What types of HIPAA waivers might I need?

When specific characteristics are satisfied, the IRB can grant a waiver of authorization under HIPAA (HIPAA waiver). The two most common types of HIPAA waivers requested by researchers are a partial HIPAA waiver for recruitment and a full HIPAA waiver. Partial HIPAA waivers for recruitment are often requested for studies when the only thing they are doing is looking into the medical records to determine if participants would be eligible even before they contact the individual. If the individual enrolls in the study, they will still need to authorize the use of their PHI prior to collection or use for the research study.

A full HIPAA waiver allows the collection and use of participant PHI for study purposes without obtaining a HIPAA authorization from the participant at all. A full HIPAA waiver is frequently approved in conjunction with a waiver of consent. 

What are the requirements for a HIPAA Waiver?

According to the Code of Federal Regulations, PHI can be used or disclosed for research if there are plans to protect and eventually destroy identifiers, and written assurances that PHI won’t be misused. The regulations state:  

1. “The use or disclosure of protected health information involves no more than a minimal risk to the privacy of individuals, based on, at least, the presence of the following elements: 
   1. An adequate plan to protect identifiers from improper use and disclosure; 
   2. An adequate plan to destroy the identifiers at the earliest opportunity consistent with conduct of the research, unless there is a health or research justification for retaining the identifiers, or such retention is otherwise required by law; and 
   3. Adequate written assurances that the PHI will not be reused or redisclosed to any other person or entity, except as required by law, for authorized oversight of the research study, or for other research for which the use or disclosure of PHI would be permitted by this subpart; 
2. The research could not practicably be conducted without the waiver or alteration; and
3. The research could not practicably be conducted without access to and use of the protected health information.”³

Generally, if there will be an interaction with the participant, or if the participant consents to be in the study, then it is practicable to get authorization as well. Likewise, if the study can be conducted without getting access to PHI, then the IRB should not grant a HIPAA waiver, and the study should be completed without access to PHI.  

What does it mean for data to be de-identified according to HIPAA?

To be de-identified, the data must not contain any of the 18 categories of identifiable information under HIPAA.⁴  

The more information collected about an individual, even if none of the 18 categories are included, the easier it is to identify that individual. When determining if a data set is truly de-identified, there needs to be an analysis of whether it is possible to re-identify the individuals in the data set either based on the data collected or when used in combination with other readily available data sources.   

If the data set does contain any identifiable information, the data may still be considered de-identified “if a person with appropriate knowledge of and experience with generally accepted statistical and scientific principles and methods for rendering information not individually identifiable determines that the risk is very small that the information could be used, alone or in combination with other reasonably available information, could identify an individual who is a participant of the information.”⁵ For example, if the data set includes birthdates and/or zip codes, there may be so many people with the same birthdate or who reside in the same zip code that it is not reasonably possible to identify any one person from that data alone. 

We are only receiving de-identified data. Do we need a waiver of authorization?

No. HIPAA only applies to identifiable information. If the data is coded or de-identified and the researcher does not have a way to re-identify the individuals, then this information is not regulated by HIPAA. 

We keep all HIPAA identifiers separate from health information. We link them by a code that is kept separate from the health information. Is this information still PHI? 

No. If the link between the data set and the identifiers is kept separate, and it is otherwise not possible to re-identify the individuals, then the data would be considered de-identified. 

Do we need to get an authorization or request a waiver of authorization to review our medical records to develop the protocol and/or to screen potential participants?

This will likely depend on institutional requirements. Some institutions specifically require their researcher to obtain a waiver of authorization to review their records. This provides an additional level of protection to ensure that the PHI is being used appropriately. 

If the institution does not have a requirement to obtain a waiver of authorization, then reviewing the medical records usually falls under the Preparatory to Research Exception of HIPAA. The regulation specifically states: 

1. “Standard: Uses and disclosures for research purposes –  
   1. Permitted uses and disclosures. A covered entity may use or disclose protected health information for research, regardless of the source of funding of the research, provided that: 
2. Reviews preparatory to research. The covered entity obtains from the researcher representations that: 
   1. Use or disclosure is sought solely to review protected health information as necessary to prepare a research protocol or for similar purposes preparatory to research; 
   2. No protected health information is to be removed from the covered entity by the researcher in the course of the review; and 
   3. The protected health information for which use or access is sought is necessary for the research purposes.”⁶ 

We will generally interpret reviewing medical records to determine which individuals could be potential participants to be similar to preparing a research protocol. 

Our data set includes dates and zip codes but otherwise does not include identifiable information. Do we need to get a HIPAA waiver?

No. This data set would be considered a Limited Data Set. Under HIPAA, this is considered to be de-identified information if there is a Data Use Agreement in place between the covered entity and the researcher where the researcher attests that they will not try to re-identify the individuals and will not disclose the information except as allowed by HIPAA.⁷ 

Do we need to get a HIPAA waiver before screening participants over the phone?

No. In this case, it is the potential participant who is providing the information, so it is not necessary to get a waiver of authorization.   

The sponsor is using remote monitoring visits, do we need to get authorization from the participants or get a waiver of authorization to provide the research records electronically to the sponsor?

In most cases, no. If the participant has authorized the sponsor to have access to their PHI, it generally does not matter if the records are provided electronically or in hard copy. Please note that if the consent form or HIPAA authorization specifically limits how the records will be viewed or shared, we will expect the site to comply with this limitation. For example, if the HIPAA authorization states that the sponsor will only have access to identifiable information when they are at the site, this limitation would preclude providing the records to the sponsor electronically, and in this case, you would need to get authorization from the participants or request a waiver of authorization. 

The participant has withdrawn from the research. Can we continue to collect information about the participant, particularly from publicly available sources like the National Death Index?

There is a distinction between withdrawing from the study and withdrawing authorization to use and disclose PHI. If the participant has withdrawn from the study but has not withdrawn their HIPAA authorization, then the site can continue to collect and use PHI as described in the consent form or HIPAA authorization. If the participant has also withdrawn their authorization to use or disclose their PHI, then the site cannot collect any additional PHI on the participant as part of the study. Please note obtaining information from publicly available data sets is not considered PHI, so sites could view the National Death Index to determine participant survivability. 

My site inadvertently sent Protected Health Information (PHI) on the participant to the sponsor. Do we need to report this as a breach? 

This will be a fact-based analysis, but generally, this will not be considered a breach. If the consent form indicates that the sponsor will have access to identifiable information, or that the research records will be provided to the sponsor, then the participant is authorizing the sponsor to have access to the PHI. In addition, the sponsor has an obligation to monitor the research, which includes going on site to review the research records, and the sponsor will have access to and may view the entire participant record. 

Questions about state-specific HIPAA expiration language added at review

Why has the board added language about HIPAA expiration dates in certain states to my consent form?

While the federal HIPAA law does not require that there be an expiration date for the HIPAA authorization, this can be modified by state law. California has long required an expiration date for the sharing of medical information. More recently, Delaware, Indiana, Illinois, and Washington have made similar requirements. In the case that a template consent form indicates that a HIPAA authorization does not expire, we will add a statement indicating an expiration date that applies to the states above. The date chosen is an arbitrary date at the end of the reasonable time needed for the completion of research goals. The expiration language is added to template consent forms rather than individual sites to avoid errors that could result in incomplete HIPAA authorizations as sites are submitted. 

