The Final Rule for Dummies

WHAT is it?

The Final Rule isn’t actually a “final rule” but simply a revision to the Common Rule. The goal was to reduce administrative and regulatory burden, as well as better protect human subjects in research.

The Final Rule was adopted and applies to 16 federal agencies:

* If research is sponsored by them, it must comply with the Final Rule.

What about studies involving the FDA?

FDA has separate regulations that can differ from the Common Rule. While the goal is to harmonize the two at some point, the FDA-regulated research must comply with the FDA regulations.

What is the Common Rule?

It’s a rule of ethics in the US that is applied to biomedical and behavioral research involving human subjects. The IRB is responsible for ensuring that the “rules” are addressed in their research applications.

 

WHEN do we have to start implementing it?

The general implementation date of the Final Rule has been moved to January 21, 2019, until further notice. The exception to the said general implementation date are multi-site studies (45 CFR 46.114). Final Rule requirements specific to this kind of studies (a.k.a. “cooperative research”) must be implemented starting January 20, 2020.

**Note: NIH studies are required to comply with these multi-site study requirements (review under a single IRB) starting January 25^th, 2018 (NIH has its own sIRB requirements).

What about my already approved/active studies? Can we just follow the old regulations?
Research approved, waived, or determined to be exempt prior to July 19, 2018 will continue under the pre-2018 rules.
* Each IRB may determine, on a study-by-study basis, whether previously approved research can or should be subject to the new rules or can remain under pre-2018 regulations. That means if investigator’s want to request their old studies fall under the Final Rule, they would have to submit a modification and request the IRB to approve that.

HOW does it affect me?

Ongoing research studies initially approved prior to the effective date (July 19, 2018) are not required to comply with the Final Rule, unless the institutional policy requires it.

While the Final Rule only affects federally funded research, the Institution has the authority to determine if the Final Rule be applied to all research, regardless of funding.

WHERE can I get more information/training on this new rule?

CITI Program has created resources to help the research community understand the revisions. For useful resources, please visit: https://about.citiprogram.org/en/final-rule-resources/

You can also locate and review the regulations directly from the regs here.

SHORT SUMMARY OF CHANGES:

• INFORMED CONSENT PROCESS: Improves the informed consent document and process to improve and ensure subject understanding.
• POSTING CONSENT FORMS: Requiring that consent forms for certain federally funded clinical trials be posted on a public website (after the study has ended, of course).
  
• COOPERATIVE RESEARCH: Requiring single Institutional Review Board (sIRB) review for cooperative research/multi-site studies (not every study, just some kinds).
  
• BROAD CONSENT: Allowing the institution to adopt an optional use of broad consent for future research for secondary studies on stored identifiable data or identifiable biospecimens. Some institutions have chosen to NOT adopt this option.
  
• DEFINITION OF HUMAN SUBJECT: The definition of “human subject” has been changed to explicitly include identifiable biospecimens.
  
• DEFINTION OF “RESEARCH”: The Final rule modifies the definition of research by identifying activities that do not meet the definition of research.
  
• CONTINUING REVIEW: No more Continuing Review! For some…Final Rule eliminates continuing review for certain minimal risk studies. You have to apply for this if you’re study has already been given an “expiration date”.
  
• EXEMPT RESEARCH: Added new exempt categories of research based on level of risk posed to subjects and modified others (i.e. exempt categories).
  

 

Above Changes Broken Down

INFORMED CONSENT PROCESS & FORMS (46.116 & 46.117)

The goal was to create a short and concise summary of key information at the beginning of the Informed Consent Form later going into detail about those elements in the body of the Informed Consent Form. See examples below:

Basically, make it is as easy as possible to comprehend. The language should be simplified so that a reasonable person (think 8^th grade level) can make a fully informed decision as to whether or not they want to participate. The other 8 Basic Elements to Informed Consent remain unchanged.

Your IRB of record likely has templates you can use to ensure you have all the required elements in your consent form.

There is no limit to how much information can or should be presented in the Informed Consent Form. However, you should provide ample detail and organize it in a way that ensures understanding.

