Acknowledging the dual enrollment challenge
Wednesday, June 15, 2016
When a sponsor or CRO is forced to throw out data or write off an entire study, millions of dollars are at stake. These are the high stakes that characterize the dual enrollment challenge.
Enrolling just one ineligible subject already in a simultaneous study could cost a sponsor tens of thousands of dollars or more. When dual enrollment goes undetected and the entire study must be repeated, millions of dollars, and more importantly time, is wasted. Dual enrollment is often unmeasured and considered by many to be much less common than it once was. However, current data reveal it to be a very real risk that is still widespread.
The reasons behind dual enrollment are varied. Some patients are simply seeking the best care and treatment available. Bonnie A. Brescia, founding principal of BBK Worldwide, said, “Patients are looking for more and better options to address their conditions and diseases. When patients come to believe that one study isn’t right for them, they may move on to another study offering greater hope for success. Often, these same patients stay in the two studies with the belief that finishing their participation is a value to the study and to the development of future treatments.”
Sponsors may be unwittingly creating environments that foster dual enrollment. “Sponsors are challenged by the impact of confounded data along with worries about safety whenever participants deviate from the protocol,” added Brescia. “Increasingly, sponsors—and all stakeholders—are adopting patient-centric practices and committing themselves to treating study participants as true partners. The better partnerships we create with study participants, the more respect we provide patients, the greater the likelihood that inadvertent dual enrollment will not occur. Patients, in our experience, are not interested in gaming the system, but rather in receiving the care and treatments they require.”
Kerri Weingard, chief operating officer of Verified Clinical Trials (VCT), finds that common reasons for dual enrollment include financial gain, loss of a job, loss of insurance and the cost of standardized care.
The issue at hand
Dual enrollment can cause problems on multiple levels. First, it compromises study integrity. When someone is enrolled in more than one study protocol at the same time, it can profoundly affect both studies.
As Gary Zammit, Ph.D., president and CEO of Clinilabs, explained, “In cases where the subject is taking two or more study drugs according to the different protocols, the investigator’s ability to derive meaningful data from the subject’s participation in both projects may be so impacted that the data provided by the subject are useless. When combined with data from other subjects participating in a clinical trial, the dual enroller’s data may corrupt the entire data set. The investigator’s ability to derive meaningful conclusions about efficacy and safety based on such data is unquestionably impaired.”
Likewise, if the subject is taking the study drug from one protocol but not the other, both studies are once again affected. Even in cases where the subject is enrolled in multiple studies and not taking any study drug, the results of all enrolled studies are corrupted.
Even subjects who are not taking a study drug may still be putting themselves at risk due to the procedures involved in various studies. In studies requiring multiple blood draws, subjects may have too much blood drawn. For studies involving exposure to radiation, subjects may be overexposed.
Also at issue is the subject’s overall honesty and willingness to report adverse effects. VCT’s Weingard said, “Dual enrollment also affects the subject’s personal safety. When a volunteer enrolls in more than one trial, they may suffer an adverse or serious adverse event due to the effects of the concomitant investigational products. The volunteer may also not be forthcoming and may mask effects of the drug or misrepresent actual drug therapy responses to ensure that they stay in the trial. This can obviously increase the placebo rates of the investigational product, making the perceived efficacy less than expected.”
Zammit also delves below the surface of the issue. He said, “In general, I am concerned that subjects who misrepresent their participation in clinical trials in order to dual enroll also may misrepresent their compliance with self-administration of study medication. Some of these subjects also may misrepresent their medical histories in order to gain entry into multiple studies. In some cases, it clearly is fraud.”
Christian Burns, president of Clinical Operations and Marketing at ClinEdge, concurred. “Patients have even discussed clinical studies on social media and which are the best to turn a profit! I have even seen some patients abusing the system say they can make over $50,000 per year by participating in multiple studies.”
Dual enrollment can also violate regulatory compliance if the study protocol specifies that a subject should not have participated in another clinical study within a certain amount of time before starting the present study; and if certain medications are prohibited by the study’s inclusion and exclusion criteria, and the subject is receiving that medication as part of their participation in another trial.
Lastly, dual enrollment can also lead to financial consequences for the investigative site. If a subject falsifies their social security numbers, when investigators report payments to the federal government on 1099 forms as required, the subject’s name and social security number do not match, and the research site becomes responsible for paying the tax.
Prevalence and geography
Industry experts estimate that 10% to as much as 28% of all volunteers in a given clinical trial are dual enrollees. The prevalence of dual enrollment varies widely by geographic region, therapeutic area and especially by study phase.
BBK Worldwide’s Brescia has seen a large drop in dual enrollment rates during the last five-to-10 years. She attributes this to the fact that more and more clinical research is supported by technologies that enhance data monitoring, adding that while this type of dual enrollment has decreased in most countries, in places like Japan where electronic data capture isn’t fully used, the problem has increased.
Brescia sees greater risk of dual enrollment in countries where patients have free access to choose their healthcare providers, including Belgium, Japan and the U.S. This risk is due to there being fewer safeguards able to detect overlapping participation. The greatest dual enrollment she sees continues to be in studies of healthy volunteers.
