Human-subjects research: Trial and error

http://www.nature.com/nature/journal/v448/n7153/full/448530a.htmlNews Feature Nature 448, 530-532 (2 August 2007)
Human-subjects research: Trial and error
Heidi Ledford1

The ethics committees that oversee research done in humans have beenattacked from all sides. Heidi Ledford recounts the struggle to come upwith alternatives.Fourteen years of treating people with tuberculosis has taught physicianWilliam Burman what to expect when a patient walks through his door.Tuberculosis is not typically a disease of the well-heeled. Manypatients in the United States are foreign born. English is their secondlanguage. Fewer than half have completed a high-school education, andmany have spent time in jails or homeless shelters.So when Burman, of the University of Colorado in Denver, joined in twostudies run by the Tuberculosis Trials Consortium, he knew that theconsent forms needed to cater to people with an eighth-grade readinglevel (comprehensible to an educated 13-year-old). The trials involvedmultiple institutions, and the forms were sent to 39 institutionalreview boards (IRBs) - committees designed to determine whether aproposed experiment is ethically sound. The final approvals came in 346days later, but what the IRBs sent back, Burman found disturbing."The consent forms were longer. The language was more complex," Burmansays. "And errors were inserted at a surprising frequency." In one case,a potential negative side effect of the treatment had been accidentallyedited out. Burman responded to the problem as any researcher would: hestudied it. He had an independent panel review the changes. Thereviewers found that 85% of the changes did not affect the meaning ofthe consent forms, but that the average reading level had jumped fromthat of an eighth grader to that of a twelfth grader (around 17 yearsold)1. His results confirmed something he'd suspected for some time. "Istarted to think about what was happening and it just seemed like thesystem was flawed." It was time to change the system.Burman is not alone. In the 40 years since their birth (see 'Time forethics'), IRBs, also known as research ethics committees, have facedcriticism from all sides. They're too slow, or too hasty,overprotective, or they flout basic safety. They're bureaucratic,wasteful and unavoidable. So, what are researchers to do? The will forchange exists, says Sarah Greene, a researcher at the Group HealthCenter for Health Studies in Seattle, Washington. But recent attempts tofix the system have struggled to gain a foothold.Figure 1: Time for ethicsHigh resolution image and legend (221K)Obstacle courseIn many countries, a complex network of local ethics committees handlesthe approval of research on humans. This focus on local resources allowscommittees to account for specific laws or cultural concerns in aparticular region. But it leads to problems in multicentre trials, suchas Burman's, which are becoming more frequent. When IRBs were firstfounded, multicentre trials were almost unheard of. A 1998 report2 fromthe inspector-general of the US Department of Health and Human Servicesin Washington DC stated that a rise in the number of multicentre studieswas throwing the system into crisis. And a recent analysis3 showed thatfive of 20 trials seeking IRB approval reported significant delays as aresult of IRB negotiations. Seventeen noted inconsistencies both inIRBs' review process and in their recommendations. In one case,negotiations between 65 IRBs delayed the study by a year.More frighteningly, the cumbersome system could even endanger the healthof the studies' participants. The higher the hurdles - and the moreunfair they seem - the less inclined researchers will be to jump them."It's slow and frustrating to researchers," says Ezekiel Emanuel, chairof the US Department of Bioethics at the National Institutes of Healthin Bethesda, Maryland. Researchers have reported that they are morelikely to violate the regulations set by ethics committee if they feelthat they or their application have been mishandled4.And even though IRBs are made up mostly of volunteers, they areexpensive to run. In 2002, the median cost of running an IRB, takinginto account the time spent by IRB members, was $742,000; the maximumwas over $4 million5. So, for every protocol they assess, they charge afee to cover support staff, facilities, and outside consulting. Thesefees are typically pulled from grants as part of the institutionaloverhead, or as direct charges to commercial sponsors, and they averagejust over US$1000 (ref. 5).A proposed solution to the copious problems with IRBs is outsourcing,especially for multicentre studies, to some form of centralized review.That movement has met with resistance from those who say that localreview provides valuable local context. But Burman counters that localcontext had little bearing on the changes in his consent forms. In histrials, only 1.5% of the tweaks to the consent forms were made toaccount for local context1.Risky processBut that's not enough to rule out the importance of local review arguesDavid Wynes, vice-president for research administration at EmoryUniversity in Atlanta, Georgia. "I agree that the vast majority ofchanges are editorial, but I think there's a value in an institutionhaving a process for identifying when local context is an issue," hesays. "You might have to review a hundred protocols before you can seethe value of local context. Is it OK if only 1% of