Ethical Foundations and Requirements
Alternative procedures for disclosing information and obtaining authorization for research participation may be allowable, but should remain consistent with the ethical principles outlined in the Belmont Report. Alternative forms of disclosure and authorization may be less burdensome and ethically sound in the conduct of some types research, such as some PCTs or when this research is randomized by cluster (i.e., by hospital, primary care provider, etc).
An IRB may waive or alter the requirements of informed consent if all of the below are deemed true:
“(1) The research involves no more than minimal risk to the subjects;
(2) The waiver or alteration will not adversely affect the rights and welfare of the subjects;
(3) The research could not practicably be carried out without the waiver or alteration; and
(4) Whenever appropriate, the subjects will be provided with additional pertinent information after participation.” §46.116
In this section, we expand on 2 key elements in the requirements to waive or alter informed consent: minimal risk and practicability.
Minimal Risk Research
Numerous questions have been raised about how best to define minimal risk: Does randomization itself cause more than minimal risk? In a cluster-randomized trial, if sites are randomized to interventions thought to be in clinical equipoise, is that minimal risk? Should minimal risk be judged relative to healthy people or to people with the disease or problem under investigation? In a cluster, is minimal risk determination an assessment of the average or does the study need to be minimal risk for every person in it?
A definition of “minimal risk” is provided in the Common Rule:
“Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” §46.102
However, this the definition has proved hard to apply in actual practice. For example, the Time to Reduce End Stage Renal disease (TiME) trial evaluates a minimum hemodialysis session duration of at least 4.25 hours (if determined medically appropriate by the treating nephrologist) compared with usual care (no trial-driven approach to session duration) for patients with end-stage renal disease to improve survival and quality of life for patients with kidney failure (Dember et al. 2016). The patients are, arguably, a high-risk population because they have end-stage renal disease. Although observational data suggest that longer dialysis times are associated with better outcomes, there was initial concern about the ability to designate this research as “minimal risk” because of the study population.
The notion of what, exactly “practicability” means in the clause “the research could not practicably be carried out without a waiver” can also be difficult to discern. To clarify this, the Secretary’s Advisory Committee on Human Research Protections (SACHRP) put out a set of recommendations regarding why research could not reasonably be carried out without a waiver include:
- “scientific validity would be compromised if consent were required because it would introduce bias to the sample selection
- subjects’ behaviors or responses would be altered, such that study conclusions would be biased
- the consent procedure would itself create additional threats to privacy that would otherwise not exist
- there is risk of inflicting significant psychological, social or other harm by contacting individuals or families.” (From Attachment D: Informed Consent and Waiver of Consent)
Once the IRB has determined that the waiver or alteration does not adversely impact the ethical nature or scientific rigor of the research, logistical issues for a proposed modified consent process may be considered.
Possible Future Regulatory Requirements Related to Alternative Approaches to Disclosure and Authorization
The proposed changes to the Common Rule establish new exempt categories of research based on risk profile, and research fitting these categories would need only limited IRB review to ensure adequate privacy safeguards for the research.
The revised Common Rule also allows the use of broad consent for the use of identifiable information or identifiable biospecimens for other research studies (other than the proposed one) for
- Storage and maintenance for secondary research use
- Secondary research (including future uses)
Broad consent is permitted as an alternative to informed consent for a future research study. In addition to selected standard elements of traditional informed consent, broad consent should also include:
- A description of the types of research that may be conducted
- What information/biospecimens will be used
- Period of time of storage and maintenance
- If applicable, the subject will not be informed about specific research studies
- Disposition of clinically relevant research results
- Contact information §__.116.d
If broad consent is implemented for a particular study, and a potential participant refuses to consent, then the IRB can no longer grant a waiver of consent. This may make this approach to doing research under broad consent logistically complicated or infeasible.
Approaches to Alteration of Consent
In cases when traditional informed consent is waived or alteration of consent is approved, the approaches to disclosure and authorization shown below may be appropriate from both a regulatory and ethics perspective.
- Broad notification includes using posters, emails, brochures, social media or web portals, etc. to provide opportunities to inform patients that research is being conducted (McGraw et al. 2015). In some cases, a waiver of consent may be granted, but an IRB may still require that particular study information be posted.
- Example: The Randomized Evaluation of Decolonization versus Universal Clearance to Eliminate MRSA (REDUCE MRSA) trial (Huang et al. 2013), compared three strategies in current use for preventing methicillin-resistant Staphylococcus aureus (MRSA) infections in adult intensive care units (ICUs) of a single health system. Although a waiver was granted, the IRB required that notices were posted in each ICU room to provide an opportunity for patients and their families to be informed.
- Potential participants can decline to participate.
