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By all accounts, Jolee Mohr was an active woman inrelatively good health. Though she had rheuma-toid arthritis, it did not keep her from holding

down an office job and spending her leisure time boatingwith her husband and their young daughter. But the thir-ty-six-year-old Illinois woman’s life came to an unexpect-ed end last July, three weeks after an experimental genetherapy was injected into her right knee during a phaseI/II clinical trial aimed only at assessing the agent’s toxic-ity. Mohr’s rheumatologist had recruited her for thestudy and had given her the injection in his office. Herdeath was caused by organ failure from histoplasmosis, acommon fungal infection that normally produces onlymild illness.

The tragedy immediately sparked comparisons withthe story of Jesse Gelsinger, a vital eighteen-year-old whodied in 1999 during a gene therapy trial at the Universi-ty of Pennsylvania. Gelsinger’s death was the first to bedefinitively linked to a gene therapy trial. Would Mohr’sbe another? The trial was halted pending an investigationby the National Institutes of Health’s Recombinant Advi-sory Committee.

The RAC’s report, released last December, delivered amixed message. It concluded that the experimental treat-ment was unlikely to have contributed to Mohr’s death,

but it also said that the possibility “cannot definitively beruled out.” Howard Federman, the committee chairman,told Science, “we are still missing key pieces of informa-tion” needed to answer the ultimate question posed byMohr’s husband: Would she be alive today if she had notenrolled in the trial? In any case, the Food and Drug Ad-ministration allowed the trial to resume.

The investigation, though, brought to the surface dis-turbing aspects of clinical research left inadequately ad-dressed since Gelsinger’s death: the pressure to enrollrecord numbers of human subjects in record numbers oftrials, financial conflicts of interest, shortcomings inoversight by the federal government and ethical reviewboards, and the implication of all of these trends for thesafety of human subjects. These problems have beenaired in medical and bioethics journals, op-ed pieces, andsome memorable investigative journalism. But the Mohrcase gave them new urgency. By infusing the all-too-fa-miliar issues with flesh-and-blood drama, it revived con-cerns that clinical trials generally—not just research ongene therapy—may be headed for crisis.

So far, there are more questions than answers. Shouldsomeone who is not seriously ill be enrolled in a phase Isafety study, or is the risk too high? What can be done toprevent subjects from developing the misconception thatthey will benefit from an experimental therapy? Is thismisconception exacerbated when the researcher recruit-ing the subject is his or her physician? Did Mohr havethis misconception, even though the consent form stat-ed, “We do not expect you to receive any direct medicalbenefit from participation in this study”?

The financial relationships between drug companysponsors and researchers and between the drug compa-nies and ethics review boards constitute a conversation alltheir own. What regulatory changes are needed to pre-vent financial interests from turning scientific researchinto a marketing tool and the ethical review process intoa rubber stamp? Researchers are obliged to disclose anyfinancial relationships with the research sponsor to theFDA, but not to potential research subjects. WouldMohr have consented had she known that her physicianwas being paid by the trial sponsor, Targeted Genetics, to

ESSAYS

Trials and Tribulations

B Y S U S A N G I L B E R T

Susan Gilbert, “Trials and Tribulations,” Hastings Center Report 38, no. 2(2008): 14-18.

The clinical research landscape is changing rapidly, and the system for overseeing researchhas failed to keep pace. The mechanisms for protecting subjects may be too stringent in some

places, too weak in others, and overtaxed and unreliable overall. These essays survey the troublespots and point the way to effective reform.

H A S T I N G S C E N T E R R E P O R T 15March-April 2008

recruit her for the study? Did the money lead her doctor, con-sciously or not, to talk up the benefits of volunteering for thetrial and downplay the risks?

Government regulations are supposed to protect humanresearch subjects from unethical treatment and unsafe condi-tions. But this task has gone from merely challenging to ex-cruciatingly difficult in recent years. The explosive growth inthe number of trials makes them harder to track. Changes inwho conducts clinical research, and where, have shifted manytrials into regulatory gray areas. And according to nearly allcommentators, ethics review boards are strangled by red tape.All this leaves the courageous individuals who put themselveson the line in these trials morevulnerable than they are sup-posed to be.