What are the state regulations that differ regarding requirements for authorization expiration dates?

While most states are aligned with the federal HIPAA requirements, if your trial has sites in the states of California, Delaware, Indiana, Illinois, or Washington, you may need to be aware of laws in those states impacting the expiration of authorizations to share PHI. These regulations are discussed below. 

Federal HIPAA regulations state:

The final sentence allows the statement “this authorization does not expire” or similar for research purposes. 

Several states require a specific date of expiry and/or omit the federal allowance for “no expiration” of HIPAA authorizations for research purposes.  

1. The California Civil Code requires an authorization to disclose medical information. 
   
   “States an expiration date or event. The expiration date or event shall limit the duration of the authorization to one year or less, unless the person signing the authorization requests a specific date beyond a year or unless the authorization is related to an approved clinical trial, as defined in Section 1370.6 of the Health and Safety Code, or medical research study, in which case the authorization may extend beyond one year if the expiration date or event extends no longer than the completion of the relevant clinical trial or research study.” ⁹   
   
   California does not include the allowance that research uses of medical information need not expire, but providing a specific date satisfies the state regulations.

2. Washington regulations state that the authorization “…contain an expiration date or an expiration event that relates to the patient or the purpose of the use or disclosure.”¹⁰  

3. Delaware requires that the “…authorization shall be dated and shall specify to whom the disclosure is authorized, the general purpose for such disclosure, and the time period in which the authorization for the disclosure is effective.”¹¹   

4. Similarly, Indiana requires the “date, event, or condition on which the consent will expire if not previously revoked.”¹²   

5. Illinois expiry pertains specifically to studies including mental health information. However, state law defines mental health very broadly and could include mental health scales commonly used or accessed in many types of medical care and clinical trials. Specifically, “mental health or developmental disabilities services” or “services” includes but is not limited to examination, diagnosis, evaluation, treatment, training, pharmaceuticals, aftercare, habilitation or rehabilitation.¹³   

The state regulations in Illinois must include “…the calendar date on which the consent expires, provided that if no calendar date is stated, information may be released only on the day the consent form is received by the therapist…”¹³ 

Questionnaires and assessments that relate to how the participant is feeling or thinking could be considered mental health, and WCG has chosen to be conservative and include an expiration date for Illinois, even for studies that are not mental health studies. 

The Board added an expiration date for specific states to my HIPAA authorization language for my consent form. Can a different expiration date be chosen? 

Yes. The date is an arbitrary date far enough in the future to encompass the needs of most research, but it can be adjusted to meet the needs of your specific research. Since the sponsor and site may not know when the research will be completed, WCG has chosen an outside date by which the study should have been completed, and it is no longer necessary to use or disclose the medical information collected as part of the research. If the study has been completed, there should not be a reason for the site or sponsor to use and disclose the information, even if the expiration date has not been reached. 

If the site and/or sponsor have a better idea of when the study will be completed, then they can use an expiration date that is more closely aligned with the completion of the study. 

My site is not in a state that has specific requirements for the authorization to share PHI expiration language, but the Board added language about expiration dates for sites in other states to my consent form. Can I request the removal of this sentence from my site’s consent form?

Yes, although the statement is intentionally worded so that it will be accurate regardless of the location of the site, you can request for the language to be removed if your site is not in one of the affected states.  

Conclusion

There are many nuances around requirements for obtaining consent to use PHI in clinical research. To ensure compliance and protect participant’s privacy, it is essential to understand the regulations and implications. If you still have questions regarding HIPAA and PHI, feel free to contact WCG’s IRB experts today by completing the form below. We are at the ready to answer your questions and set your study up for success. 

References

1. Summary of the HIPAA Privacy rule: https://www.hhs.gov/sites/default/files/privacysummary.pdf.
2. Protecting Personal Health Information in Research: Understanding the Privacy Rule: http://privacyruleandresearch.nih.gov/pdf/HIPAA_Privacy_Rule_Booklet.pdf.
3. 45 CFR 164.512(i)(2)(ii).
4. 45 CFR 164.514(b)(2).
5. 45 CFR 164.514(b)(1).
6. 45 CFR 164.512(i)(1)(ii).
7. 45 CFR 164.512.
8. 45 CFR 164.508(c)(1)(v).
9. California Civil Code Division1, Part 2.6, chapter 2 § 56.11(b)(8): https://leginfo.legislature.ca.gov/faces/codes_displayText.xhtml?lawCode=CIV&division=1.&title=&part=2.6.&chapter=2.&article=.
10. Wash. Rev. Code Ann. § 70.02.030(3)(f): https://app.leg.wa.gov/rcw/default.aspx?cite=70.02.030.
11. 16 Delaware Code § 1210(2): https://delcode.delaware.gov/title16/c012/sc02/index.html#1210.
12. Indiana Code 16-39-1-4(9): https://iga.in.gov/laws/2023/ic/titles/16#16-39-1-4.
13. 740 ILCS 110/5(b)(6): https://www.ilga.gov/legislation/ilcs/ilcs3.asp?ActID=2043&ChapterID=57.

The post Answering FAQs on HIPAA & PHI: Protect Participants’ Privacy & Ensure Compliance appeared first on WCG.

Studies conducted under both 50.23 and 50.24 can be controversial and due to the nature of the study there may be increased regulatory risk. One of the controversial aspects of both pathways is that they allow for a waiver of consent. The Institutional Review Board (IRB) must carefully balance the need to advance critical clinical research in traumatic and emergent care settings with the need to maintain the autonomy of choice for the patient, especially in light of past abuses and missteps in medical research.

Obtaining Consent

Informed consent remains the bedrock principle upon which almost all clinical trials are built. Through the informed consent process, an individual, or their legally authorized representative (LAR), can decide if they want to participate in the research. In some cases, there may be other alternatives they wish to pursue, or the individual does not want any additional treatment, or the individual has questions they need answered before agreeing to participate.

In an emergency situation, time is limited and it may not be feasible to obtain consent from the individual or the LAR prior to when treatment needs to be provided. In some cases, the individual will either be unconscious or of limited mental capacity at the time treatment is required, and delaying treatment while attempts are made to contact someone legally authorized to provide consent on the individual’s behalf could have deadly consequences. The ethical challenge is then balancing treating an individual with an investigational product in a life-threatening situation and ensuring they have the autonomy to decide if they want to participate in research.

Special Considerations Under 50.23 – Emergency Use

Under the current system, the IRB is tasked with trying to strike an appropriate balance and ensure the rights and welfare of the participant are protected. However, treating an individual patient using an investigational product under 50.23 may occur without prior IRB review. If a provider believes there is no alternative option that presents equal or greater likelihood of saving the individual’s life, the provider can use the investigational product. If there is sufficient time, the provider must obtain confirmation from another physician, independent of the research, that the use of the investigational product is appropriate. If there is not sufficient time to get confirmation from a second physician, then the only person involved in the decision is the provider. Even if there is a second physician involved, due to the shortage of time, there may not be much time to review the medical records and determine if there are equally effective alternatives or if this is truly the best and only option for the individual.