Collection of Private Information or Identifiable Biospecimens for Future Research (46.116(b)(9):

New requirements are to include one of two statements about the collection of private information or identifiable biospecimens for future research:

• “Identifiers might be removed and the de-identified information or biospecimens used for future research without additional informed consent from the subject.”
• “The subject’s information or biospecimens will not be used or distributed for future research studies even if identifiers are removed.”

Use of identifiable and de-identified biospecimens in research / Consent requirements:

If the specimens are de-identified, no consent is required.

The catch is:

• The specimens have to be used for secondary research
• They are not readily identifiable to the researcher

These are exceptions:

1. If genomic data is involved (NIH repositories won’t accept genetic data unless there is a consent form)
2. If the specimens are being gathered prospectively for primary analysis, a consent form is needed.

   Three New Requirements (46.116(c)):

   There will also be a requirement to add language about identifiers and the use/storage of data/specimens. Scenarios to be addressed are:

(1)   46.116(c)(7): information on whether biospecimens (even with identifiers removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit,

Example Language: “Any of your samples which are used in research may result in new products, test or discoveries. In some instances, these may have potential commercial value and may be developed and owned by the Investigators, SRI and/or others. However, donors of samples do not retain any property rights to the materials. Therefore, you would not share in any financial benefits from these products, tests or discoveries.”

(2)   46.116(c)(8): whether clinically relevant or individually relevant results will be disclosed to the subject,

Example Language:

• 1. Option 1: “The results of the study of your samples will be used for research purposes only and you will not be told the results of the tests.” Or
  2. Option 2: “You will be told the results of tests that are part of your clinical care, but you will not be told the results of the research tests, including any future research tests.”
     and,

(3)   46.116(c)(9): whether the research might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen).

Example Language: “Research testing on your sample will include whole genome sequencing. This means we will map your entire genetic code. If you have questions about this ask the study staff.”

Waiver of Consent for Screening (46.116(g)):

The Final Rule allows the IRB to approve a research proposal in which an investigator will obtain information or biospecimens for the purpose of screening, recruiting, or determining the eligibility of prospective subjects without their informed consent” if certain conditions are met:

1. The information will be obtained by communicating with the prospective subjects
2. The information will be obtained by accessing records or stored biospecimens.

** This is not a waiver of the consent requirement for the actual study but rather an exception to the requirement

Investigators must provide compelling evidence that the research could not practicably be carried out without accessing or using such information or biospecimens in an identifiable format.

*Non-identified information should be used whenever possible to respect subjects’ interests in protecting the confidentiality of their information and biospecimens.
*IRB cannot waive informed consent under broad consent, or omit or alter any of the required broad consent elements.

Electronic Consent (46.116(f)):

The Final Rule allows the use of electronic consent, but the PI must provide the investigator with a written copy of the Informed Consent Form.
**You must inform the IRB of the use of Electronic Consent in the initial application or via modification.

POSTING CONSENT FORMS: A NEW MANDATE:

Who is going to post (46.116(h)(1))?

The responsibility for posting is on the awardee or the federal department or agency component conducting the study.

Where do we post?

OHRP has not identified the site for posting yet. The Final Rule’s preamble states “ClinicalTrials.gov might be an appropriate choice as the website … the fact that these trials already have a record in the database will mean that the burden of submission of the informed consent document will be substantially lower.

What do we post?

You should work with your IRB and Legal Department to determine what type of information needs to be redacted from the consent forms you post. The redaction of proprietary or institutionally sensitive information of portions of consent forms is allowed.

COOPERATIVE RESEARCH (46.114):

Changes to Cooperative Research (a.k.a., “multi-site studies”) in the Final Rule now require that a single IRB serve as oversight.

The following research is not subject to this provision:
Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.

This allows the lead institution to propose the reviewing IRB, “subject to the acceptance of the federal department or agency supporting the research”

Who gets to be the lead?

The regulations allow the lead institution to propose which IRB will serve as the IRB of record, but leaves the final decision to the federal department or agency funding the research.

**IMPORTANT** Revisions requiring use of a sIRB will take effect January 20^th 2020.

BROAD CONSENT:

Some institutions may choose to implement the use of Broad Consent in their Informed Consent Form process. Many have elected NOT to adopt Broad Consent due to complications tracking and honoring the “no” responses in order to determine if the data/specimens could be used by an investigator in the future.

