No Modifications Without Prior IRB Approval
In most cases, no protocol, consent process, or consent form may be changed without prior approval from the IRB, except to eliminate an apparent, immediate hazard to one or more subjects. Also, the investigator is responsible for updating information about his or her research contacts with the OIRB. For more information, see the sections on Continuing Review & Approval and Project Revisions & Amendments.
Notify OIRB of all Reportable Problems
The Principal Investigator must report promptly to the IRB and sponsor any clinical trial research-related injuries to human participants or any unanticipated problems involving risks to human subjects or others, at UAB, multi-center trial safety reports from other participating sites, as well as DSMB reports. The IRB may require that any research project that has been associated with unexpected serious harm to the participants be terminated. If the research involves an investigational new drug or device, the Investigator must report such incidents to the Sponsor and/or the FDA as well as the IRB. See the section on Reporting Research-Related Problems for definitions and reporting guidelines.
Provide OIRB with Copies of All Monitoring Reports
Investigators are required to submit a copy of any and all internal and external monitoring reports within 2 weeks of receiving them. Such reports include those generated by
- A clinical research organization,
- A data safety monitor (e.g., DSMB, DSMC)
- An internal monitoring process.
Participant Withdrawal from Research--Guidance for Investigators
When a participant withdraws from a research study, the data collected on the participant up to that point remains part of the study’s database and cannot be removed.
The Investigator may ask the participant who wishes to withdraw if they would agree to provide continued follow-up and further data collection subsequent to their withdrawal from the interventional portion, such as that for clinical outcome information obtained through a chart review and would need an addendum consent form addressing the maintenance of privacy and confidentiality of the participant’s information if this type of situation was not addressed in the original informed consent. The IRB must approve this type of addendum consent form prior to its use.
If the participant withdraws from the research study and does not consent to continued follow-up, the investigator cannot access the participants’ medical record or other confidential records for purposes related to the research study. An investigator may; however; review the records prior to the withdrawal and consult public records, such as those establishing survival status.
Under Alabama law (Ala. Code 26-1-1), a minor is a person younger than 19 years old, unless such a person has been emancipated. A person who is age 18 and is either married or widowed is automatically emancipated. Further, Alabama law now permits a person who is 18 years old and older to consent to participate in IRB approved research conducted by a college or university that is accredited by a federally recognized accrediting agency.
Investigators who propose research involving persons younger than 18 years of age must provide protocol-specific information about their involvement. The IRB must be able to determine that the proposed research meets the requirements of all applicable federal regulations. Investigators use the Special Population Review Form—Children to provide information that is sufficient for the IRB to confirm that the applicable requirements are met and to describe the research as fitting Children´s Risk Level (CRL) 1, 2, 3, or 4. (These risk levels are described on the form.)
Federal regulations require special protections for "children" in research. The protections are in 45 CFR Part 46 Subpart D and, as applicable, 21 CFR Part 50 Subpart D, and 34 CFR Part 97 Subpart D. However, the criteria that define "children" come from local laws and institutional policy. When research procedures are to be performed in another state, investigators should contact the IRB for guidance on meeting local requirements.
UAB Office of Counsel has defined people younger than 18 as "minors." Usually, minors cannot provide legally effective consent for medical treatment or research procedures. Therefore, the UAB IRB requires that all applicable federal protections for children be incorporated in protocols that allow enrollment of participants younger than 18.
One required federal protection is commonly called "parental consent." It requires that a child-participant's parents or guardian be informed about the research and consent to the child's participation. In practice, it is important to ensure that this consent/permission comes from a person who is legally authorized to give consent for the minor-participant.
- If the proposed research involves no more than minimal risk (CRL 1), or does involve greater than minimal risk but is of possible direct benefit to the child (CRL 2), the consent of both parents is required unless the IRB finds that the permission of one parent is sufficient for the proposed research.
- If the research involves greater than minimal risk without direct individual benefit (CRL 3), permission must be obtained from both parents unless there is only one reasonably available parent. Guardian consent should be substituted for parental under appropriate legal constraints.
- Requires the following when children as wards of the state are involved in research determined to be CRL 3 or CRL 4:
- Appointment of an advocate for each child in addition to any other individual acting on behalf of the child as guardian or in loco parentis (An advocate may serve for more than one child.)
- The advocate to be an individual who has the background and experience to act in, and agrees to act in the best interests of the child for the duration of the child´s participation in the research; and
- The advocate to have no association in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization.
A parent, for purposes of consent, means either a child´s biological or adoptive parent. In some instances, the consent of a guardian may be used in lieu of parental consent. A guardian is an individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care. For purposes of research conducted in Alabama a guardian is
- A person appointed guardian of a child pursuant to the Alabama Uniform Guardianship and Protective Proceedings Act (Code of Alabama, Title 26) as documented by a valid court order;
- A person having legal custody of a child and as documented by court order;
- A person acting in loco parentis, regardless of whether such is documented by a court order.
A person acts in loco parentis of a child where the individual voluntarily assumes responsibility for the child´s custody, care, and maintenance even though no court order exists formally appointing the person as the guardian, legal custodian, or adoptive parent of the child.
