- Requesting Feedback About IRB Educational Resources
- Subversive Subjects in Clinical Trials
- ClinicalTrials.gov – Pushing Research Forward
- IRB Advisor, December 2017: Finding a Path to Informed Consent for the Addicted
Requesting Feedback About IRB Educational Resources
As 2017 comes to a close, I am reflecting back and planning ahead. The IRB Connection Newsletter is just one of many educational resources offered by the IRB Education & Outreach Group in the Human Subjects Office. We hope the content has been useful for you. We would very much appreciate your feedback about all of our educational resources to help us provide guidance and support that meet the needs of the UI research community in the coming year. Click here to complete a very brief (2 minute) feedback survey.
You may also contact me directly at firstname.lastname@example.org or 319-335-8477.
Subversive Subjects in Clinical Trials
By Patricia Katopol, PhD
Prior to the 1970s, it was common for pharmaceutical firms to use prisoners as research subjects. Prisoners were available in large numbers, did not question study risks (usually because they were not told about them or were misled about the level of risk), and would accept any compensation because frequently they had no other way to earn income while incarcerated. The introduction in 1978 of federal protections reduced the availability of this population for research, so that pharmaceutical companies felt the pressure as they came to need more subjects for an increasing number of trials. This increased need sometimes resulted in less stringent subject selection. This article reviews some of the concerns raised in Subversive Subjects: Rule-breaking and Deception in Clinical Trials about the effect of subversive behavior in a clinical trial.
Subversive Subjects - Investigators may assume that the 20 million people who participate in US trials each year volunteer with the best intentions, however, literature framing the clinical trial volunteer as ‘subversive’ suggests something different. Subversive subjects place their own interests and concerns above those of the trial - adjusting medication doses, ignoring dietary restrictions, lying about pre-existing conditions, etc. This should not be surprising, as subjects are humans who continue to act primarily for their own good and to reach non-altruistic goals. For example, in Professional Guinea Pig: Big Pharma and the Risky World of Human Subjects, the author noted that a number of Philadelphia anarchists participated in trials to raise money to purchase group houses for the anarchist community.
‘Professional’ subjects (those who participate in multiple studies as a source of income) are on a continuum. On one end, they tend to be white, educated, with money to travel to test sites around the country, and with access to information about trials – learning which ones to avoid or which pay the most. Riskier trials often attract low-income minorities, recently released prisoners, the unemployed, and the unemployable - those on the other end of the continuum. Poor black and Latino subjects wind up in trials that provide needed medical care or that pay small amounts for multiple visits while healthy white subjects stay on site and participate in studies with substantial compensation. Participating in multiple trials is not the sole indicia of subversiveness, but can be a strong predictor that subversive behavior may occur.
Investigator conduct and subversive subjects –Investigator conduct, beginning with the study design itself, may lead to subject misbehavior. Design that does not consider human behavior may contribute to subversive actions such as violating rules for mandatory bedtimes, seeking outside food, drinking alcohol, or taking non-study drugs. Failing to explain study risks adequately can encourage subversion if subjects come to believe that they cannot trust the research team. Lack of study oversight (misconduct) can also encourage subjects to be subversive. When PIs overlook exclusion criteria (thereby increasing risk), treat subjects poorly with long waiting times, inconsiderate staff, or staff who lack knowledge about the study, some subjects may drop out, but other subjects may be encouraged to put up with these problems, gaming the system for their benefit.
Subversive subjects may manipulate their behavior during the trial so that they appear to be compliant, making them attractive to investigators, who may even recruit them for new trials before the first one is completed and before the recommended 30 day waiting period. Or, when volunteering for new studies, subjects may give no indication of their previous involvement in other studies, detoxing with diets and herbal remedies or taking iron supplements to hide the effects of multiple blood samples. Subjects may fall into subversion when they do not report symptoms related to the test drugs because they want to receive the entire compensation for completing the study or because they believe that the study drug will improve their health. Clinical trial protocols typically require investigators to withdraw subjects when necessary to protect the subject, even if the subject wishes to remain in the study.
Investigators may be unable to do all of the investigation necessary to reveal subversive subjects, but there are ways to minimize the likelihood of enrolling them or limit their negative effect on the study results. For example, one study used inhalers that recorded the day and time of dosing, making it easy for the PI to determine whether the subject had dosed as reported. Investigators can also ask for more demographic data to track subject travel and uncover possible participation in other trials.
Conclusion – Subversive subjects may be present at higher levels than investigators want to believe. Their behavior can cause adverse events that may be wrongly attributed to study interventions, or even result in the termination of a trial. Whether subjects enter into a moral agreement that obligates them to abide by study rules is debatable. It is easy to put all of the blame on the subject, however, investigators share this blame when they fail to do the due diligence that might reveal pre-existing conditions, participation in multiple trials in a short span of time, design studies that make it easy for subjects to subvert the protocol, or provide compensation that incentivizes subjects to take risks they would normally avoid.
ClinicalTrials.gov – Pushing Research Forward
By Brian Brotzman, MA
ClinicalTrials.gov is a public database containing information about federally and privately supported clinical trials for an array of diseases and conditions. All Applicable Clinical Trials (ACT) are required to register, with the potential to accrue severe penalties for non-compliance. Additionally, studies with NIH funding or studies that are planning to publish trial information in an ICMJE journal may require registration.
