staff, the patient remained in the room for eight days. Moshen was assured that he was "okay."
He wasn't okay. He later turned out to have active tuberculosis (TB). Moshen and eight other study participants have now tested positive for latent TB. SFBC Anapharm staff did not initially test Moshen's room-mate for TB. Even though the study protocol involved an immunosuppressant drug that could activate latent TB, the study protocol did not require prospective subjects to be screened for TB by skin PPD testing or chest x-rays.
On learning that he had latent TB presumably acquired from his room-mate during the study, Moshen said "I was shocked." "They never apologized. They don't care. They don't give a damn."
The study was ostensibly supervised by a for-profit IRB, Aurora. Its argument for not requiring TB testing of study participants was since Montreal has a large Haitian population, "many potential participants would likely tested positive and have been excluded from the trial. 'It's clear the test has not utility,' said [Aurora President Jack] Corman." Responded Professor Steven Miles of the University of Minnesota, "That statement doesn't make any sense."
SFBC International's lawyer reacted to Moshen's anger by saying, "Anapharm very much regrets that the subject feels this way. They hope he recalls that Dr. Larouche apologized to him and to his fellow volunteers." SFBC International, however, has also asked study participants to sign a waiver releasing the company from any claims. Trudo Lemmons, a Professor of Law and Bioethics at the University of Toronto, described the requests for a waiver, "outrageous," and "unethical."
Have we fallen so far? Clinical research is the only way to tell what tests and treatments really do for patients. Clinical research was once an honorable undertaking, done mainly at teaching hospitals and academic medical centers. As a physician, I have taught about the importance of clinical research and how best to use its results to make better health care decisions. I have urged patients to enter clinical trials. Putting my money where my mouth was, I was the proud participant in one major trial (and just had my five-year follow-up visits for it.)
But we have noted again and again how commercial research sponsors may manipulate how clinical research is designed, carried out, analyzed, and disseminated. Now I would be very cautious about suggesting anyone should enroll in a clinical trial, especially if it has commercial sponsorship.
And hearing about these outrageous practices perpetrated by commercial research firms with the acquiescence of commercial IRBs, I sadly would not suggest that anyone enroll in a trial run by a for-profit research firm. We have fallen so far.

Post Title → More Shoddy Work by Commercial Research Firm

Commercial Clinical Research Firm Accused of Intimidating Study Subjects Who Talked to Reporters

Bloomberg News has published another article on the commercial clinical research industry, this time focused entirely on the firm SFBC International. We had posted here about a previous report by Bloomberg that alleged conduct of clinical research by such commercial firm was sloppy and shoddy, with minimal oversight by commercial institutional review boards (IRBs).

The new report begins by quoting SFBC International Chairman Lisa Krinsky MD, who completely contradicted allegations made in the first article, "Approximately 99 percent of the information that was documented regarding SFBC is a total fabrication, and the remaining 1 percent was entirely misquoted."
The report then alleged that SFBC International intimidated study subjects who may have provided material to Bloomberg for its first article.

• "When the two [study subjects] arrived and identified themselves, they were taken to an office, where they were met by [SFBC International CEO Arnold] Hantman [CPA] and other SFBC officials, the drug test participants says. CEO Hantman asked the participant if he was an illegal alien, and then threatened to call immigration officials who could arrest and deport him, the participant says. The test participant says he first told Hantman the truth: that the reporter had properly identified himself and had told him he was researching an article about clinical trials. The drug trial participant says Hantman asked that he sign a statement saying the reporter hadn't clearly said he would publish an article or use his photograph. In a taped interview, the drug test participant says he agreed to say what Hantman wanted because the CEO told him that was the only way to prevent him from being arrested and deported. "
• "The drug test participant says that that when he returned to SFBC for part of a clinical trial, a person at SFBC asked him to sign another version of the statement. The second piece of paper said the reporter never identified himself as a journalist and didn't say he was preparing an article. The participant says he signed the second statement because he would have signed anything just so he would be allowed to leave. The second paper was false, he says."
• "Another test subject says an AFBC executive told him that SFBC wouldn't pay him for a clinical trial he had participated in and would alert immmigration officials if he didn't sign a statement saying the reported hadn't told him he would publish an article or use his photo. He says the executive said SFBC would pay him for the clinical trial if he signed the paper. The test participant says he agreed to endorse the false information because he thought it was the only way he could leave the test center and avoid being turned over to immigration officials."
• "A third drug test participant says he went to SFBC 10 days ago to try to enroll in a clinical trial because he needed the money. He says that after he identified himself, a man who said he worked for SFBC security told him to wait in an office. Eventually [CEO] Hantman came into the room and screamed at him with curse words, the participant says. A group of SFBC employees joined Hantman in questioning about how he knew the reporter. Hantman said he would never allow him to be paid for a clinical trial again.... Hantman also threatened to investigate the participant's immigration status, he says. The CEO also said he many look into whether the participant was paying his taxes to the Internal Revenue Service, the participant says."