The underlying issue involving consent is that the individual did not freely consent. In this situation, the issue can be framed as would the individual, or their LAR, have consented, if they could. Most of the time we can assume the patient or their LAR would agree to receive the investigational product if they could because it may be the only option to save their life. For example, if the individual is having a heart attack due to a blocked coronary artery and the only available stent that can be used with this individual is investigational, but it is fairly similar to approved stents. It is reasonable to assume that the individual would not have any concerns with using the investigational stent.

In contrast, some people may have strong personal beliefs and would not choose to receive an investigational product if given the opportunity. However, if there are no other options to save the individual’s life they may be given the investigational product regardless of what they would want.

Regulatory Issues

Providers are required to notify the IRB within five working days of the justification for using an investigational product along with confirmation by a second physician. WCG’s process is that if the IRB agrees that the use of an investigational product was appropriate for a particular individual, then the IRB simply acknowledges the use. However, the IRB may, in rare circumstances, see the situation differently. If the IRB has significant issues with the use meeting the regulatory requirements under 50.23, they could determine the provider to be in Serious Non-Compliance and report the issue to the regulatory agencies . This action could lead to an inspection by the FDA and/or Office for Human Research Protections (OHRP), which could then result in further observations of non-compliance or a Warning Letter.

Special Considerations Under 50.24 – Research in Emergency Situations

For research that requires the study of products used in emergency situations, under 50.24, the normal Investigational New Drug (IND) and Investigational Device Exemption (IDE) requirements still apply, with specific additional steps in place to safeguard participants. These additional steps include community consultation, public disclosure, data monitoring committee (DMC) oversight, and a commitment by the investigator to attempt to contact a family member who is not a legally authorized representative.

Community Consultation and Public Disclosure

In lieu of obtaining consent from each participant, the regulations provide for an exception to informed consent, when the community is aware of the emergency research and agrees the study can be done in that community. Community consultation, as interpreted by the FDA, is meant to be a two-way communication between the research team and a wide group of community representatives. This ensures that the community or communities in which this emergency research is being conducted has an opportunity to be informed about the research, its potential risks and benefits, and that community members are given an opportunity to ask questions and provide feedback.

Public disclosure means disclosure of the study and any trial results to the community and the research team by the sponsor. This is meant to be a one-way dissemination of information by the sponsor and occurs prior to the start of the research, after completion of the research, and at any time the IRB determines there is something necessary to disclose.

In both community consultation and public disclosure, the disseminated information must include information about the clinical trial including its risks and any expected benefits, a summary of the protocol and trial design, how to opt out of participation, and who to contact for any additional questions or information. These can be conducted via radio announcements, television ads, random telephone surveys, public meetings, and focus groups, among others.

The IRB must review the plans for both community consultation and public disclosure prior to the implementation of either. If any concerns or objections were raised during a community consultation session, those objections and concerns should be considered by the IRB when deciding whether to approve or modify an emergency research clinical trial. The IRB may decide to invite members of the community to a meeting, add board members who are members of the community, use community members as consultants, request additional community consultations by the investigator and sponsor, or conduct community consultations on its own, if the board decides additional information is necessary.

Knowledge of the community make up, including religious and cultural groups, socioeconomic factors, racial composition, whether it is urban or rural community, and understanding the beliefs and practices of the population with respect to medical care are critical in determining the means of outreach and who may attend the public meetings. As such the community consultation plans could vary widely from one community to another, even in similar geographic areas.

Possible pitfalls in community consultation relate to the diversity of audience and method of information dissemination. Researchers and IRB members alike must remain aware of the makeup of the people who attend the community consultations, the population of the community where the research takes place as a whole, and the methods of communication. Often the method of dissemination of information is itself a barrier, leading to situations wherein a very small subset of the community is actively engaged in making decisions for the population at large, leading to disparity. For example, a more rural area might not have widespread access to the internet, depending on infrastructure, leading to those in the urban center representing the population in public discourse. The local newspaper or radio station might appeal to a specific racial, political, age, or economic demographic, while largely failing to reach the rest of the community. In addition, the people who attend in-person meetings and public presentations frequently are not representative of the community as a whole and may not even be those most likely to be in the research. Historical barriers to attendance at public forums and focus groups, such as transportation needs, work schedules, disabilities involving the ability to see and hear, and community sentiment toward medical research are all to be considered.

There are a couple major challenges with community consultations, including getting people to attend the public meetings on the emergency research project and that those who do attend may not be representative of the community as a whole. This means that a few hundred people, who may not be representative of the population as a whole, could decide that an emergency research study can be conducted in a community of several thousand or hundreds of thousands of people.

Ensuring that community members know that opting out is an option, and how to do so effectively, should be a priority. Generally, any advertisements or public disclosures will provide information for how members of the community could opt out of the research. One common method would be to request a medical alert bracelet indicating that the individual chooses not to participate in the emergency research.

Separate IND and IDE

It is important to note that any research conducted under 50.24 requires the submission of a separate IND and IDE for each study conducted under 50.24 even if an IND or IDE already exists. Information previously submitted in support of other applications may be included as reference. For instance, if a drug is being studied under both 50.24 and the normal IND procedures, there will be one IND for the study conducted under 50.24 and another IND for any other studies for that particular drug product. For the FDA to allow a study to proceed under 50.24, the study must meet the regulatory requirements under 50.24 in addition to the IND or IDE requirements.

Placebo Controlled Studies

One of the more controversial aspects of conducting research in an emergency situation is the use of placebo-controlled studies. In order to determine if the intervention is effective, the FDA requires that there be well-controlled studies, for which placebo is often the most effective, and most of the interventions used in an emergency situation cannot be adequately tested except in an emergency situation. If there is no current treatment, then the participants would be in the same position as if they were not in the study. However, if there is an approved therapy, participants could be denied effective treatment if they are randomized to the placebo arm. Even if the treatment is only marginally effective or there are serious side effects from the treatment, in a life-threatening situation, getting some treatment is likely going to better than getting a placebo.

Obtaining Consent

Each emergency protocol will include a therapeutic window of when the intervention needs to be initiated to be effective. During the therapeutic window, the study team must try to obtain consent from the participant, an LAR, or a close family member. For some conditions, like a heart attack, the therapeutic window may only be a few minutes, and it would not be practical to get consent during this time and in this instance the intervention begins immediately. In contrast, some conditions such as traumatic brain injury or stroke may have a therapeutic window that is several hours long. However, these interventions are generally more efficacious the earlier they are administered. If the therapeutic window is several hours long, the study staff are expected to attempt to get consent, but not to the extent that effective treatment for the participant may be delayed.

Even if the participant is able to consent or there is an LAR available, it may be difficult to determine if consent is truly freely given. The participant is in a stressful, life-threatening situation and there is not time to stop and think about the consequences of being in the study or considering other alternatives. Participants, or their LAR, may feel like being in the study is their only option, even if there are other alternatives. In contrast to non-emergent clinical trials, the participants, or their LAR, can review the study, ask questions, and possibly discuss participation in the study with another physician or trusted individuals.

Conclusion

When conducting research in an emergency situation it is necessary to evaluate interventions to be used to save lives during similar situations. However, these studies are complex, regulatorily risky, and generally deny autonomy to the individual by including them in research they may not have agreed to otherwise. When conducting research under 50.24, the sponsor and IRB must pay particular attention to the community consultation plan to ensure the community is well represented and the researchers obtain feedback from different community groups and populations.