- Example: The Strategies and Opportunities to Stop Colorectal Cancer in Priority Populations (STOP CRC) trial was designed to improve rates of colorectal-cancer screening among the predominantly minority and low-income patients who receive health care services through Federally Qualified Health Centers (FQHCs; Coronado, Burdick, et al. 2014). Prospective participants are identified in the electronic health record as being aged 50-74 years and not up-to-date with colorectal-cancer screening guidelines. Investigators send these individuals an Introduction Letter that explains the program and provides an option to opt out of the mailed program by contacting the FQHC (Coronado, Vollmer, et al. 2014). The letter says: “If you have had a colonoscopy in the past 9 years or prefer that we not mail you a test, please contact us at xxx-xxx-xxxx.” Patients who do not opt out subsequently receive a fecal immunochemical test (FIT) kit in the mail with a letter and a set of wordless instructions. Participants who do not opt out are also reminded by post card or phone to complete their tests. It is worth noting that the letter did not include an option to opt out of data collection for research activities. De-identified data was provided to the investigators from the Oregon Community Health Information Network (OCHIN).
- Prospective participants are asked (either in writing or orally) if they would like to participate in a research trial, and are included if they say “yes” or opt in. This agreement is usually documented in the EHR.
- Example: The goal of the Collaborative Care for Chronic Pain in Primary Care/Pain Program for Active Coping and Training (PPACT) trial is to coordinate and integrate services for helping patients adopt self-management skills for managing chronic pain, limit use of opioid medications, and identify exacerbating factors amenable to treatment that are feasible and sustainable within the primary care setting (Debar et al. 2012). Prospective participants are sent a letter that explains the program and that someone from the PPACT team may call to explain more about the program. The letter provides a phone number to call if the individual would prefer no further contact with the investigative team—to opt out. When the team member discusses the program, the individual will be given the opportunity to opt in, which will be recorded in the EHR.
- A short form may be used stating that the elements of informed consent as required by §46.116 were presented orally, although the consent document is shorter, the consent process itself may be longer (McKinney et al. 2015). According to §46.117 the requirements for using a short form include:
- A witness to the oral presentation
- An IRB-approved written summary of what is to be said to the participant (or representative)
- Signatures, as follows
- Short form to be signed by participant (or representative) and witness
- Copy of the summary to be signed by witness and person actually obtaining consent
The Office for Human Research Protections (OHRP) and the Food and Drug Administration (FDA) published a Guidance for Institutional Review Boards, Investigators, and Sponsors on use of electronic consent. According to the guidance:
- Electronic consent must contain all required elements of informed consent, be presented in an easily understandable manner, and minimize the possibility of coercion.
- If the consent process takes place remotely, the electronic system “must include a method to ensure that the person electronically signing the informed consent is the subject who will be participating in the research study or is the subjects legally authorized representative.”
- Subjects should be given contact information for questions.
- Interactive technology (such as quizzes) may be used to assess comprehension
- The electronic consent form must include a statement that significant findings that could affect the participant’s willingness to participate will be shared.
- Electronic signatures can be used to document consent, although steps should be taken to verify the identity of participants before commencing study-related activities.
- For pediatric studies, parental permission may be obtained electronically using the same procedures as informed consent.
- Informed Consent
- Alternative Approaches to Disclosure and Authorization
- Non-disclosure of Research Activities
- Data on Different Approaches to Disclosure
- Appendix: US Regulatory Agencies
- Appendix: Regulatory Frameworks
- Appendix: Institutional Regulatory Oversight
- Appendix: Emerging Regulatory Issues
For pragmatic clinical trials, minimal risk determinations have been variable and confusing. The authors of the article, Considerations in the evaluation and determination of minimal risk in pragmatic clinical trials (Lantos et al. 2015) examine factors involved in the determination of minimal risk for pragmatic clinical trials and advocate for an assessment based on incremental risk. The implications for informed consent are also explored.
In October and November of 2017, the PCORnet E-consent Workgroup hosted a two-part webinar series to share real-world experience with implementing electronic consent within PCORnet and to disseminate best practices.
Debar LL, Kindler L, Keefe FJ, et al. 2012. A primary care-based interdisciplinary team approach to the treatment of chronic pain utilizing a pragmatic clinical trials framework. Transl Behav Med. 2:523–530. doi:10.1007/s13142-012-0163-2. PMID: 23440672.
Dember LM, Archdeacon P, Krishnan M, et al. 2016. Pragmatic trials in maintenance dialysis: perspectives from the Kidney Health Initiative. J Am Soc Nephrol. 27:2955–2963. doi:10.1681/ASN.2016030340. PMID: 27401689.
Huang SS, Septimus E, Kleinman K, et al. 2013. Targeted versus universal decolonization to prevent ICU infection. N Engl J Med. 368:2255–2265. doi:10.1056/NEJMoa1207290. PMID: 23718152
Lantos JD, Wendler D, Septimus E, Wahba S, Madigan R, Bliss G. 2015. Considerations in the evaluation and determination of minimal risk in pragmatic clinical trials. Clin Trials. 12:485–493. doi:10.1177/1740774515597687. PMID: 26374686.
McGraw D, Greene SM, Miner CS, Staman KL, Welch MJ, Rubel A. 2015. Privacy and confidentiality in pragmatic clinical trials. Clin Trials. 12:520–529. doi:10.1177/1740774515597677. PMID: 26374682.
McKinney RE, Beskow LM, Ford DE, et al. 2015. Use of altered informed consent in pragmatic clinical research. Clin Trials. 12:494–502. doi:10.1177/1740774515597688. PMID: 26374677.