What a way to run clinical research projects.
In an article in the South Florida Business Journal, SFBC said, "The assertions from 'anonymous sources' concerning coercion and threats by SFBC employees, including contacting immigration authorities, are basesless. In fact, Arnold Hantman, chief executive officer of SFBC International, has never met with any of the participants contrary to the reporting in the article, and, to the best of his knowledge, none of the participants have ever met him." Furthermore, "the company said that it told participants they will not be allowed to take part in further SFBC trials, but that was because the participants told Bloomberg they falsified forms and presented false government identification. The participants also violated the confidentiality agreement that is part of the consent form process, SFBC added."
So at the moment, we have two completely different versions of what happened. Bloomberg reported that SFBC International intimidated its study subjects into signing false documents about their discussions with news reporters. SFBC International completely denies these accusations, but in doing so acknowledged that they were using study subjects who had falsified data forms, and that they had required study subjects to sign confidentiality agreements, and practice almost unheard of in clinical research done in academic settings.
The new Bloomberg article also included strong condemnations of the alleged way SFBC International conducts research. For example, from Arthur Caplan, from the Center for Bioethics at the University of Pennsylvania:

It's clearly beyond the pale to bully and coerce people because they reported ethical violations. It's simply heinous to try and cover up misdeeds with these actions.

From Senator Charles Grassley, Chair of the Senate Finance Committee:

The process which some of these companties are going through to test drugs on human beings is putting in jeopardy the life, and sometimes even taking the life, of some of these people.

From Adil Shamoo, Professor of Biochemistry at the University of Maryland Medical School, and co-founder of Citizens for Responsible Care and Research:

If this happened, it's awful, unethical, and inappropriate. Oversight and monitoring of clinical trials is very poor. This is further evidence that the system for human subject protection is very broken.

Again, even if one accepts the SFBC International version, major questions have been raised about how commercial firms carry out clinical research. This suggests that physicians and patients need to exercise extreme skepticism about the results of such research and how, or whether it should be applied to clinical care.

Post Title → Commercial Clinical Research Firm Accused of Intimidating Study Subjects Who Talked to Reporters

Clinical Trials Performed by Commercial Firms, and the Commercial IRBs that Oversee Them

Bloomberg News published an investigative series (see links here and here to the version in the Seattle Times) about commercial firms that perform drug trials and the commercial institutional review boards (IRBs) that are supposed to supervise them.
The articles noted that most (75%) of US drug trials are now done by commercial firms, rather than by academic researchers. In 1991, 80% of trials were done in academia. Most of these trials have been approved by commercial, rather than academic IRBs.
This arrangement may have inherent conflicts of interest. For example, former New England Journal of Medicine Editor Marcia Angell charged, "the fundamental problem is a system in which investor-owned businesses have control over the evaluation of their own products. Oversight of clinical trials is too important to leave in the hands of drug companies and their agents."
The Bloomberg News articles suggest that there are major problems afflicting the conduct of these commercial trials. Visits by reporters to a 675-bed trial site in Miami owned by SFBC International revealed the shoddy condition of its physical plant (a bathroom with "chipped white tiles [which] reeks with urine; its floor is covered with muddy footprints and paper towels.")
The reporters suggested that trial subjects are frequently poor. They may ignore study rules to forego alcohol and narcotics. Most trial participants stated that "they barely read" informed consent documents. Reporters noted that "participants in the Miami clinical trials openly talk about how they violate SFBC rules intended to protect the integrity of the research findings."
Ken Goodman, the Director of the Bioetics Program at the University of Miami, visited the SFBC International Center, and declared

The setting is jarring. It's an eye-opener. Every one of these people should probably raise a red flag. It these human-subject recruitment mills are the norm around the country, then our system is in deep trouble.

The reporters reviewed FDA records that also suggest that commercial trial centers "have used poorly trained and unlicensed clinicians." They "sometimes have incomplete or illegible records. In California and Texas, clinicians have used themselves, staff or family members as drug-trial participants."
Dr. Joanne Rhoads, who directs the FDA Division of Scientific Investigations, noted, "unfortunately, I don't think it's been recognized how important it is that people who actually conduct the trial be trained. We oftentimes see people with no qualifications whatsoever, but they'll go to a one-day training course and they call themselves a certified study coordinator."
The reporters also suggested that oversight by commercial IRBs is weak. For example, Western IRB, which is responsible for overseeing 17,000 US trials, had approved trials whose investigators ended up convicted of "lying to the FDA and endangering trial participants." Leaders of commercial IRBs have been accused of conflicts of interest. For example, Bloomberg News noted that Southern IRB, which has approved SFBC International's trials, is owned by Alison Shamblen, wife of the SFBC International vice president of clinical operations, E. Cooper Shamblen.
Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, commented,

This whole world gives me hives, this privatized review process. They've had conflicts of interest since the beginning.

We previously have posted about how commercial research sponsors may try to manipulate the design, conduct, and reporting of studies to increase the likelihood of results favorable to their interests. These concerns mainly applied to studies done in academic settings.
These disturbing articles suggest that we should be even more skeptical about trials conducted by commercial firms.

Post Title → Clinical Trials Performed by Commercial Firms, and the Commercial IRBs that Oversee Them