Growth andCommercialization ofClinical Research

In the period from 2000 to2006, the number of clinical

trials in the United Statesjumped nearly 50 percent, fromforty to fifty-nine thousand, ac-cording to CenterWatch, a com-pany that tracks information onclinical studies. Along with thistremendous growth has come asignificant shift in who financesand conducts trials. In 1991, 80percent of them were funded bythe federal government or phil-anthropic organizations andtook place in academic medicalcenters. Now, most are financedby pharmaceutical companiesand take place in private doctors’offices and clinics. A key driver of the clinical trials boom isthe quest by drug companies for new blockbuster drugs to re-place the ones that will go off patent in the next few years, in-cluding Lipitor for high cholesterol and Advair for asthma.With stiff competition and billions of dollars at stake, speedin testing new drugs is a high priority.

Frustrated by the slow pace of research at academic institu-tions, drug companies have turned to contract research orga-nizations. These private companies, which manage trials andhave a national and sometimes international reach, are betterable than university medical centers to find the hundreds ofthousands of researchers and millions of volunteers needed tokeep clinical trials going year after year. They also completetrials faster, according to a 2006 study by the Tufts Center forthe Study of Drug Development. CROs design protocols andfrequently hire community doctors as investigators, oftenpaying these doctors to recruit patients as study volunteers.CROs also cover the ethical review of clinical trials, hiring in-

stitutional review boards or even forming their own reviewboards. CROs were significantly involved in 64 percent ofclinical trials in 2003, up from just 28 percent in 1993, ac-cording to CenterWatch.

The Tufts study found that the quality of the research wascomparable in CROs and academic groups, but many expertsare not so sure. In an article in the New England Journal ofMedicine last October, Miriam Shuchman, a correspondentfor the journal, explored questions about the qualifications ofCROs, their ethics, their accountability, and their indepen-dence from their clients.

Many of the concerns can be traced to a groundbreakinginvestigation of CROs by themagazine Bloomberg Markets in2005, which exposed some par-ticularly egregious ethical andprofessional infractions atSFBC International, a largeCRO. SFBC had put an unli-censed physician in charge ofclinical trials in its Miami test-ing facility, the largest in NorthAmerica, in 2005. The compa-ny targeted poor immigrants ashuman volunteers for the trials,enticing them with paymentsand neglecting to inform themclearly that participating in thetrials carried risks of injury ordeath. The facility was shutdown and last August the com-pany, now called PharmaNet,settled a shareholder class-ac-tion lawsuit for $28.5 million.

In Shuchman’s view, one ofthe biggest obstacles to qualityresearch by CROs is a work-force that has inadequate train-

ing and a high turnover rate. “CRO employees are generallyyounger, less skilled, less experienced, and less educated thanresearchers in the pharmaceutical industry or academia,” shewrote, adding that staff turnover “can be as high as 100 per-cent during the lifespan of a single project.”

Not surprisingly, the Association for Clinical Research Or-ganizations, the trade group that represents CROs, rejectsShuchman’s criticisms. “CROs draw their professional and re-search staff from the same pool of talent used by pharmaceu-tical and biotechnology companies,” asserts the association’sWeb site.

Concern about inadequate training in clinical trials ex-tends to private physicians, who make up a growing share ofresearch investigators. In a survey of its membership in 2005,the American College of Physicians found that nearly 60 per-cent had been asked to participate in research in the previoustwo years, but that more than 33 percent felt unprepared toevaluate whether the research proposals were ethical. In re-

The Mohr investigationhighlighted some disturbing aspects of clinical research:

the pressure to enroll subjects,the conflicts of interest, theshortcomings in oversight,

and the implication of thesetrends for subjects’ safety.