Looking at specific geographic regions of the U.S., ClinEdge’s Burns said, “Dual enrollment is definitely an issue across clinical trials right now, especially in primary care indications. As clinical trials become more accessible and heavily advertised, ‘professional patients’ can easily find clinical trials that offer monetary compensation. In geographic locations such as Florida, California and Texas, we see the highest amount of dual enrollment happening. There is a research facility on every block in some of those areas.”
Brad Vince, D.O., CEO and medical director of Vince & Associates, said, “Dual enrollment is a significant issue that effects all phases of clinical research and is more common than most clinical sites realize.”
VCT’s Weingard added, “Probably the most important concept is that no clinical trial is immune to the problem of dual enrollment.”
Clinilabs’ Zammit feels strongly that while dual enrollment is very common, the magnitude of the problem has not been quantified. He said, “Some organizations or investigators publicly claim that the problem is rare or that ‘it doesn’t happen at my research facility.’ However, they absolutely are in denial, and do not have the data to back up their conclusions.”
Nearly 24% of potential enrollees were found to be in violation of the protocol in a case study of 286 consecutive subjects submitted at Clinilabs’ New York facility. Of these, nearly 11% were screening elsewhere or were potential dual enrollers. Concerning these results, Zammit said, “These findings are not idiosyncratic to NYC or to our facility; I believe that all investigator sites have this happening at about the same level, and some may be worse. It does not relate to the population density of a community or the number of clinical trials in a geographic area.”
VCT has measured high prevalence of dual enrollment and protocol violations in healthy volunteers followed by phase II and III pain, migraine, insomnia, CNS and endocrine system studies.
The time needed to screen for potential dual enrollers can range from five to 15 minutes per participant, depending on the method used. Several strategies are available, and using them in combination is considered most effective.
Burns reports that at ClinEdge, a simple pre-screening questionnaire implemented by their in-house call center can weed out patients already enrolled in a clinical trial or those who seem unusually interested in compensation, consistently reducing the Screen Fail Ratio across studies. In areas known for dual enrollment, they rely on other solutions as well, including the services of an electronic database.
Clinilabs also relies on a commercial database to determine whether a subject is screening or enrolled at another site, or in a lockout period. Zammit details a seven-step subject authentication process that includes photocopying each subject’s government-issued photo ID, collecting the subject’s W-9 form and comparing a given social security number to the IRS database, directly asking them if they’re enrolled in other trials and evaluating a subject more than once to make sure their responses are consistent.
Zammit recommends that all investigative sites perform a similar process and that all sponsors include it in their study budgets. “Since we started subject authentication, the number of dual enrollers who even try to get into a study at our facility has dropped dramatically,” said Zammit. “But they do go elsewhere and get in!”
VCT’s Weingard said, “Despite best efforts, unless they use a research subject database, there is absolutely no way to prevent dual enrollment, washout period violations and same-compound violations.”
Such a database offers many practical advantages. First, it unmasks potential subjects who attempt to lie, as HIPAA guidelines prevent investigators from accessing research records without the subject’s written consent. Even when written consent is given, it can take weeks to obtain the records from another site. Further delays are caused when records are kept off-site, or when a site closes. The information available is often limited at best, excluding compound dosing information. Furthermore, even honest patients may not remember the details of their past study participation.
VCT offers a database that incorporates security measures. VCT has conducted over 100,000 verifications on potential research volunteers. VCT’s Weingard reported, “In phase I, healthy volunteer studies, up to 25% of protocol violations and attempted dual enrollment can be stopped by utilizing a research subject database. In phase II-III studies, specifically in pain, psychiatry, CNS, musculoskeletal, endocrine and subjective diseases, nearly 15% of protocol violations and dual enrollment attempts can be prevented by using this clinical trials research database.”
The VCT database works like this: all partial identifiers entered into it are run through a robust algorithm and encrypted to create a de-identified unique identification code connected to that research volunteer’s research history within VCT. Only the research site and VCT staff can view the subject’s personally identifiable information, and VCT holds the subject’s information in a private silo in a secure, encrypted environment. The database generates a report listing each potential subject along with the activity that disqualifies them from entering the current study—everything from their involvement in screening at a different site, previous enrollment in the same protocol number or being in a lockout/washout period.
Another service used to prevent dual enrollment is clinicalRSVP, which uses unique technology to screen the biometric fingerprints of potential subjects. After the screening, clinicalRSVP provides investigators with a report detailing the potential subject’s past study participation, and stores their eligibility data securely in a central blinded database. Using fingerprints means that names do not need to be collected, and study data is also not collected, eliminating any risk to sensitive study data.
Dual enrollment is more prevalent than commonly believed and it may be getting worse. More importantly, a small number of dual enrollers can dramatically jeopardize data quality and efficacy. Preventative steps, such as administering a detailed questionnaire, collecting and verifying identification information and relying on the services of a commercial database can help detect and disqualify dual enrollers of all kinds, safeguarding clinical studies in which so much time and money have been invested.
Lisa Chontos is a freelance medical writer with 15 years of experience writing for hospitals, biotech firms, pharmaceutical companies and publications like CenterWatch. You can contact her at email@example.com.
This article was reprinted from Volume 23, Issue 06, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>