Passive, opt-out recruitment strategies have the potential to improve efficiency and enlarge the participant pool for clinical studies. We report on the feasibility of using a passive consent strategy for a multicenter pediatric study.
We assessed the response to passive and active control recruitment strategies used in a multicenter pediatric cohort study and describe the variability in acceptance among institutional review boards (IRBs) and parents of pediatric patients.
Twenty-six pediatric centers submitted IRB applications; 24 centers participated. Sixteen IRBs approved the proposed passive recruitment strategy, and 6 IRBs required active consent strategies; 2 centers used a modified participation mode using control subjects from neighboring centers. In all, 4529 potential participants were identified across 22 centers. In the pre-enrollment phase, opt-out rates were significantly lower in the passive consent group compared with the active recruitment centers (1.6% vs 11.8%; P < .001). During the enrollment phase, however, refusal rates in the passive consent group were significantly higher (38.1% vs 12.2%; P = .004). The overall refusal rate across both groups was 33.3%.
IRB variability in interpretation and application of regulations affects consistency of study procedure across sites and may reduce validity of study findings. Opt-out consent allowed us to create a large representative pool of control subjects. Parents were more likely to refuse to be approached for a study in the pre-enrollment phase when active consent was used, but were more likely to decline actual study enrollment when passive consent was used in the pre-enrollment period.
Clarifying Human Subjects Regulations Enables More Consistent Application
Dr. Schreiner's comments (1) underscore the challenges in interpreting and applying multiple human subjects and HIPAA regulations surrounding research in children. Our paper was aimed at a clinical researcher audience, highlighting variability in IRB application of these regulations to multi-step control subject recruitment and consent processes and the effect of this variation on enrollment. Dr. Schreiner's points highlight one of the primary conclusions of our article, which is that IRBs and researchers often have different interpretations of these regulations, and need additional guidance from the regulatory agencies and professional societies for consistent interpretation and application.
When referring to the described opt out process in the protocol for initial recruitment into a pool of potential controls, Dr. Schreiner hypothesizes that variability across IRBs whether they approved the opt out process or required active consent, is likely explained by whether or not IRBs had "checked the box" on their OHRP Federalwide Assurance.(1) He continues that FDA regulations do not require consent or a waiver of consent for recruitment activities such as review of records or sending recruitment letters to prospective subjects whereas OHRP regulations do. Our observational study was not considered by the CDC (the funding source) to be under FDA regulation. CDC requires that all research involving human participants conducted or supported by CDC must comply with the HHS Policy for Protection of Human Research Subjects (45 CFR part 46).(2) Therefore all sites needed to comply with 45 CFR part 46 and the issue of whether sites checked the box was irrelevant.
Dr. Schreiner states that "there is no such thing as passive consent".(1) He references the OHRP's summary of this topic which acknowledges that the terms "passive or implied consent" are used by researchers, but that the current regulations do not explicitly recognize these terms.(3) The OHRP summary notes specifically the following example: "The term "passive consent" is sometimes used in research with children to describe situations in which the investigator can assume that a parent is permitting a child to participate. For example, researchers collecting survey and behavioral data from children at school provide parents with information regarding the study by mail and ask the parent(s) to return a form if they do not want their child to participate....If the IRB determines that the conditions for waiver of parental permission can be met, then the IRB could waive the requirement for parental permission under 45 CFR 46.408(c) or 45 CFR 46.116(c) or (d)."(3) Although we acknowledge that we did not use the term "passive consent" in the submitted protocol, when we prepared the manuscript we wanted to describe a complex recruitment and enrollment process using terms we thought would be more recognizable to researchers, and consistent with what was already in the literature. In the protocol we used the term "opt out" and the process for control recruitment was similar to the OHRP example, with an opt out letter sent to parents stating in bold that if they did not want their child's limited personal and health information to be sent to Abt for consideration as a potential control, that they needed to notify the site to decline. We completely agree that passive consent or failure to opt-out does not substitute for seeking and obtaining parental permission when a waiver of informed consent cannot be justified.
Finally, we thank Dr. Schreiner for clarifying that our manuscript's protocol requested from IRBs a partial waiver of HIPAA authorization to obtain from each site the minimum information required to identify, contact, and recruit parents of potential controls. If the local site IRB did not grant the partial waiver of HIPAA authorization, then the site had to obtain permission from the parent or legal guardian of each potential control, prior to providing contact information or any other protected health information to Abt Associates. Abt Associates and all study partners entered into agreements required by each covered entity to obtain the PHI needed for the study. We described how sites varied in the types of agreements required. Some required only the subcontract with Abt and others entered into a formal business associate agreement.