the time you putsubjects at risk?"Is it OK if only 1% of the time you put subjects at risk?David WynesBurman argues that expertise with a specific patient group or diseaseshould trump local context from detached review boards. "The local IRBsdon't know the patients I take care of, because if they did, the lastthing they would do is increase the length of the consent form and makethe language more complex," he says. Instead, Burman and his colleagueshave worked to create a designated panel at the Centers for DiseaseControl and Prevention (CDC) in Atlanta, Georgia, which keeps track ofdisease epidemiology in the United States, to review all tuberculosisstudies.Top trumpsBut a centralized system will work only if the local boards are notallowed to overrule the decision of the central board, says Emanuel.It's a lesson, he adds, that the United Kingdom has had to learn thehard way.In 1997, the United Kingdom created a system of regional review boardsin which trials needed approval from just one board to proceed. In 2000,the system was brought under the auspices of the Central Office ofResearch Ethics Committees (COREC), based in London. The trouble was,local ethics committees refused to surrender control, and instead ofexpediting review, COREC had created a new layer of bureaucracy."Researchers were very upset with the way things were going," says EmmaCave, a lecturer at the Leeds School of Law, UK. "They thought theregulations were making the United Kingdom a bad place for research." InApril, Britain dissolved COREC in favour of the new National ResearchEthics Service, and changed the regulations to restrict the ability oflocal ethics committees to change the protocol approved by the nationaloffice.In 2001, the US National Cancer Institute (NCI) in Bethesda, Maryland,launched a similar experiment - a central review board to review allNCI-funded research on humans. Local review boards retained the power todo a full review, but could opt instead for an expedited review in whichthey merely adjust for local context. (The NCI formed a similar reviewboard for paediatric studies in 2004.)The project immediately ran into trouble. The central board spent toomuch effort on scientifically reviewing proposals that had already beenreviewed by the granting arm of NCI, says Richard Schilsky, chairman ofCancer and Leukemia Group B, an NCI-sponsored cancer clinical trialsgroup. And at first, few local IRBs were willing to cede control to thecentral review board. "The concept is good," says Schilsky, "but thedevil has been in the details of the implementation."Since 2001, the number of participating institutions has climbed to 300.More than half of those have accepted the reviews of NCI's centralboard; the remainder are still developing ways to incorporate thecentral boards review into their own review process.. But Schilsky saysthat only about 20% of the institutions involved in his clinical-trialsgroup - the largest in the United States - have signed on. The resultwas similar to what happened in Britain, adding to the bureaucracy.Schilsky estimates that the system has added two to three months to thetime it takes to activate a new study.Lainie Ross, a paediatrician and member of the IRB at the University ofChicago Medical School, says that she is opposed to surrendering localcontrol. "A national IRB could fail to recognize different needs ofdifferent communities. I'm not just going to accept someone else's wordfor it."A national IRB could fail to recognize different needs of differentcommunities.Lainie RossWithout fail, IRB members interviewed by Nature who were opposed toceding control to a centralized board cited concerns about patientsafety as their main reason. But Emanuel, who has also served on an IRB,says that there's another cause for concern. "There are no good datasuggesting that there are local factors that are ethically relevant,"says Emanuel. "It's really liability that's driving this."Vulnerable populationsLiability is a thorny issue for local IRBs contemplating handing overcontrol to NCI's central IRB, says Wynes. If a participant in a clinicaltrial felt that he or she were unjustly harmed during the course of theresearch, they could not hold the NCI legally responsible because it isa branch of the federal government. That leaves the local IRB legallyvulnerable, says Clint Hermes, general council at St. Jude Children'sResearch Hospital in Memphis, Tennessee.It is rare, but IRBs and even individual IRB members have been sued inthe past. Bioethicist Arthur Caplan at the University of Pennsylvania inPhiladelphia says that he has served on two IRBs that were sued butstill thinks it's important to have a mechanism in place to holdnegligent IRBs accountable.D. PARKINSMeanwhile, a profitable industry in private, commercial IRBs has sprungup. Although commercial IRBs can provide a sense of security by assuminglegal liability, the institution doing the experiment will bear ultimateresponsibility. But partial indemnity seems sufficient to comfort manyresearchers: commercial IRBs serve hundreds of companies, hospitals andresearch institutions. In 2005, the consulting firm Deloitte namedChesapeake Research Review of Columbia, Maryland - a commercial IRB andconsulting service - as one of the fastest-growing technology companiesin North America. The firm increased its revenues by 244% in five years,to reach nearly $5.5 million in 2004.Proponents of commercial IRBs say that larger companies have goodreputations