The post Review of Emergency Research appeared first on WCG.

The ability to use IVG for human reproduction is still many years away, but researchers are excited by the results in studies so far.  Researchers have been able to produce primitive egg and sperm cells from induced pluripotent stem cells, but neither are developed enough to create an embryo, although the field is evolving rapidly.¹

Since we are at least several years away from seeing clinical trials with embryos created by IVG, now is the perfect time to consider the legal and regulatory implications of this technology.  This paper will focus on the regulatory status of IVG. 

FEDERAL STATUTES AND REGULATIONS

Research on embryos created through IVG is already underway, but there are no federal laws that govern both public and privately funded research involving embryos.²  Federal laws don’t necessarily prohibit research on embryos created through IVG or otherwise, rather the restrictions are budgetary and if the US government will pay for the research. Under the Dickey-Wicker Amendment (DWA) the federal government is prohibited from funding research that creates, destroys, or seriously injures embryos.  This includes the creation of human embryos that are ‘derived by fertilization, parthogenesis, cloning, or any other means from one or more human gametes or human diploid cells’.³

While federal statutes do not prohibit research on the embryos created by IVG, the Food and Drug Administration (FDA) is prohibited from accepting a clinical trial application in which the embryo is intentionally created or modified to include heritable genetic modifications.⁴  At a meeting of the National Academies of Science, Engineering, and Medicine Dr. Peter Marks, the Director of the Center for Biologics Evaluations and Research at the FDA, confirmed that this prohibition applies to embryos created through IVG.⁵  This prohibition was introduced in Congress as a rider to the 2016 Appropriations Bill and has been included every year since.⁶ 

STATE LAWS

As the federal statutes and regulations are mainly about what can and cannot be funded with federal dollars, where the research can occur will be heavily dependent on state laws.  State laws create a complicated patchwork ranging from allowing and funding embryonic research to complete bans.

To further complicate matters, many of the state laws were developed to address other issues, such as abortion, fetal tissue research, reproductive cloning, and human embryonic stem cells (hESC).  Some of these laws will overlap with IVG and some of them do not address embryonic research at all.⁷

There may be other factors that influence the policies and legislation of a given state, including the political party in power, prior morality laws, the policies and attitudes of neighboring states, the strength of the scientific community, and the discussions occurring at the federal level.

States can be grouped into three categories related to embryonic research – states that are permissive, states that are prohibitive, and states that are silent.

Permissive States

Eighteen states permit some or all embryonic research:  Arizona, California, Connecticut, Florida, Illinois, Indiana, Iowa, Maine, Maryland, Massachusetts, Michigan, Montana, New Jersey, New York, Ohio, Utah, and Virginia.  Of these California, Connecticut, Michigan, Montana, and New York, specifically allow embryonic research.  The other states would allow research on embryos due to vague or overly specific legislation around other areas such as hESC research, and research on fetal tissues derived from abortion.

California was the first state to approve legislation allowing embryonic research when Proposition 71 (Prop 71) was enacted in 2004.  Not only does Prop 71 allow research on hESC and embryos, it also provides funding for stem cell research and established a new agency, the California Institute of Regenerative Medicine (CIRM), to oversee this research. Shortly after this, other states, including Connecticut and Maryland, started to fund stem cell research.  Other states affirm their support of embryonic research by developing regulations that ensure their residents have access to stem cell therapies and cures.

While these states may be supportive of embryonic research, they do have related restrictions.  Several states prohibit the creation of embryos solely for research purposes but do allow experimentation on leftover embryos from in vitro fertilization (IVF).  Other states will continue to place time frame restrictions ranging from 12 days post fertilization or the development of the primitive streak, to gastrulation, which typically occurs 17 days post fertilization.  Still other state laws are silent or define a fetus to start at implantation and therefore would allow in vitro research on the embryos but would prohibit research on fetal tissue obtained from an abortion.

Prohibitive States

Eleven states have legislation banning human embryo research: Arkansas, Kentucky, Louisiana, Minnesota, Nebraska, New Mexico, North Dakota, Oklahoma, Pennsylvania, Rhode Island, and South Dakota.  These statutes range from explicitly banning human embryo research, to prohibitions on using public funds or facilities for embryonic research, but do not outright ban it.

Some of the states prohibit fetal research and define fetus to include conception through birth, and therefore all embryonic research would be fetal research.  Other statutes are framed as “do no harm” and prohibit the destruction of an embryo, the manipulation of an embryo, or non-therapeutic research or medical treatment.  Four states, Arkansas, Kentucky, Nebraska, and Oklahoma, prohibit the use of public funds and facilities to be used for embryonic research, but do not otherwise prohibit it.

Silent States

The remaining 21 states do not have any specific laws regarding embryonic research and rely on federal laws, regulations, and policies.  These states are Alabama, Alaska, Colorado, Delaware, Georgia, Hawaii, Idaho, Kansas, Mississippi, Nevada, New Hampshire, North Carolina, Oregon, South Carolina, Tennessee, Texas, Vermont, Washington, West Virginia, Wisconsin, and Wyoming.

CONCLUSION

In vitro gametogenesis has the potential to help untold numbers of people to produce genetically related offspring that would not be able to do so otherwise. Considering the vastly different approaches between the states, it is highly unlikely that there will ever be a consistent approach within the US that facilitates embryonic research.  Even in the states that are permissive to embryonic research, there are still limits and many of these statutes are open to interpretation. Consequently, given the current regulatory landscape, there are hurdles to having the U.S. lead in this research endeavor.

One would hope, as the technology improves and it is shown to be safe and effective, particularly if it is done in other countries outside the U.S., there may be more initiatives to create a unified system to foster embryonic research and ultimately allow more clinical trials in the US.

References

1. Creating a sperm or egg from any cell? Reproduction revolution on the horizon, Rob Stein, NPR https://www.npr.org/sections/health-shots/2023/05/27/1177191913/sperm-or-egg-in-lab-breakthrough-in-reproduction-designer-babies-ivg
2. Can we do that here? An analysis of US federal and state policies guiding human embryo and embryoid research, Kirstin Mattews and Daniel Morali.  Journal of Law and the Biosciences, Volume 9, Issue 1, January-June 2022, lsac014, https://doi.org/10.1093/jlb/lsac014
3. Consolidated Appropriation Act, H.R 133,116^th Cong.(2021). (Dickey-Wicker Amendment).
4. H.R. 2029 Consolidated Appropriations Act, 2016 (114th Congress), §749
5. Creating a sperm or egg from any cell? Reproduction revolution on the horizon, Rob Stein, NPR https://www.npr.org/sections/health-shots/2023/05/27/1177191913/sperm-or-egg-in-lab-breakthrough-in-reproduction-designer-babies-ivg
6. Congress Revives Ban on Altering the DNA of Human Embryos Used for Pregnancies, Andrew Joseph, STAT June 5, 2019 Congress Revives Ban on Altering the DNA of Human Embryos Used for Pregnancies – Scientific American
7. Can we do that here? An analysis of US federal and state policies guiding human embryo and embryoid research, Kirstin Mattews and Daniel Morali.  Journal of Law and the Biosciences, Volume 9, Issue 1, January-June 2022, lsac014, https://doi.org/10.1093/jlb/lsac014

The post A Review Of The Regulatory Landscape for In Vitro Gametogenesis appeared first on WCG.

