Clinical Trials, Doctors And Conflicts Of Interest
8 CommentsBy Ed Silverman // December 2nd, 2009 // 9:25 am
Recruiting and enrolling patients in clinical trials is just one behind-the-scenes link in the complicated process that results in medications winning regulatory approval and the subsequent marketing to doctors. But like a lot of steps in that process, the clinical trial machinery is coming under scrutiny as questions arise over the extent to which doctors are compensated for their participation.
The issue has been the subject of an ongoing investigation by the Senate Finance Committee’s Chuck Grassley, who has probed undisclosed conflicts among various academic researchers who simultaneously receive industry and federal funding. And so the faculty at the Center for Health & Pharmaceutical Law & Policy at the Seton Hall Law School have issued a 62-page paper with some suggestions for greater oversight of the financial relationships with doctors.
For instance, they suggest the federal government should bar payments solely for a referral to a trial; payment tied to screening potential trial participants, and bonuses for recruiting or retaining a certain number of participants. Why? Payments might otherwise encourage enrollment of patients who don’t belong in a study or deemphasize info that might discourage someone from enrolling.
What else? Their report says the federal government should also prohibit compensation for research in the form of an equity interest in the sponsor of a clinical trial. And federal policy should specify certain conflicts, such as stock holdings, that will disqualify a researcher from serving as an investigator. And federal regs should require all other conflicts should be identified and managed.
Here are more suggestions from their paper: At the outset of a trial, institutions should “evaluate relationships between industry and physicians to determine if the magnitude and form of the individual’s financial interest with the sponsor, the longevity of the relationship, or other factors suggest that there is a conflict of interest requiring elimination, reduction, or management.”
“Investigators should be required to report all financial interests, irrespective of amount, to an institutional committee for review, rather than leaving it up to investigators to determine if the interest could reasonably be expected to affect the research. Institutions should also be required to establish internal databases that investigators must update as information changes about their financial relationships with for-profit entities.”
“Individual institutions should have the discretion to determine whether to create a special conflicts of interest committee to review and manage individual investigator conflicts or whether to delegate those responsibilities to the institutional review board.”
“For research conducted in academic medical centers, a board of directors committee, including members independent of management and the faculty, should oversee institutional conflicts in research. The committee oversight should extend beyond primary institutions, such as a medical school or university, to any not-for-profit institutes or for-profit corporate entities that are substantially controlled by or operate under the auspices of the medical school or university.”
“Review and management of investigator or institutional conflicts prior to the time that research begins should be mandated by regulation and subject to contemporaneous government oversight.”
“Federal regulations should charge IRBs with reviewing conflicts held by investigators and entities conducting research in community settings. Federal regs should provide clear guidance to IRBs about the nature and scope of info to review, standards for review, and alternatives for eliminating, minimizing, or managing a conflict, both for investigators and institutions.
“Federal regs should also spell out clearly the obligation of community-based physicians acting as investigators or institutions acting on their behalf to report information about compensation for research and other financial interests to IRBs.”
“Federal law should require disclosure of payments for conducting trials and other relevant financial interests. Before research begins, research sponsors should report to the FDA and recipients of federal grants should report to the granting federal agency relevant equity and ownership interests as well as all payments…to the investigator and the investigator’s institution or practice group by the company whose product is under review in the clinical trial.”
Photo courtesy of Jerome Kassirer
pharmavet
I conducted pharmaceutical clinical trials for 25 year, and the seasoned investigators know how to milk the system, or at least try to. Here are some observations.
1) It is standard procedure when doing a pre-study visit to ask the Principal Investigator (PI) how many other studies they are doing so as to assess their capability to do my study. They know that they can get away with a low number because we have no legal means of verification. After the study starts, the enrollment is slow, and you find out from the coordinator that the PI is really doing a ton of studies in your disease states, you resort to “incentivizing” the PI per the white paper to give your study priority, thus starts the slippery slop.
2) Some investigators have huge screen failure rates while actually completing few patients. If payments for screen failures are not capped (I used to cap them at 15% of the total budget), a PI can make a lot of money just from screen failures. If the PI exceeds the cap, then he/she has to eat the cost.
3) I never pay the full salary for nurses or other support staff, although surprisingly many companies do. With multiple companies paying full salaries it is easy to see how PI’s can pull in a lot of money.