Clinical Trials.gov is a service of the U.S. National Library of Medicine (NLM) of the National Institutes of Health (NIH), and operates in compliance with Food and Drug Administration Amendment Act (FDAAA 801). Although the federal regulation pertains to the FDA, they do not actually oversee ClinicalTrials.gov. Similar to how IRB’s must endeavor to avoid potential conflict and bias from the institution they represent, ClinicalTrials.gov operates outside of the FDA to assure the law is interpreted and implemented without bias.
According to the September 2016 posting in the Federal Register, this database is intended to:
- Help patients find trials for which they might qualify
- Enhance the design of clinical trials and prevent duplication of unsuccessful or unsafe trials
- Improve the evidence based that informs clinical care
- Increase the efficiency of drug and device development processes
- Improve clinical research practice
- Build public trust in clinical research.
The regulations require the posting of the results of both successful and unsuccessful clinical trials, providing information that has not been available in the past when only the small proportion of studies that showed favorable results were submitted for publication. The requirement to publically post clinical trial information holds investigators to a higher standard, which improves the quality of human subjects research.
Applicable Clinical Trials
There is an Applicable Clinical Trial (ACT) checklist on ClinicalTrials.gov which can be used to determine if a study is subject to the reporting requirements of FDAAA 801. Find the full checklist at https://prsinfo.clinicaltrials.gov/ACT_Checklist.pdf.
Applicable Clinical Trials meet the following criteria as outlined in the checklist:
- Prospective assignment to an intervention(s)
- At least one of the following are true:
- At least one study site is in the US OR
- The study is conducted under an Investigational New Drug (IND) application or an Investigational Device Exemption (IDE) OR
- The study drug, biologic or device manufactured in the U.S. and exported for the research to be conducted in another country
- The study evaluates a drug, device, or biologic regulated by the FDA
- The study is not a phase 1 study or an early device feasibility study
Penalties for Noncompliance
The penalties for non-compliance are significant and can apply to both the sponsor (or sponsor-investigator) and the institution. A UI investigator found in non-compliance could affect the current and/or future funding to the institution as a whole. Penalties include the following:
- Fines of up to $11,383 per day until the issue is resolved
- Loss or denial of funding
- A notice of noncompliance published in the public record
- Potential criminal prosecution.
Protocol Registration and Results System
To publish information on the public website, www.clinicaltrials.gov, sponsors and PIs must use the Protocol Registration and Results System (PRS) at register.clinicaltrials.gov. From the homepage, users will enter their HawkID and password, along with an organizational ID to connect with their institution’s database. The University of Iowa’s organizational ID is ‘uiowa’.
The PRS record consists of two parts: the Registration, or Protocol, Section and the Results Section. The PRS record may be updated at any time, but there are time frames for certain changes.
- Results must be reported within one year of the Primary Completion Date.
- Protocol changes must be reported within 30 days.
- A change in approval or clearance status of a device must be reported within 15 days.
NIH & ICJME Requirements Regarding ClinicalTrials.gov
For some studies, registration on ClinicalTrials.gov is required even if the trial does not meet the criteria of the federal regulations. Both the NIH and the International Committee of Medical Journal Editors (ICMJE) have specific related policies.
All NIH-funded clinical trials must now register in ClinicalTrials.gov, even phase 1 and device feasibility trials which are exempt from the federal regulations. The NIH definition of ‘clinical trial’ includes any study involving prospective assignment and an intervention to evaluate a biomedical or health related outcome. This means, for example, that NIH could require registration for studies that evaluate a behavioral intervention, even if no drug or device are involved. More information on the NIH policy can be found at https://grants.nih.gov/policy/clinical-trials/definition.htm.
ICMJE policy is similar to the NIH policy. Most studies that want to publish in their scientific journals must register on ClinicalTrials.gov. However, unlike NIH regulations and FDAAA 801 which give investigators 21 days after enrolling a subject to register the trial, ICMJE requires registration prior to enrolling the first subject. More information on ICMJE policy can be found at http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html.
See the Clinical Trials.gov page of the Human Subjects Office website for additional information about clinical trial registration and results reporting.
IRB Advisor December 2017
Finding a Path to Informed Consent for the Addicted
Ninety-one Americans die every day from an opioid overdose. Since 1999, deaths from opioid overdoses have tripled. Research in addiction is key to solving the opioid crisis. But a major question remains: what can be done to ensure that researchers obtain effective informed consent from people who are addicted to drugs? Laura Roberts, PhD, at the Stanford University School of Medicine, is leading a team to try to answer this question. Dr. Roberts and her team are working with IRB members, neuroethicists, and research subjects to try to develop new tools to ensure individuals with addiction and mental health issues are giving properly informed consent.
The IRB Advisor article is a Q&A between the editors of IRB Advisor and Dr. Roberts, that covers Dr. Roberts’ background, the purpose and aims of the research, how they plan to work with the IRB, and how the research might affect future addiction treatment as well as consent.
You can read the full article, “Finding a Path to Informed Consent for the Addicted,” in this month’s IRB Advisor. Other articles in the December issue of IRB Advisor include:
- IRBs Must Prepare for Studies Involving Transgender Populations
- De-identifying Data in Qualitative Research Is Complex, Time-consuming
- Informed Consent Conundrum: Making the Complex Concise
- PRIM&R Finds Itself Caught in State Travel Ban Controversy
- Are Organ Transplant Recipients in a Trial Protocol Considered Research Subjects?
Current and Past Issues
There is a link to current and past issues of IRB Advisor on the Education and Training page of the Human Subjects Office web site. This link provides automatic access to the newsletter from all computers with a University of Iowa IP address.
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Continuing Education Credits
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