To draw the distinction, in this paper, the term ‘simple consent form’ is used to denote a word-processed, text-only, standard format informed consent document.

Detailing Study Procedures and Activities in a Table Versus in Paragraphs or Lists

It is fairly common for sites and sponsors to list all of the study procedures and activities in a table, either in the body of the consent form or as an appendix.

Strengths

A table of study procedures

• puts all of the study procedures together and often makes it easier to see what will happen and when. 
• makes consent forms shorter as information does not need to be repeated for each study visit
• can provide the information in an efficient way.
• breaks up the consent form and creates white space which can increase readability and understandability of the consent form as a whole.
• makes it easy to update an entire table, by copy and pasting the table(s) from the protocol.
• helps to reduce copy-paste errors and inconsistent or contrary information between the study visits.
• makes it easier to update the information as it is in one spot on the table as opposed to updating the information for each study visit where the change may occur. 

Challenges

When using a table of study procedures

• some participants may have trouble reading and understanding tables and may not grasp which procedures will be done and when. 
• there may be space limitations for the columns and there may not be sufficient explanations of what the procedures entail, or explanations require complicated footnotes.
• editing or modifying parts of tables can be challenging, particularly when new procedures or study visits are being added.  This will often change how the table appears and may require the table to be reformatted. 
• it is often challenging to format the text in a way that can be easily readable to the participants within the space limitations.

One possible approach would be to describe the research procedures in the consent form and then also include a table as a consent form addendum or additional participant information that can be used as a quick reference.

Using Separate Consent Forms for Different Participant Populations or Cohorts

Sometimes a research study will recruit from multiple different participant populations (e.g., minors consented via parental permission and adults who consent for themselves) or will involve multiple cohorts (e.g., a study comparing different treatment regimens with their own respective risks and procedures) and there could be a different consent form for each group.  

Strengths

The benefits of using multiple separate consent forms include that

• the language in the body of the consent form can be tailored to each participant population. If the procedures, dosages, or compensation offered varies between groups, the consent language can be made specific to that individual participant without including information that does not apply to them.
• the document will require fewer signature lines. If decision-making adult participants have their own consent form, then the document will not also require signature lines for documenting parental permission for the adolescent participants or documenting the signature of a legally authorized representative if the participant is lacking capacity. This approach will help prevent errors that may occur when a participant or study team member signs the wrong section of the consent form.
• if a participant population or cohort completes the research, or if a part of the study completes (e.g, optional first-dose intensive PK sampling, after everyone has completed the first dose) then that consent document will no longer need to be maintained going forward.

Challenges

Some of the challenges of having multiple separate consent forms are that

• having multiple consent forms for different groups means having multiple documents to maintain and revise as the research changes with protocol revisions and amendments. Keeping track of these documents and ensuring they are consistent can be burdensome over time. If the differences between the consent forms for each group are minimal, it might be preferable to use one document and add language that clarifies whether certain sections to apply to a participant.
• using multiple consent forms for the same research study can also introduce the possibility of documentation errors if the study team member obtaining consent uses the wrong consent form. For example: if a participant gives consent for Cohort A, but  later  the research staff inadvertently uses the consent form for Cohort B, to re consent the participant, there is a possibility the participant did not receive the new information that is most pertinent to their participation.

Reconsenting Active Participants Using and Addendum Instead of a Revised Consent Form

The question of whether an active participant should be “reconsented” arises whenever there is a protocol revision, new or updated study risk, or an update to the consent form language. As noted in this WCG White paper, Providing Research Participants with New Information: Is “Re-Consent” Always Necessary?, reconsenting participants should be performed whenever significant new findings may affect a participant’s decision to continue in the research. Reconsenting is most often done in one of two ways: 1) having the participant review the revised consent form in its entirety and consent again, or 2) having the participant review a consent form addendum that outlines the key changes in the research, or that changes that apply to their stage in the study.

Strengths

When using a consent addendum

• it is easier for the participant to understand the key changes without having to re-review information that has not changed since they initially joined the research.
• the consent form addendum will be much shorter than a revised consent form, and the reconsenting process will be take less time for study team members to administer. 

Challenges

When using a consent addendum

• this approach introduces another document that will need to be revised and maintained over the course of a study. If the research is still enrolling, the existing consent form will also need to be updated to incorporate the revised information for new participants. The addendum approach to reconsenting is best suited for situations where enrollment is permanently closed, but there is new information that needs to be communicated to active participants.

Including Optional Components in the Main Consent Form

Sometimes research will involve sub-studies or optional procedures that require separate consent. This information can either be appended to the main consent form or conveyed in a separate consent form addendum.

Strengths

When keeping sub-study information in the main consent form

• there will be fewer documents to maintain and update over the life of the research. This will be easier for study teams, CROs, and IRBs to manage.
• if all decisions related to participation are in one document, it will be easier for the person obtaining consent to ensure all relevant consent has been obtained. There will be fewer consent documentation errors that occur when a study team fails to document one or more of the participant’s choices.

Challenges

• Including optional components in the main consent form can introduce the possibility of other errors. For example, this approach can lead to situations where a study team member fails to obtain a signature or participant decision on one of the optional sections.
• It can also lead to situations during reconsenting where a participant makes a different choice than they originally did. If this discrepancy is not noticed or resolved, it can make it difficult to determine whether the participant meant to change their prior consent or simply forgot the choice they made earlier. If a single consent form for all procedures, both required and optional, is used, it is a good practice for the study team member to have the participant’s prior choices available to reference during the reconsenting process.

Electronic Consent (eConsent)

The term electronic consent (often abbreviated as “eConsent”) can mean multiple things, including uploading an approved consent document onto a platform that can be viewed on a tablet , phone, or computerror the use of electronic platforms that incorporate the consent form with dictionaries, storyboards, animation, videos, graphics, and/or images.  Since these involve two different processes, we will discuss the strengths and challenges of them separately.

Uploaded Consent Document

Strengths

When uploading a simple consent document to be used electronically

• once the IRB has approved the simple consent form it is generally very easy to upload into an electronic document. If there are no changes to the consent form, uploading it does not require any additional review by the IRB.
• the research site will not need to have printed versions of the consent form available for each participant; rather the site would be using the same file on the tablet each time and saving it as a separate file once the participant has signed the form.
• the site may not need to keep paper copies of the signed consent form which could help in decreasing the space needed to store study records, as well as reducing the risk that the consent forms get lost, or inadvertently destroyed, particularly if the data system is backed up.
• if the data system is searchable, then it could also be quicker and easier to determine if a particular participant has signed the consent form(s), and when.

Challenges

When uploading a simple consent document to be used electronically

• the system used to obtain consent and store the electronic consent forms must be compliant with 21 CFR Part 11 for any clinical trials regulated by the FDA¹. Note that if participants are physically signing the consent form using a stylus or their finger, rather than typing a “signature”, this is considered to be a “wet signature” and the system does not need to be compliant with 21 CFR Part 11.
• the site will likely still need to print off the signed consent form to provide the signed version to the participants (per ICH GCP )², but this would be the case even if the site was using paper based consent forms.
• if the electronic form gets corrupted or inadvertently deleted, the site may not have a usable consent form

The site should maintain at least one current copy of the simple consent form to serve as a back-up in case there are technical issues or the electronic version can’t be used.