4) One simple rule. If I use a physician as a PI I don’t use him as a speaker, and vice verse. This reduces conflict of interest.
5) When most studies were done in academia, it was typical to pay 40-60% in overhead to the university as the fee to get in the door. In non-university settings, I offer no overhead at first, and most of the time pay 10-15% if anything.
6) Train the CRO’s to be tough negotiators with PI’s. Since it’s not their money they don’t see it as their role. Once I, as a sponsor begin to deny CRO change orders for more funds to the PI they begin to see the picture more clearly.
7) I used competitive enrollment, but didn’t reward it with a bonus to the PI. It was always something like sending a coordinator to an educational meeting, which the sponsor paid for directly.
Just a few thoughts.
Larry Husten
Pharmavet,
Thanks for the fascinating insight into the real world of clinical trials. Amazing.
Can you provide some more detail about rule #4? From what we’ve all been reading lately, the distinction between researchers and speakers has been pretty blurry. How commonly is this rule applied? And to what degree would the industry person in charge of the trial have any say over who the marketing and/or education people could use as speakers?
Best,
Larry
Robert
So these pharmaceutical investigators are actually working several cases at a time?
patrons99
To Robert: dozens of studies at any one time is not at all uncommon.
To Pharmavet: is the true incidence of screening failures ALWAYS reported? if so, to whom? do the pharma sponsors ALWAYS pay the investigator for screening failures? does Medicare/Medicaid/Tricare routinely pay for screening failures? do these insurers EVER pay for screening failures? If so, is it routinely disclosed to the insurer that patient was being screened for research study? Are formal informed consents for study participation obtained PRIOR to screening for study participation? Or are formal informed consents for study participation obtained AFTER repeating the screening procedures? In your experience, how exactly did the pharma sponsors “incentivize” faster study enrollment?
patrons99
Thanks for posting this topic. Several thoughts come to mind: IRBs have an abysmal track record of monitoring clinical research studies. Why does anyone think that IRBs will ever straighten up and fly right? Don’t investigators and pharma sponsors often get to choose their own IRB? Where are the retractions of the bogus research on which sinecures and university prestige have been built? Or is there nothing left after retraction?
patrons99
Just few more questions for pharmavet:
Do the pharma sponsors routinely grant exceptions, exemptions, and special dispensation for research protocol violations reported by the principal investigator, as a means of increasing enrollment?
Do the pharma research sponsors routinely award additional research studies to the principal investigator and the academic institution as incentives to increase study enrollment?
Does the net effect of indirect transfers of value and surrogates (e.g., IRBs and CROs) lessen risk of liability or culpability to pharma for fraudulent research studies?
Nancy Fruge
Well done, Seton Hall faculty…
“Federal regulation should require that training about the nature of conflicts of interest, their potential for harm, and the ways that conflicts can be managed, reduced, or eliminated should be mandatory for all investigators who conduct clinical research within and outside of academic medical centers. For physician-investigators outside of academic medicine, training should also cover key elements of research: the importance of inclusion and exclusion criteria and informed consent, the ethical and scientific issues posed by particular research methods such as double blind placebo-controlled studies, and their obligations as an investigator as compared with those of a treating physician.”
As well, training programs for academic physician-investigators should include information on their obligations as a treating physician as compared with those of an investigator.
“When investigators have financial interests in the outcome of the research or stand to gain substantially from conducting a clinical trial, it may affect their judgment throughout the conduct of the trial, including the many judgments that must be made during the process of enrolling and recruiting individuals to participate as research subjects. Potential participants can be harmed by recruitment practices that insufficiently inform them of the risks of the study, ignore medical conditions that place them at risk in the trial, or encourage them to discontinue or forego a treatment regimen likely to be better for them than the regimen being evaluated in the trial.”
Research participants may question the motives of a physician-investigator who appears in advertisements for products he evaluated in clinical trials.
http://tinyurl.com/yhz5cve
patrons99
To Ed:
As a suggested followup to this topic, a simple recitation of some of most egregious violations of the The Nuremberg Code and Declaration of Helinski in pharma-sponsored clinical research, over the last two decades, might be instructive, especially to new physicians contemplating careers in the pharmaceutical industry. The list is lengthy. It’s a veritable rogue’s gallery.