Additionally, the IRB cannot waive the consent form requirements of those that opt out of Broad Consent.

What is Broad Consent Anyway?  

Broad Consent describes what info might be used, how it’s shared, the time span specimens will be stored/used, informs the participant that they won’t be told some of the findings, as well as the types of institutions or researchers that might conduct research. It also requires that information regarding contact info for questions in the case of a research-related injury were to occur. Most of this is similar to the current Common Rule, however, Broad Consent differs in that it allows for the use of identifiable data and specimens to be used in future research without the participant’s consent, even if the research is not related to what the participant originally signed up for. With Broad Consent, if a subject says “No” then the IRB cannot override the subject’s wishes through waiver of consent process (IRB cannot waive consent).

Optional banking for specified types of future research use is preferable. It is my personal believe that if an institution chooses to adopt Broad Consent, it MUST be used with caution.

DEFINITION OF HUMAN SUBJECT:

The Final Rule defines “human subject” to mean a living individual about whom an investigator (whether professional or student) conducting research:

1. Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes their information or biospecimens; or
2. Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

** Note: Due to advances in technology, the definition of “identifiable biospecimens” and “identifiable private information” will be re-examined within one year of publication of the rule and every four years thereafter (see section 46.103 for more information).

Additional Considerations:

‘About’ living individuals: Although data may be obtained from living individuals, it may not be about them (i.e. the research is about a “what”, rather than a “whom.”).  Also, research dealing with tissues or specimens obtained from deceased individuals or cadavers is not considered to be about living individuals.

Interaction: Includes communication or interpersonal contact between investigator and subject (including online surveys)

Obtaining:  Receiving or accessing identifiable private information or identifiable specimens for research purposes.  OHRP interprets obtaining to include an investigator’s use, study, or analysis for research purposes of identifiable private information or identifiable specimens already in the possession of the investigator.  Note:  If private individually identifiable information is received by the researcher and subsequently de-identified, the study is still considered to involve human subjects.

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 which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record, school grades, or height and weight measurements).  Private information must be individually identifiable (i.e., the identity of the subject is or may be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.  Examples of studies using private information include chart reviews, obtaining lab studies on identifiable tissues and specimens, or using identifiable information from data or tissue repositories, obtaining school grades, private interviews, or surveys of opinions and attitudes.

Coded: Data or specimens are considered coded when identifying information that would enable the investigator to readily ascertain the identity of the individual to whom the private information or specimens pertain (e.g., name, social security number, etc.) has been replaced with a code (e.g., a number, letter, symbol, or combination thereof), and a key to decipher the code exists, enabling linkage of the identifying information to the private information or specimens.

DEFINITION OF RESEARCH (46.103):

The Final Rule extends the definition of research to exclude certain types of research. This doesn’t change the OHRP original definition.

In determining if the study is Human Subject Research, we have to break it down into two parts:

1. Is my study Research? And
2. Is my study Human Subject

Is my study “Research”?

Research is defined as (DHHS 45 CFR 46.102(d): a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.

The Belmont Report provides additional clarification:

“…the term ‘research’ designates an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships). Research is usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective.”

Activities that do not meet the definition of research
(NEW from the Final Rule):

1. Scholarly and journalistic activities (e.g., oral history, journalism, biography, literary criticism, legal research and historical scholarship)… that focus directly on the specific individuals about whom the information is collected
2. Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions or public health importance
3. Certain criminal justice and intelligence activities.

   PRE-2018 RULE ACTIVITIES GENERALLY NOT CONSIDERED TO BE RESEARCH 
   (STILL STANDING FROM COMMON RULE)

1. Research Practicum or training activities
2. Quality Assurance (QA), Quality Improvement (QI), Course or program evaluation
3. Oral Histories *
4. Case Studies
5. Pilot Studies **
   

Intent to Publish:

As per previous rules, Intent to publish is not part of the definition of “research”. Intent to publish may signify that generalizable results are anticipated. However, activities that do not meet the regulatory definition of research will not be considered research even if published or intended for publication.