Electronic platforms incorporating dictionaries, animation, storyboards, and/or videos

Increasingly sites and sponsors are using consent processes that are incorporated into an electronic platform and will include embedded dictionaries, animation, videos, storyboards, and other visual information to help explain the study.  The text of the consent form is also generally incorporated as part of the electronic platform and the participants may digitally or physically sign the consent form as part of the electronic platform.

Strengths

When using multi-format electronic platforms for the informed consent process

• this format may improve participant satisfaction with the consent process, and help increases the participants’ comprehension of the study and the associated procedures, risks, benefits, and alternatives by providing an interactive learning approach.³
• electronic platforms make it easy for the participants to go back to specific sections to re-review information if they have questions.
• the multi-modality platforms help people with different learning styles, such as auditory and visual learners understand the consent form as opposed to simply relying on reading the consent form.
• When consent information needs to be updated during a study, once changes have been approved by the central IRB, they could be pushed out to all of the sites simultaneously. This helps to make sure all of the sites are always using the most current version of the consent form.
• the integration of videos, images and other tools may make it easier to visualize complex ideas or procedures

Challenges

When using multi-format electronic platforms for the informed consent process

• they are expensive, compared to paper-based forms or simple electronic forms
• they can be time-consuming to develop initially and to change when needed
• consent incorporating tools such as voice-overs, videos, or animations will generally require a second IRB review (following initial review of the simple consent document) as the content is different than what is included in the simple consent document.
• if using both a simple consent document and the multi-modality electronic format, the site and sponsor may need to update multiple documents when there are changes, including the simple consent document and the consent form provided as part of the electronic platform.
• this electronic platform will need to comply with 21 CFR Part 11 and the site will still need to provide a printed copy of the consent form to the participants.

Concluding Thoughts

There are many formatting options to consider when drafting an informed consent form, each with their own advantages and disadvantages. The format of the ideal consent form may vary by situation and study. When drafting an informed consent form, the sponsor and study team should evaluate their needs and constraints to design an informed consent form that will be easy to understand for potential participants and efficient to implement for study teams. The IRB can be a resource for discussing options and implications on the review and implementation process.

References

1. 21 CFR § 11.1
2. See Integrated Addendum To ICH E6(R1):Guideline For Good Clinical Practice Section 4.8.11, https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
3. See for example Abudjarad, et al, Comparing a Multimedia Digital Informed Consent Tool With Traditional Paper-Based Methods: Randomized Controlled Trial, JMIR Form Res. 2021 Oct 19;5(10):e20458. doi: 10.2196/20458. PMID: 34665142; PMCID: PMC8564662. (https://pubmed.ncbi.nlm.nih.gov/34665142/ Accessed 02-16-2023) and Gesualdo F, et al. Digital tools in the informed consent process: a systematic review. BMC Med Ethics. 2021 Feb 27;22(1):18. doi: 10.1186/s12910-021-00585-8. PMID: 33639926; PMCID: PMC7913441. (https://pubmed.ncbi.nlm.nih.gov/33639926/ Accessed 02-16-2023)

The post Function over Form: Assessing Different Consent Form Formats appeared first on WCG.

We are conducting an online longitudinal survey involving children as research participants. Adolescents will enter data via their own registered portal.  Should parents be allowed to view the data; and if so, until what age?

-CEO, Research Foundation

Response:

When research involves children, federal regulations require parental permission. These regulations define a child as: “… persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.” ⁱ

If there are research specific statutes indicating when a minor can consent on their own behalf, the IRB would default to those provisions. However, most states do not have research specific statutes and therefore we will apply the statutes related to when a minor can consent to healthcare to determine when the child will be treated as an adult. If the child is considered an adult for a particular treatment or service, the child will be able to consent for themselves and this also means that they will have control over who can have access to the information from that treatment or service. All states have provision for allowing minors to consent on their own to healthcare related to pregnancy and sexually transmitted infections (STIs) and some states allow minors to consent for themselves for substance abuse and chemical dependency. Likewise, most states will allow a minor who is married and/or in the military to consent for their own healthcare.

With respect to treatment related to pregnancy and STIs, some states will set a lower age limit at which the minor can consent and others do not. If the state has set a lower age limit, such as 13 years old, a minor younger than that would need parental consent for the treatment. In this case, since the child does is not treated as an adult, the parents would have access to the information. If on the other hand, the child is 13 years old, they would be able to consent to the treatment. In this case, the child is able to say that they do not want their parents to have access to the information.

Outside of the limited situations where the state will allow the child to consent for themselves, the expectation is that the parents/guardians will consent for the child to be in the research and as such, the parents/guardians would have access to any information collected on the child and the survey results.

If the above referenced study is one where the child could consent to participant on their own, then the parents/guardians would not be able to get access to the information or survey results unless the participant agreed that the parents could see it. One approach that the sponsor could consider is requiring the parents to have access to the information and survey data in order for the participant to be part of the study. Based on the above description, the participant is not receiving care directly through the research, rather they are just answering survey questions. If the participant decides not to allow their parents to have access to their information or the survey results, the participant will not be enrolled. This approach will not impact the participant’s ability to get treatment if the states allows them to consent on their own behalf but it will be administratively easier to manage the study as it does not stratify the study by participants who have agreed to allow their parents to see their data, those who have not agreed to allow their parents to see their data, and those who are not able to consent for themselves.

References

i. Regulatory Definition of Children:

• https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/common-rule-subpart-d/index.html#46.402
• https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.3

The post Should Parents Be Allowed to View their Child’s Survey Responses? appeared first on WCG.

The earliest phases of research often require the participation of healthy individuals, and this population can be difficult to reach. Additionally, some studies require more targeted patients due to the nature of the study population and this can make it difficult to identify and reach appropriate individuals who may qualify for the research. Often, the best person to encourage others to participate in research studies is someone who has had a positive experience as a research participant them self. Therefore, one of the recruitment strategies frequently employed to overcome recruitment hurdles is called patient-to-patient referral.

Patient-to-Patient Referral Programs

“Patient-to-patient” referral programs – which often refer to healthy volunteers rather than patients with a disease or condition – are generally designed to motivate someone who has had experience with being a research participant to reach out to their friends, family members, and other personal contacts. The experienced participant encourages others to either consider enrolling in a specific clinical study, or to consider research participation in general. To persuade them toward this outreach effort, researchers or research facilities provide a monetary reward to the referring person, usually for each contact who contacts the site about participation in a study. Many referral programs, especially for healthy volunteer research, are not for specific studies, but rather encourage others to join a database from which future studies can be recruited.

One specific type of patient-to-patient referral program is ”snowball sampling”, which is a non-probability sampling method in which a participant in the research study is asked to help recruit other participants by relaying information about the study to peers they know who are in the group being studied; for example, other people who are community leaders, other people living with long-term HIV, or other families where someone has a specific rare disease. Snowball sampling is frequently used in qualitative research, when the researchers are seeking a group with very specific characteristics, and when people within that group are likely to know others within the group. Study populations obtained through snowball sampling techniques cannot be considered a random or representative sample of the population, so it is not appropriate for certain types of research and researchers must be aware of the potential for selection bias and the possible impact that may have on study conclusions. Snowball sampling would not be used for clinical trials for this reason, but may be used in observational biomedical research, such as when doing surveys of patients.