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sponse, the ACP has developed an education program of re-sources and workshops on conducting office-based research.Educational information from the ACP discusses how to eval-uate a study’s validity, what constitutes fair compensation,and how to ensure proper ethical review. A document on itsWeb site called “Ethics Case Study” warns that ethical reviewunder a CRO may not be sufficient, and it advises physiciansto contract with a nearby academic IRB that may be willingto review protocols for a fee, which could then be billed to theCRO.

IRBs: Conflicts of Interest and Red Tape

One of the most heated de-bates about clinical trials

concerns IRBs and how wellthey do their job. The federalgovernment mandated the es-tablishment of IRBs threedecades ago to evaluate trialprotocols, approve those thatabide by a set of ethical princi-ples, and monitor the trials tomake sure that they upholdthose principles. Regulations re-quire IRBs to be without anyconflicts of interest, but con-flicts of interest are becomingharder to avoid.

When most research tookplace in academia, IRBs consist-ed of university researchers andclinicians who volunteered toreview research proposals sub-mitted by their colleagues. Asthe number of trials increased, academic IRBs became in-creasingly overburdened and overworked, and notoriouslyslow. For-profit IRB companies, promising greater speed andefficiency, came into being, and today, commercial IRBs re-view most clinical trials. Western IRB, the oldest for-profitIRB in this country, alone reviews more than half of all trialsof new drugs submitted for FDA approval, including the trialin which Jolee Mohr participated. Several universities nowoutsource their research protocols to commercial IRBs.

Many ethicists and others involved with research policydeny that for-profit IRBs are capable of objective review.“Commercial IRBs have a fundamental conflict of interest,”wrote Trudo Lemmens, an associate professor of law at theUniversity of Toronto, and Carl Elliott, a professor ofbioethics at the University of Minnesota, in PloS Medicine inJuly 2006. “They are in a client-provider business relationshipwith the commercial entities whose studies they review.” Al-though the IRBs are subject to FDA regulations, the regula-tions “fail to prevent CROs from selecting the IRB least like-ly to reject the trial or delay approval by imposing too many

restrictions,” they wrote. “If one IRB is too stringent, theycan simply go to the one next door.”

The Bloomberg report described conflicts of interest be-tween two commercial IRBs and the troubled companieswhose studies they reviewed. Southern IRB was owned by thewife of a vice president at SFBC, the large CRO that em-ployed an unlicensed physician and conducted inadequate in-formed consent. The Human Investigation Committee, an-other IRB, was founded by a doctor who ran the Fabre Re-search Clinic in Houston, a testing center that was closed in2005 for falsifying records and numerous other legal and eth-ical violations.

Ezekiel J. Emanuel, chair-man of clinical bioethics at theNational Institutes of Health,disputes the criticism of for-profit IRBs. Although therehave been no studies comparingtheir performance with that ofacademic IRBs, he points totwo indicators of quality. Forone thing, most of the unex-pected deaths of relativelyhealthy research participants oc-curred in trials with academicIRBs (Jolee Mohr’s was an ex-ception). In addition, Emanuelsaid, the FDA has issued hun-dreds of warning letters to acad-emic IRBs, but only one suchletter to a for-profit IRB.

To be sure, conflicts of inter-est are not unique to for-profitIRBs. A survey of 574 academicIRB members revealed that a

sizable minority have financial relationships that are relevantto their service on the IRB. The survey, published in the NewEngland Journal of Medicine in 2006, found that 15 percentof the IRB members had conflicts of interest, meaning thatthey reviewed at least one protocol sponsored either by acompany with which they had a relationship or by a com-petitor of that company. Nearly one-quarter of the IRB mem-bers with conflicts of interest said that they never disclosedthem to their IRBs. The process for disclosing conflicts of in-terest was unclear to many of the respondents, with 33 per-cent saying either that their IRB had no formal disclosureprocess or that they did not know of one.