* An oral history study may not require IRB review because it is not generally thought to be a systematic investigation designed to contribute to generalizable knowledge beyond the individual being interviewed.   However, when using oral history as a technique in human subject research it may require IRB review. Researchers proposing such work are strongly encouraged to contact the IRB to determine whether their project requires approval.

** Medical interventions or interactions for research purposes, especially those involving invasive procedures, do require IRB review regardless of the size of the study.

CONTINUING REVIEW (46.109 and 46.115):

Continuing Review will no longer be required for any projects approved through expedited review, projects where remaining activity is data analysis or data collection.

• Continuing Review is still required for studies approved by a convened IRB (full board studies).
• Research approved via expedited review and governed by the pre-2018 rule still requires continuing review.

Please note, the IRB maintains authority to require continuing review. Investigators are not able to make the decision of whether their study qualifies as no longer needing Continuing Review.

*Note: if a study is determined that it does not require Continuing Review, the investigator is not required to annually confirm to the IRB that research is ongoing and no changes have been made. HOWEVER, investigators are STILL required to submit modifications (if any changes are being proposed to the study, prior to implementation) and reports.

EXEMPTIONS (46.104):

The Final Rule revised some categories and added two more. It also updated Subpart applicability.

What was added:

The two new ones are 6 & 7: Limited IRB Review and Broad Consent. I.e., There are now 8 instead of 6 Exempt Categories (46.104(d)(1-8).

Category 7 – Storage or Maintenance for Secondary Use for Which Broad Consent is Required: This is like creating a databank/tissue bank/repository in that it is for storage of identifiable biospecimens and identifiable private information prior to secondary analysis. The IRB will need to conduct Limited IRB Review in order for this to qualify. The Consent form to be used does not have to be Broad Consent, and can be provided via a template by the IRB.

*This is only applicable for IRB’s that have chosen to adopt Broad Consent.

Category 8 – Secondary Research for Which Broad Consent is Required: allows the secondary analysis of existing private identifiable data and identifiable biospecimens provided broad consent was secured and the documentation of consent was either secured or waived. Limited IRB Review is required.

*This is only applicable for IRB’s that have chosen to adopt Broad Consent. 

What was modified?

Category 1, 2, 4, and 5 were modified. Category 3 was replaced.

Category 1 – Research in Established or Commonly Accepted Educational Settings: includes a condition that “research is not likely to have adverse impacts on students learning required educational content or assessment of educators who provide instruction.

What does “assessment” refer to?

Example Scenario:

A researcher proposes conducting a study in an established educational setting in which the behavior of the teachers towards minority students will be recorded and coded.

The “behavior” is not defined in this scenario, so it is not clear if the data collection about the behavior of the educators would adversely affect the assessment of educators who provide instruction or not. If an activity does not completely fit in the exemption category, then it cannot be exempt.

* This can only be used for studies ABOUT normal educational practices. 

Category 2 – Educational Tests, Surveys, Interviews, Observations of Public Behavior: now allows for exemption if any/either 3 criteria or met (and no other part of the study is non-exempt):

• Information obtained is not identifiable
• Disclosure outside of the research would not put subjects at risk of harm
• Information obtained can be identifiable but the IRB has conducted Limited IRB Review (46.111(a)(7), ensuring adequate provisions are in place to protect privacy and maintenance of confidentiality.

*This category can include visual or auditory recording as research methods, but cannot include collection of biospecimens or interventions. 
*When the research is subject to Subpart D and includes children, Category 2 still does not allow surveys or interviews or the observer participating with children (public behavior observation without intervention is permitted).

Category 4 – Secondary Research (Data or BioSpecimens) for Which Consent is Not Required: If 1 of the 4 criteria are met, it can be Exempt:

1. Use of publicly available identifiable private information or identifiable biospecimens.
2. Information recorded by the investigator in such a way that the identity of the subjects cannot be readily ascertained, and the investigator will neither contact the subjects nor re-identify subjects.
3. Research use of identifiable health information when that use is regulated by HIPAA as health care operations, research, or public health activities and purposes as those terms are defined in HIPAA.
4. Analysis of data on behalf of a federal agency or department – as opposed to an investigator-initiated analysis of federally supplied data – if the requirements of certain federal laws are met.