for speedy turnaround and thorough reviews. Several,including the two largest players, Chesapeake Research Review andWestern IRB in Olympia, Washington, have been officially accredited bythe Association for the Accreditation of Human Research ProtectionPrograms in Washington DC. Such societies provide a stamp of approvalfor IRBs, providing oversight and standardization to the field.Financial gainStill, others worry about the potential conflict of interest inherent tocommercial IRBs, who could benefit financially from pleasing theircustomers and passing protocols with minimal fuss. "I'm a littlecautious about this drive towards commercial IRBs," says Richard Bianco,associate vice-president for regulatory affairs at the University ofMinnesota in Minneapolis, and a 15-year IRB veteran. Nevertheless,Bianco and other critics acknowledge that local IRBs also have aconflict of interest - clinical trials can bring in serious cash andprestige to the institutions they serve, and IRB members that are alsoscientists at the institution may feel pressured to approve a trial."I'm somewhat surprised that no one has ever pushed to reform theprivate side of IRBs," says Caplan. "It's growing like crazy. Industryhires them because they're fast and efficient. It doesn't mean thatthey're right."Industry hires private IRBs because they're fast and efficient. Itdoesn't mean that they're right.Arthur CaplanBianco also says that his colleagues have been under "intense pressure"by industry collaborators to relinquish control to commercial IRBs. Sometrial sponsors, he says, even issue ultimatums: use the commercial IRBthat we recommend or don't participate in the trial. "That waspressure," says Bianco. "But I've been around a long time. You come toknow what to ignore." None of those threats ever came to fruition, hesays.ADVERTISEMENTFor others, initial scepticism of commercial IRBs has given way toacceptance. "When I first came across independent IRBs, I questionedthem, too," says Wynes. "But I've taken the time to get to know how theyoperate, and my comfort level has changed." In November 2005, whileWynes was still at the University of Iowa in Iowa City, he helped theuniversity to switch to outsourcing industry-sponsored trials to WesternIRB. Prices vary, but outsourcing to industry can cost twice as much asprocessing the application in-house, although commercial IRBs typicallyboast a quicker turnaround time. Whereas many commercial IRBs aim toreview applications within a week of their receipt, non-commercial IRBsmay meet only once a month.Some see commercial IRBs as a stop-gap measure in lieu of realregulatory change. But despite the roadblocks, substantial change isinevitable, says Emanuel. The lingering problem, he adds, is that itwill probably take a new scandal to push reform to the top of theagenda. "I think we're just one accident away, but it will still takethe accident," he says. "In my opinion, that's the sad fact."See Editorial, page 511.Top of pageReferencesBurman, W. et al. Control. Clin. Trials 24, 245-255 (2003).Office of the Inspector General, Department of Health and HumanServices. Institutional review boards: a time for reform. (US GovernmentPrinting Office, Washington, DC, 1998).Greene, S. M. & Geiger, A. M. J. Clin. Epidemiol. 59, 784-790 (2006).Keith-Spiegel, P. & Koocher, G. P. Ethics Behav. 15, 339-349 (2005).Sugarman, J. et al. N. Engl. J. Med. 352, 1825-1827 (2005).

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http://www.philly.com/philly/health_and_science/20070709_Its_Blow__an_energy_drink_.html

Blow is a white energy powder, with plenty of caffeine, and is designed to mix in drinks, particularly alcoholic.Erika GebelPhiladelphia InquirerIt's a white powder, it'll keep you wired all night, and it's called Blow.But it's not cocaine. It's a crystalline energy drink, a sweet mix like Kool-Aid, aimed at the bar scene."Our product is not designed to be an illicit-drug alternative," says Logan Gola, the brains behind Blow. Still, it arrived at The Inquirer in a faux dusty box. Inside were vials of Blow, a toy credit card, and a mirror. (But no dollar bill.)The new mix is being peddled to a market that is hooked: Energy-drink sales increased by 50 percent between 2005 and 2006, according to the Beverage Marketing Corp.Blow, like most energy drinks, includes a cavalcade of impressive-sounding ingredients - taurine, B vitamins, inositol, L-carnitine - but the tried-and-true upper is the ever-present caffeine. Perhaps too much."There have been alarming rates of all these health problems associated with high caffeine," said Lisa Hark, director of the Nutrition Education and Prevention Program at the University of Pennsylvania. To find out how much is too much, go to www.energyfiend.com's death-by-caffeine calculator.Then there's the booze issue. Red Bull, the flagship energy drink, is often mixed with vodka or taken with a shot of the liqueur Jägermeister, the widely guzzled "Jäger Bomb." In the April 2006 issue of Alcoholism: Clinical & Experimental Research, researchers reported that drinking Red Bull made subjects feel less drunk, but not act less drunk.The impact of a drink mix like Blow forges new territory. It cuts out the liquid middleman and can be dissolved directly into any cocktail. "It's being sold in liquor stores," said Lauren Seal, Blow promoter. "People have put it in anything: shots, vodka-based cocktails, gin."But heed the warning on the vial: "Do not snort Blow."