Conflicts of interest need not be financial. Most membersof IRBs at medical schools are employees of those institutionsand have personal relationships with the researchers. Theseties may make it difficult for academic IRBs to be objective inevaluating their institutions’ protocols. “Disapproval of suchprotocols means that less money will flow into the institutionand its clinical-trials operation, with a potential deleterious fi-nancial effect,” wrote Franklin G. Miller of the National In-stitutes of Health last March in a letter in the New England

An almost universal concern about federal

regulations is that they addso many requirements forbureaucratic details thatIRBs are left strangled

by red tape.

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Journal of Medicine. Paul Gelsinger, Jesse’s father, raises thepossibility of conflict of interest at the University of Pennsyl-vania IRB that reviewed the trial in which his son died. Mostof the IRB members were university employees.

No one knows how often conflicts of interest lead IRBs toapprove clinical trials of questionable ethics or scientific value.Research on that question would be a giant step toward im-proving ethical reviews, but would likely not be sufficient toensure that IRBs can do their jobs. Experts point to anothermajor problem plaguing IRBs: regulatory bureaucracy.

An almost universal concern about federal regulations isthat they have left IRBs strangled by red tape. In the name ofhuman research protection, regulations have added so manyrequirements for documentation and other bureaucratic de-tails that IRBs appear at times to have lost the forest for thetrees. “The national system for the protection of human re-search participation is indeed a system in jeopardy,” assertedNorman Fost, director of the program in medical ethics at theUniversity of Wisconsin, and Robert Levine, a clinical profes-sor at Yale, in a widely read editorial in the Journal of theAmerican Medical Association last November. Fost and Levinecriticized the regulations for “meticulous documentation ofcompliance with narrow interpretations of regulations andpolicies.” And they warned, “In some cases, these activities ac-tually appear to be reducing protections for participants in re-search.” (This opinion is echoed by Greg Koski, the first di-rector of the Office for Human Research Protections, in anessay in this issue.)

In a wrongful death lawsuit, Paul Gelsinger charged theUniversity of Pennsylvania IRB with inadequate oversightcaused not only by conflict of interest, but also by an excessiveworkload. The lawsuit was settled out of court, leaving theIRB’s responsibility for Jesse’s death unresolved. What role, ifany, IRBs have played in the handful of other unexpecteddeaths in clinical trials is unclear. But Fost and Levine believethat the increasing bureaucratic burden being placed on IRBswould not have prevented any of the deaths. “To the con-trary,” they wrote, “the increasing focus on minutiae has beendistracting IRBs from more substantive issues.” Those issuesinclude a lack of clarity in the informed consent process.

Commentators who want to restore IRBs to their missionof protecting human research subjects are now calling forchange from everyone involved in clinical trials—the FDA,OHRP, research institutions, and scientists themselves. Koskilays some of the blame for the increased red tape on scientistswho try to skirt regulatory oversight by passing off their clin-ical research as quality improvement projects, which are ex-empt from IRB approval. Were researchers to act more re-sponsibly, he argues in his essay, regulations could be relaxedand IRBs could be more flexible. Koski suggests that OHRPwork with the research community on this shared goal.

Regulatory Oversight: Overburdened and Outdated

Recent research points to other problems with the regula-tory system. Last September a report showed that the

FDA audits fewer than 1 percent of all sites where new drugsand medical devices are tested. The report, by the InspectorGeneral of the Department of Health and Human Services,found that the agency was simply overwhelmed.

Still another problem is that the regulatory system is out-dated. The regulations were written in the 1970s, decades be-fore CROs even existed. CROs constitute a regulatory grayarea. It is not clear who is responsible for reporting adverseevents to the FDA: the drug company sponsor of a trial or theCRO that the company hires. Such confusion can cause ad-verse events to go unreported.

In her New England Journal of Medicine article, Shuchmandescribed how hazardous side effects nearly fell through thecracks in a postmarketing safety study involving aprotinin(Trasylol), an antifibrinolytic drug made by Bayer. Re-searchers with Ingenix, the CRO hired to conduct the study,found that people who took the drug were at increased risk ofkidney failure, heart failure, stroke, and death. The CRO re-ported these problems to Bayer, but Bayer did not reportthem to the FDA. It was only after Alexander Walker, a re-

Microscope, by Tom Otterness, 2007, edition of 9, 17.5”x9”x3.5,”photo by Jean Vong. Courtesy of the artist.