*Data doesn’t have to be existing/retrospective (i.e., “on the shelf” but can also be collected prospectively in this Category.

Category 5 Research  and  Demonstration  Projects  that  Are  Conducted  or  Supported
by  a  Federal  Department or Agency:
Now allows research supported by a federal agency to qualify.

What was replaced?

Category 3 – Benign Behavioral Interventions in Conjunction with the Collection of Information From Adult Subjects

Benign Behavioral Interventions are defined as: “brief in duration, harmless, painless, not physically invasive, not likely to have a significant adverse lasting impact on the subjects, and the investigator has no  reason  to  think  the  subjects  will  find  the  interventions  offensive  or embarrassing”

Examples include (but are not limited to):One

• Completing a specific physical/mental action
• Survey question manipulation
• Reading vignettes/articles
• Viewing/listening to media
• Reading/writing/drawing tasks
• User interface/consumer preferences
• Design/data visualization

*Research using deception is not eligible unless subjects prospectively agree to being misled.

*Category 2 criteria must be met regarding identifiable data, disclosure risks, and adequate protections in place as reviewed by the IRB.

*Not applicable with children.

Is my study Exempt?

The IRB maintains the authority to determine if a study qualifies as exempt or not, however, it helps to know what those requirements are. So visit here if you’re interested.

What does “Exempt” mean?

Exempt means the study is not subject to the requirements of the Common Rule.

**** IMPORTANT REMINDER ****
“Exempt” does not always mean exempt from all the requirements of the Common Rule (HHS 2017). For example, the new Exempt Category 7 includes specific regulatory requirements of broad consent and Limited IRB review as a condition of being exempt from other regulatory requirements.

• The Final Rule allows research with children to be exempt for categories 1, 4, 5, 6, 7, and 8.
• The Final Rule does NOT allow exemption of research with children that includes identifiable information and is reviewed under a Limited IRB Review.
• Surveying and Interview procedures with children is (still) NOT exempt (and this is a GOOD thing).

Exempt Studies with Vulnerable Populations (46.107):

The Final Rule refers to vulnerability as meaning, “vulnerable to coercion and undue influence, in recognition that coercion or undue influence refers to the ability to make an informed decision about participating in research” (Final Rule Preamble).

The Final Rule no longer lists pregnant women and physically or mentally disabled persons as examples, but does list “individuals with impaired decision-making capacity.”

Research with prisoners can now be exempt if the research is aimed at involving a broader subject population that only incidentally includes prisoners.

Limited Review:

Limited IRB review is a new concept added by the Final Rule and is relevant to certain new exemptions (Category 2, 3, 7, and 8) (although many institutions were already doing this).

Via this “Limited IRB Review” the IRB will review and make determinations as a condition of exemption. For example, that “there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data” (46.111(a)(7)

When is Limited IRB Review Required

What is the IRB looking for when doing Limited IRB Review?

New processes are in place to document limited IRB review for exemptions.

Limited IRB review must be conducted by an IRB member (same requirement for an expedited review).

Expedited Review:

Expedited Categories do not change. The studies must present no more than minimal risk to subjects and only involve procedures listed in one or more of the expedited categories (See here for list).

The only change that affects investigators is that Continuing Review is no longer required for studies approved under Expedited Categories (unless the IRB determines otherwise). Modifications, Reports, and Closures must still be submitted to the IRB as per usual.

 

References:

U.S. Department of Health and Human Services (HHS). 2017. “Federal Policy  for the Protection of Human Subjects.” Federal Register82(12):7149-274.

CITIProgram.Org Final Rule Resources: https://about.citiprogram.org/en/final-rule-resources/

Public Responsibility in Medicine and Research (PRIM&R): https://www.primr.org/commonrule/resources-tools/

Institutional Review Boards, 21 CFR § 56 (2015).

National Institutes of Health (NIH). 2016. “Final NIH Policy on the Use of a Single Institutional Review Board for Multi-Site Research.” Accessed September 30.

Protection of Human Subjects, 21 CFR § 50 (2015)