Practicing (Clinical Trials) Medicine Without a License

Another story of dubious clinical research, this time reported by the St Petersburg (Florida, US) Times:

Vladimir Martin called himself 'doctor' and ran 17 clinical trials of new drugs for major pharmaceutical companies before one patient noticed he didn't have a medical license.

The patient alerted the St. Petersburg Times, whose resulting story led to a state investigation. On Saturday, Martin, 43, was arrested on charges of practicing medicine without a license. He was later released from the Pinellas County Jail on $10,000 bail. The felony charge carries a maximum sentence of five years in prison and maximum fine of $5,000.

The Clearwater man, who changed his last name from Kossatchev after moving to Florida in 2003, went to medical school in the former Soviet Union and practiced in a hospital in his native Ukraine.

Ruth Weber, a 74-year-old Clearwater resident, told the Times in April 2008 that the man who called himself Dr. Martin enrolled her in a study for lower-back pain and adjusted the dosage of her medicine. Only licensed physicians are supposed to conduct such activities. Patients in the study were randomly selected to receive a new Johnson & Johnson painkiller called tapentadol, a placebo or the potent narcotic oxycodone.

Though Dr. Robert Lee Jackson, a Clearwater osteopath, was listed by the FDA as the physician conducting the study, Weber said she never saw Jackson. In weekly visits to Alliance Medical Research Group on Belcher Road, Weber said it was Martin who drew blood, doled out medication and, at one point, doubled her dosage.

Martin also conducted electrocardiograms on Weber, although his techniques were so rusty the electrodes kept slipping off, she said. Weber eventually dropped out of the study when she saw no improvement for her back pain.

A second woman, Ann Reed, told investigators she also responded to an ad for a drug study trial at Alliance Medical Research. Martin took her blood, listened to her heart and gave her medications, Reed said. Martin sometimes had to stick her four times to draw blood, she said.

Like Weber, Reed said she never saw Jackson during her trial, which involved 13 visits between May 2007 and March 2008.

Greg Panico, a spokesman for Johnson & Johnson, said the company audited Alliance Medical after the Times' story and submitted its findings to the FDA. He declined to discuss the nature of the report, but said the drug company is no longer working with Alliance Medical.

Panico also said data collected in the tapentadol study at that site was not submitted to the FDA.

The drugmaker said it reported its findings to the Sterling Institutional Review Board in Atlanta, which had been hired by Johnson & Johnson to oversee patient safety during the trial.

Despite losing the Johnson & Johnson trial, Martin told investigators in July that he was conducting four other drug studies.

A little Google searching turned up another example on ClinicalTrials.gov of a commercially funded clinical study for which the Alliance Medical Research Group enrolled patients. This was a Phase III study sponsored by Cephalon, an "Open-Label Study to Evaluate the Effect of Treatment With Fentanyl Buccal Tablets on Pain Anxiety Symptoms When Used for the Management of Breakthrough Pain." Note also that Sterling Institutional Review Board appears to be another example of a for-profit, commercial institutional review board.

Here we have another example of remarkably bad implementation of commercially sponsored and commercially supervised clinical trials.

We have posted a number of times about sloppy and mismanagement of commercially sponsored clinical research, often under the auspices of for-profit contract research organizations (CROs) and for-profit institutional review boards (IRBs). See this 2006 vintage post on the infamous study 3014 on Ketek, sponsored by Sanofi Aventis.

In my humble opinion, in the contemporary business world, many managers are driven mainly by quarterly profits. However, what works best to boost profits in the short run may not be what works to produce valid clinical research that maximizes the safety of and respect afforded human research subjects. When all the organizations involved in the research, the sponsor, the organization implementing the research, and the organization supervising research ethics are for-profit, the incentives to cut corners are multiplied. Cutting corners can jeopardize the validity of the studies, and the safety and respectful treatment of study subjects.

I again submit that making human experimental research into a commercial enterprise, mainly serving the marketing of drugs and devices, may not produce good science, and may not be good for patients. It might be a better idea to leave human research to not-for-profit organizations and health care professionals.


Hat tip to PharmaGossip.

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.

Commercial For-Profit Institutional Review Boards: "Ethics for Sale"

Carl Elliott and Trudo Lemmens took on for-profit institutional review boards in an article in Slate. Some key points were:

The primary means of protecting research subjects are ethics committees known as institutional review boards.
The idea was that to protect the welfare of research subjects, all studies would be reviewed in advance by an ethics committee independent of the researchers conducting the study, whose scientific zeal might lead them to shortcomings safety. Traditionally, IRBs have been volunteer committees made up of scientists and clinicians working in the hospitals and medical schools where the studies they review are being carried out.
Today, however, the ethics review of more than half of all new drug submissions to the Food and Drug Administration is handled by a single for-profit IRB, Western Institutional Review Board in Olympia, Wash.
How did we get here? When IRBs were established a generation ago, medical research was conducted mainly by individual investigators working in medical schools who were funded by the federal government and who had little financial stake in their studies. These days, medical research is a massive, multinational corporate enterprise. Rather than contracting with academic researchers to test new drugs, the pharmaceutical industry has found it cheaper and more efficient to conduct studies in physicians' offices, industry laboratories, and private testing sites like SFBC's in Miami. As recently as 1994, 63 percent of clinical trials were taking place in academic settings. Ten years later, that figure had shrunk to 26 percent. Along with private-sector clinical research has come private IRBs, which market themselves by promising fast and industry-friendly service.
But the private IRBSshave a direct financial interest in keeping their drug-company clients happy. If one for-profit IRB rejects a study as unethical, the pharmaceutical company sponsoring the study can simply send it somewhere else. Free-marketeers argue that there's a countervailing pressure that should make drug companies welcome strict policing from the IRBs - the possibility that a strict ethics review on the front end could head off a lawsuit on the back end. But in reality, the incentives don't pan out that way. Lawsuits, while on the rise, are still relatively rare. For the companies bankrolling the clinical trials, litigation is a quite-manageable cost of doing business.
Surprisingly, for-profit IRBs have drawn little criticism from bioethicists. Instead, some university and government scientists are increasing their influence.
IRBs were never intended to be formal regulatory bodies. They were supposed to provide a kind of professional self-regulation, in which scientists were advised by their colleagues.
That mission might have made sense 30 years ago. Today, however, the prevalence of private-sector drug research and the push to commercialize every facet of medical research makes the original model hopelessly outdated. Research subjects need a watchdog to protect them, and not one that is owned by the pharmaceutical industry. If IRBs cannot do the job, then we need to replace them with something that can.

As the saying goes, read the whole thing.

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.

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.