The copyright holder hasdenied the Publisher permission to post thisimage online.

18 H A S T I N G S C E N T E R R E P O R T March-April 2008

searcher with the CRO, said that he would contact the FDAhimself that the drug company reported the adverse events.

It’s harder for the FDA to find out about adverse eventsand violations in privately funded studies than in publiclyfunded ones. “If the research is privately funded, there’s lessfederal oversight,” said Michelle Mello, an associate professorof health policy and law at the Harvard School of PublicHealth. “Federal funding is a hook that the government canuse for oversight. When there isn’t funding involved, the gov-ernment has to work a little harder.”

It must work harder still when clinical trials are conductedabroad. A new trend is to move clinical trials to India, China,and Eastern Europe. In 2007, 38 percent of trials registeredon ClinicalTrials.gov were conducted overseas, up from 16percent in 2001. Pharmaceutical companies expect that up to65 percent of their FDA-regulated clinical trials will takeplace offshore within the next two to three years, according tothe Tufts Center for the Study of Drug Development.

“It’s easier and cheaper to recruit subjects in India andEastern Europe,” said Mello. But, she said, there is less pro-tection for research subjects; federal regulations do not extendto all American-based trials conducted abroad. And yet thesesubjects are particularly vulnerable to exploitation because oflow education levels, illiteracy, language barriers, and poverty.“Aside from formal regulatory structures, there’s the questionof what’s going on at research sites abroad,” she said. “Inmany developing countries, the infrastructure for human sub-jects protection isn’t what it is here.” The Tufts Center pre-dicts that over the next several years, drug sponsors, regulato-ry agencies, and human subjects protection programs will in-crease training and oversight of foreign-based investigators tobring them into compliance with U.S. regulations.

Toward Safer Trials

The conversations about regulatory failures, conflicts of in-terest, and other threats to clinical research are beginning

to yield plans for averting a crisis. Responding to doubtsabout how well Jolee Mohr understood the risks of the Tar-geted Genetics trial, the American Society of Gene Therapy islooking for ways to clarify the informed consent process. “In-formed consent is challenging,” said Arthur W. Nienhuis,president of the gene therapy society. “There’s always concernabout therapeutic misconception, especially when clinical in-vestigators are often physicians recruiting their patients.”

The American College of Physicians’ educational programappears to be helping to improve communication betweenphysician-researchers and the patients they recruit for clinicaltrials. The ACP has a brochure for doctors to hand out to pa-tients who are considering participating in clinical trials. It in-cludes a long list of questions for patients to ask, such as:What are the potential benefits and risks to me of participat-ing in the study? Who is paying for the study? Who will makemoney from the results? As both a researcher and my doctor,how will your research goals affect your decisions about myregular care? “From what we have heard from physicians, we

think the program has been of assistance in raising conscious-ness about research integrity and ethics issues,” said Lois Sny-der, director of the ACP’s Center for Ethics and Professional-ism.

Another sign of hope came last September, when the Foodand Drug Administration Revitalization Act was passed. Itcontains a new requirement that efficacy trials be registered ina national database, and that all findings be available for any-one to read. This stipulation should make it harder for drugcompanies to hide adverse events. The act also increased theFDA’s funding, which, with any luck, will translate into moreinspections of clinical trials.

Where to begin reforming the oversight of clinical trials ismore challenging and controversial. How can the regulatoryreins on human research be eased to lessen the bureaucraticstranglehold without sacrificing bedrock protections of clini-cal trial subjects? What should be done to minimize conflictsof interest in clinical research and on ethical review boards?What would it take to change the culture of clinical researchto make all the participants—researchers, IRBs, and regulato-ry agencies—more committed to protecting human volun-teers? There are no answers yet. But at least the questions arebeing asked.