IRB Oversight of Patient-to-Patient Referral Programs

Any recruitment plans including potential participant referral programs must be submitted to the Institutional Review Board (IRB) in advance of beginning them, whether they are initiated at the start of the study or added later after the study has already begun. Any written materials, such as brochures prepared for current participants to distribute to others, content for them to share or post online, or scripts for them to use, must also be submitted to and approved by the IRB.

Benefits of Patient-to-Patient Referral Programs

Patient-to-patient recruitment can be particularly effective for harder to reach populations, or to reach a population with uncommon characteristics.

The potential recruitment benefits of the strategy include:

• Participants are generally more apt to trust close, personal peers rather than individuals they do not know. The referring party can provide direct, trusted knowledge to the potential participant. The referring party can describe their experience and expand on information not directly discussed during the consent process. This may include realistic expectations regarding the necessary time commitment and experiences related to the specific research. Examples of this include commuting time, parking availability, and office wait times.
• One participant may have relationships with several qualified individuals. For example, if the research involves a rare disease, a person involved with an advocacy group can provide information to the entire group via one social media post or discussion at an annual meeting.
• Participants can outreach to individuals who may not have the same access to information. Individuals frequently have access to different information compared to other people in their network, based on their socio-economic status, hobbies and interests, as well as access to healthcare providers. Patient referrals provide an opportunity to reach potential participants who may be missed by traditional recruitment campaigns.

Concerns

While patient referral methods can create new recruitment opportunities and the methods are not inherently problematic, they do raise some potential issues that need to be considered prior to setting up the program.

• Patient referrals may create a bias in the research due to having more similar participants than may naturally occur otherwise. Personal networks tend to be more analogous to the individual in terms of race, socioeconomic status, geographic location, etc., and patient referrals could bias the research by oversampling a particular group. Most research studies will have a limit to how many participants will be enrolled, and the use of patient referrals may lead to a situation where more similar participants are enrolled than may be the case without patient referrals. Even if this doesn’t bias the study, it could distort the results and/or limit the applicability as there is not a more representative cross section of the population being enrolled into the research. Of course, if the goal of the referral program is specifically to enrich the study population for a certain type of participant, this may not be a concern.
• Research sites may want to have processes to handle situations where the referring party knowingly refers unqualified participants simply to increase their payment. Programs sometimes try to manage this by paying for referrals only if the referred person is eligible for and agrees to enroll in the study. However, this is not an appropriate control since the referring participant cannot control whether someone else meets all study eligibility. Paying a participant only if their referral agrees to be in the study can cause incentive for the participant to unduly influence the referred party to agree to participate. or to encourage them to lie about their eligibility for the study. It would be acceptable for the research site to put some restrictions on the referral program, which could include a prescreening process to evaluate basic eligibility requirements such as appropriate age and condition, and restrictions on concurrent research participation. The site could also limit the number of referrals provided by each referring party. As many of these programs are used due to low recruitment or to increase pre-screening databases, this may not be an overly burdensome issue.
• Patient referral programs may include the possibility of coercion. Coercion is the act of persuading someone to do something, by threats or influence. For example, relationships between the referring party and the potential participant may include a power imbalance, where the potential participant is more likely to join the study or to stay in a study they would have otherwise withdrawn from simply so that the referring party gets paid.

Setting Up a Patient-to-Patient Recruitment Program

A well-designed patient-to-patient referral program should include:

• Payment to the referring party based on the referral, without requiring the potential participant to meet certain milestones such as randomization, length of participation, or completion of the study.
• Specificity about when the payment will be made. For example, the program may require that the referring party receives payment after the potential participant sets up an appointment, or completes a screening visit, but the payment should not be contingent on actual enrollment or randomization of the potential participant in the study.
• Payment in an amount that is unlikely to provide an incentive for the referring party to pressure the potential participant to enroll in or stay in the research.

Individuals tend to trust the people they know and are more likely to do something if the suggestion comes from a family member, a friend, colleague, or even an acquaintance. Because of this, patient referral practices can be extremely effective. Patient referral programs have the potential to increase enrollment into research studies by allowing trusted individuals to share their knowledge and experiences with their friends and family members. Ideally, these strategies reach individuals who may not otherwise be aware of the research or may be hesitant to participate. When designing these programs, research sites should be aware of the factors that may create the potential for coercion or undue influence, bias the participant pool, or create a drain on staff resources.

The post Ethical and Regulatory Considerations in Patient-to-Patient-Referral Recruitment Plans appeared first on WCG.

Definitions

Neither the Food and Drug Administration (FDA), which is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation¹, nor the Office of Human Research Protections (OHRP), which provides leadership in the protection of the rights, welfare, and wellbeing of subjects involved in research conducted or supported by the U.S. Department of Health and Human Services², define anonymous data or de-identified data, nor does there appear to be a consensus definition for these terms. In some instances, de-identified means any identifiers are irrevocably removed from the dataset and there is not a link back to identifiable information. In other instances, de-identified data means any identifiers are irrevocably removed from the dataset but there is a link back to identifiable information. This is often referred to as coded data.

This paper will use the following definitions:

• Anonymous – The dataset does not contain any identifiable information and there is no way to link the information back to identifiable information.
• De-identified – The dataset does not contain any identifiable information, but there is a way to link the information back to identifiable information.

It is also important to make a distinction between datasets that have to comply with the Health Insurance Portability and Accountability Act (HIPAA) and those that do not. Under HIPAA, a dataset is considered de-identified if all 18 identifiers listed at 45 CFR 164.514(b)(2) are removed (see page 6 for a list of the 18 identifiers). If the dataset is not subject to HIPAA, it is considered anonymous if the identity of the human subjects cannot be readily ascertained. Identity is considered readily ascertainable if the information is publicly available or could be determined from publicly available information. Regardless of whether the dataset is considered anonymous or de-identified, the more unique information that is collected about an individual, the
easier it is to identify the individual, even if all of the information by itself is considered de-identified.

How Do Regulations Apply?

The reason it is important to understand the distinction between anonymous data and de-identified data is because research with anonymous data is not considered human subject research and does not need to comply with the federal regulations regarding human subjects research. In contrast, de-identified data is considered human subjects research and does need to comply with the federal regulations for human subjects research known as the Revised Common Rule.

The federal regulations define a human subject as:

(e) (1) Human subject means a living individual about whom an investigator (whether professional or student) conducting research:

(i) Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or

(ii) Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

(2) Intervention includes both physical procedures by which information or biospecimens are gathered (e.g., venipuncture) and manipulations of the subject or the subject’s environment that are performed for research purposes.

(3) Interaction includes communication or
interpersonal contact between investigator
and subject.

(4) Private information includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information that has been provided for specific purposes by an individual and that the individual can reasonably expect will not be made public (e.g., a medical record).

(5) Identifiable private information is private information for which the identity of the subject is or may readily be ascertained by the investigator or associated with the information

(6) An identifiable biospecimen is a biospecimen for which the identity of the subject is or may readily be ascertained by the investigator or associated with the biospecimen.