We thank Dr. Schreiner for raising these issues, which enhances the understanding of our findings. We hope that the above clarifications will assist IRBs to more consistently evaluate studies similar to ours.
References 1. Schreiner, MS. There is no such thing as passive consent. Pediatrics. eLetter posted August 23, 2014. 2. Centers for Disease Control and Prevention. Human Participant Protection in CDC Research. Available at: http://www.cdc.gov/od/science/integrity/hrpo/ (Accessed October 1, 2014). 3. Department of Health and Human Services. Office for Human Research Protections. Can consent or parental permission ever be "passive" or "implied"? Available at: http://answers.hhs.gov/ohrp/questions/7249 (Accessed September 30, 2014).
Conflict of Interest:
None declared
As a chair of one of the local IRBs that reviewed and approved clinical trial entitled Influenza Vaccine Effectiveness in High-Risk Children, I read Higgerson et al.'s recent paper Variability in IRBs Regarding Parental Acceptance of Passive Consent with particular interest. (1) Unfortunately, some of terminology, starting with the title, is inaccurate and in other places the paper misrepresents some of the regulatory issues. In particular, the use of the terms passive consent and opt-out consent are incorrect as is part of the discussion of HIPAA.
While the title and much of the paper uses the terms opt-out consent and passive consent, neither is mentioned in the protocol and for good reason. Neither the FDA nor OHRP accept the validity of passive consent; consent must be obtained directly from research participants unless the IRB waives the requirement for consent. (2) In any case, the investigators were sending a recruitment letter, a procedure that does not, in and of itself require consent.
The consent requirements for the recruitment of subjects - review of medical records and retention of contact information - differed between the IRBs depending on whether or not the local IRB had "checked the box" on their FWA application. OHRP's interpretation is that consent is required to retain a record of potential subjects while the FDA does not require consent for recruitment activities. (3) Since this study was subject to FDA regulations, IRBs who had not checked the box did not have to issue a waiver of consent for review of records or to send a recruitment letter to prospective subjects. On the other hand, institutions that had checked the box needed to either obtain the prospective subject's consent or to have the IRB issue a waiver of consent.
In their discussion of HIPAA, the authors inaccurately state that the required authorization for use of PHI "can be waived for activities preparatory to research". The use of PHI for reviews preparatory to research does not require a waiver by an IRB. Rather, "The covered entity obtains from the researcher representations that..." the review meets the criteria enumerated in 45 CFR 164.512(i)(1)(ii). Further, reviews preparatory to research would not have been relevant to this study because PHI was being transferred from the local site to Abt and ?164.512(i)(1)(ii) states that "No protected health information is to be removed from the covered entity by the researcher in the course of the review."
In describing variability between IRBs it is important to accurately report the regulatory requirements, both globally and as they apply to the local sites. Without an analysis or discussion of the status of each IRB's obligations under their FWA, important information is missing needed to understand IRB variability. The regulatory requirements for the various waivers were accurately outlined in the protocol; unfortunately this information did not make its way intact into the paper. Instead, the authors used inaccurate terminology and misrepresented some of the HIPAA regulations. As a result, the value of this contribution to the literature has been greatly diminished.
1. Higgerson RA, Olsho LE, Christie LM, Rehder K, Doksum T, Gedeit R, Giuliano JS, Brennan B, Wendlandt and R, Randolph AG, and PALISI PICFlu Study Investigators. Variability in IRBs Regarding Parental Acceptance of Passive Consent. Pediatrics. 2014;134(2):e496-503.
2. Department of Health and Human Services. Office of Human Research Protections. Can consent or parental permission ever be "passive" or "implied"? Available at: http://answers.hhs.gov/ohrp/questions/7249. Accessed August 22, 2014
3. Informed Consent Information Sheet. Guidance for IRBs, Clinical Investigators, and Sponsors. Draft Guidance. Available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM405006.pdf. Accessed August 22, 2014.
4. Institutional Review Boards and the HIPAA Privacy Rule. Available at: http://privacyruleandresearch.nih.gov/irbandprivacyrule.asp. Accessed August 22, 2014
Conflict of Interest:
None declared