Research that involves directly interacting or intervening with subjects to collect data is considered to be research involving human subjects, even if no identifiable information is being recorded.

The 18 identifiers listed at 45 CR 164.514(b)(2). Under HIPAA, a dataset is considered de-identified if all 18 of these identifiers are removed:

(2)(i) The following identifiers of the individual or of relatives, employers, or household members of the individual, are removed:

(A) Names;

(B) All geographic subdivisions smaller than a State, including street address, city, county, precinct, zip code, and their equivalent geocodes, except for the initial three digits of a zip code if, according to the current publicly available data from the Bureau of the Census:

(1) The geographic unit formed by combining all zip codes with the same three initial digits contains more than 20,000 people; and

(2) The initial three digits of a zip code for all such geographic units containing 20,000 or fewer people is changed to 000.

(C) All elements of dates (except year) for dates directly related to an individual, including birth date, admission date, discharge date, date of death; and all ages over 89 and all elements of dates (including year) indicative of such age, except that such ages and elements may be aggregated into a single category of age 90 or older;

(D) Telephone Numbers;

(E) Fax Numbers;

(F) Electronic mail addresses;

(G) Social security numbers;

(H) Medical record numbers;

(I) Health plan beneficiary numbers;

(J) Account numbers;

(K) Certificate/license numbers;

(L) Vehicle identifiers and serial numbers,
including license plate numbers;

(M) Device identifiers and serial numbers;

(N) Web Universal Resource Locators (URLs);

(O) Internet Protocol (IP) address numbers;

(P) Biometric identifiers, including finger
and voice prints;

(Q) Full face photographic images and any
comparable images; and

(R) Any other unique identifying number,
characteristic, or code, except as
permitted by paragraph (c) of this
section; and 45 CFR 164.514(b)(2).

References

1. Food and Drug Administration | USAGov; https://www.usa.gov/federal-agencies/food-and-drug-administration (Accessed 05-18-2021)
2. About OHRP | HHS.gov; https://www.hhs.gov/ohrp/about-ohrp/index.html (Accessed 05-18-2021)
3. 45 CFR 46.102(e)

The post Do You Know Me?: The Subtle Distinction Between “Anonymous” and “De-identified” Data in Clinical Research appeared first on WCG.

This white paper will discuss a reasoned approach to applying the right amount of consent discussion for the right situation when there is new information in ongoing research.

Background

Federal regulations require that the consent form notify participants that they will be informed of ‘significant new findings developed during the course of the study’.¹  While it is clear that participants need to be provided with significant new findings and be advised of changes that affect them, (which we will refer to as “new information,”) during the study, the details of how this information is provided and documented is not defined. While the default approach is that the new information is included in a revised consent form and the participants are formally “reconsented” in a process similar to the initial consent discussion, it can be more effort than is necessary. 

The regulations do not mention reconsent or what this process should look like.  The FDA Information Sheet – A Guide to Informed Consent² (1998) only provides the following information:

The FDA Draft Guidance – Informed Consent Information Sheet³ (2014) also does not provide guidance on how new information should be provided. 

Recommendations

Recently the Secretary’s Advisory Committee on Human Research Protections (SACHRP) provided recommendations⁴ to the Office of Human Research Protections (OHRP) on the issue of providing new information to research participants. These recommendations draw a distinction between providing new information to participants, and a formal re-consent process.  The recommendations use re-consent to mean “subjects will go through a complete consent process that supersedes the original consent using a document that contains all required elements of consent and is documented in accordance with the federal regulations.”  In contrast, the recommendations recognize that there may be other mechanisms of providing new information to participants, such as the use of information sheets and consent form addenda that would not be considered legal informed consent. Furthermore, it indicates that there are many ways new information could be provided to participants so they can “reaffirm their willingness to continue to participate in the research.”

We agree that IRBs, sites, and sponsors should consider the new information to be provided to participants and determine what approach could be used to satisfy the regulatory requirement to provide the participants significant new information, but in the least burdensome way. “Burdensome” in this case refers both to the inconvenience for the participant, and for the administrative and logistic burdens on research sponsors and clinical site study teams.  Unnecessarily burdensome approaches do not provide more protections for participants and thus are a burden without benefit. A reasoned approach will allow a maintained respect for persons while ensuring appropriate protections when they are needed.  The options on how to provide new information to participants should be based on the kind of information to be provided and if participants need to document that they wish to remain in the study.

Our Proposed Hierarchy

Our proposed hierarchy for the provision of new information, which is consistent with the SACHRP recommendations, is:

Verbal Discussion:

Providing information to participants verbally may be sufficient if the information is simple, not likely to change the individual’s decision to remain in the study and doesn’t require the participants to document that they want to remain in the study.  Examples include informing participants that certain procedures are no longer necessary without changes to the visit schedule (e.g., “We won’t need to do an eye exam when you come for your Week 12 study visit”).

Letter:

It may be appropriate to send a letter to the participants to provide new information when the information is simple and self-explanatory, but it is important for the participants to have something in writing for future reference.  The new information likely will not impact a participant’s decision to remain in the study.  Examples include informing participants that they can use a commercial lab to have blood samples drawn or informing the participants of a change of investigator.

Addendum:

This is an in-between step, when information may be somewhat complex or important, but not to the level of needing full reconsent and discussion of the entire study. Examples include new safety information, the addition of a single new study procedure, or changes to how the participant’s information will be kept confidential. The new information may impact a participant’s decision to remain in the study, and there should be documentation (by signature) that the participant agrees to remain in the study.  The benefit of using a consent form addendum is that it can provide a focused discussion of the new information and will be more efficient that a full reconsent process.

Note that a verbal discussion also may be the initial step of providing participants with new information if it is urgent to provide that information while the written information is being created.

Reconsent:

Due to the time and effort involved, this is best for situations where there is no time pressure and there is complex information to be conveyed. Participants will have not started or will still be undergoing research procedures and having regularly scheduled study visits. Sites and sponsors should reconsent participants when the changes are so significant or pervasive that it would require a thorough consent discussion to re-explain the study and that the participants will need to document their agreement to remain in the study.  Examples include situations where participants are moving into a new cohort or phase of the study that is very different from what they are currently doing, when an adaptive study design may be changing, or when there are multiple changes being made to the study and it would be impractical to provide the new information in any other way.

In Closing

In line with the guidance provided by SACHRP, we want to encourage investigators and sponsors to consider approaches other than a full reconsent process for providing new information to currently enrolled participants.  Using mechanisms that are the least burdensome approach is based in ethical principles. As such, there should be a hierarchy of providing participants new information that ranges from verbally notifying the participants of the changes, to using letters, consent form addenda, and finally a complete consent discussion based on a revised consent form.  In situations in which the approach to providing new information may not be clear, both sponsors and researchers can talk to the IRB to help determine the most appropriate pathway.

References

1. 21 CFR § 50.25(b)(5) and 45 CFR § 46.116(c)(5).
2. FDA Information Sheet – A Guide to Informed Consent. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guide-informed-consent
3. FDA Draft Guidance – Informed Consent Information Sheet. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent
4. Attachment A – New Information Provided to Previously Enrolled Research Subjects https://www.hhs.gov/ohrp/sachrp-committee/recommendations/april-7-2020-attachment-a/index.html

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