In two situations the investigator can request that the UAB IRB waive the requirement for parental consent when a potential participant may be younger than 18:
- The UAB IRB does not require parental consent if the potential participant is an "emancipated minor." The Code of Alabama (26-21-2) defines an "emancipated minor" as "a minor who is or has been married or has by court order otherwise been legally freed from the care, custody and control of her [sic] parents." The IRB will base its decision on applicable state law. In this situation, federal requirements for consent and assent still apply to any participants who are younger than 18 and not emancipated. The IRB will review, on a case-by-case basis, studies in which adolescents (14-18 years of age or >12 years of age in the case of STDs) will be participating and in which the investigator requests an exception to parental consent.
- The federal requirement for parental consent recognizes an exception when "parental or guardian permission is not a reasonable requirement to protect the participants (for example, neglected or abused children)" [45 CFR 46.408(c)]. Investigators who wish to incorporate this waiver must indicate in the Human Subjects Protocol (a) why parental consent is not a reasonable requirement and (b) what protections will be used to protect the child-participants. In this situation, the IRB may request additional information from the investigator to ensure adequate protection of the child-participants.
Aside from requiring parental consent, the federal regulations also require obtaining the child's assent to participate, as determined appropriate by the IRB. Therefore, investigators must propose, in the Human Subjects Protocol (HSP), methods to obtain and document assent that are based on the age, maturity, and psychological state of the children involved. Any request to waive the assent requirement must be described in the HSP. The IRB generally recommends the following methods by age (in years):
- Younger than 7: Obtaining assent may be appropriate, depending upon the participant population. If assent is to be obtained, a written assent document may also be appropriate.
- 7 and older but younger than 14: Assent must be obtained unless this requirement is waived by the IRB. An assent document should be used, written simply and at a comprehension level appropriate for a 7-year-old child. An assent section on the adult consent document may be appropriate for research that involves only adolescents (e.g., 13- and 14-year-olds).
- 14 and older but younger than 18: Assent must be obtained unless this requirement is waived by the IRB. An assent section on the adult consent document may be appropriate, or a separate assent form may be prepared in the same language as the adult consent document.
US Department of Education Funded Research
When research is funded by the US Department of Education access to instructional material (including teachers´ manuals, films, tapes, or other supplementary instructional material) used in connection with the research or experimentation program or project must be available for inspection by the parents or guardians of the children engaged in the research.
Research or experimentation program or project is defined as any program or project in any research that is designed to explore or develop new or unproven teaching methods or techniques.
Children are defined as persons enrolled in the research not above the elementary or secondary education level, who have not reached the age of majority as determined under state law which in Alabama is 18 years of age.
Several preliminary steps must be completed before the IRB can review any application. Completing these steps as described can help investigators avoid delays in receiving review by the IRB.
Scientific, Scholarly Integrity
UAB policy gives each departmental chair responsibility for determining that proper scientific and department approvals have been obtained and that the hypothesis and procedures are consistent with generally accepted scientific principles in the discipline. Therefore, the principal investigator obtains review and approval from the department in which he or she holds a primary appointment. Most departments use the Protocol Oversight Review Form to document this review. If the project involves gene transfer or the administration of recombinant materials in humans, then review by the Gene Therapy Project Review Panel must be documented on the Report of the Project Review Panel.
Conflict of Interest
UAB policy requires review by the Conflict of Interest Review Board (CIRB) for all research when the principal investigator (including immediate family) or any individual (including immediate family) associated with the design, conduct, or reporting of the research described in this protocol submission has any of the relationships listed below regardless of whether the research is extramurally or intramurally funded.
Immediate family is the spouse or a dependent of the employee. Dependent is any person, regardless of his or her legal residence or domicile, who receives 50% or more of his or her support from the public employee or his or her spouse or who resided with the public employee for more than 180 days during the reporting period.
- An ownership interest, stock options, or other financial interest related to the research
- Compensation which is $5,000 or more in the past year when aggregated for the immediate family or any amount that will be affected by the outcome of the research
- Proprietary interest related to the research including, but not limited to, a patent, trademark, copyright, or licensing agreement
- Board of executive relationship related to the research, regardless of compensation
The CIRB provides relevant information on study personnel to the OIRB to assist the IRB in its review. The IRB will determine
- Whether the methods used for management of financial interests of individuals involved in the research adequately protect the rights and welfare of human subjects;
- Whether other actions are necessary to minimize risks to subjects; and
- The kind, amount, and level of detail of information that must be disclosed to research participants regarding:
- The interests of individuals involved in performing the research and
- Any conflict management arrangements applied.
Notably, the IRB can require measures in addition to any required by the CIRB to manage an identified conflict (actual, potential, or in appearance only). Visit www.uab.edu/cirb for more information.
Subcontracts
Investigators whose studies involve human subjects and who have subcontracts with collaborating non-UAB investigators for human subjects research must obtain the IRB approval from the subcontractor’s institution and submit a copy to the UAB IRB. The subcontracting institution should have a FWA with DHHS. If it does not, then either a Memorandum of Understanding (MOU) or an Individual Investigator Agreement (IIA) is required. Investigators should call the OIRB for specific instructions. Subcontract investigators may also need to provide certification of human subjects protection training. These documents must be submitted to the IRB before any participants are enrolled or research involving human subjects begins at any subcontract site. Coordination of subcontracts is facilitated through the Office of Sponsored Programs (OSP), which maintains a web site at https://www.uab.edu/research/home/osp.
Material Transfer Agreements (MTAs)
Whenever an investigator becomes involved in the transfer of tangible research materials, outbound or inbound, the University requires you work through The UAB Research Foundation (UABRF) to put a Material Transfer Agreement (MTA) in place to facilitate the transfer because these transfers involve important rights and obligations. MTA’s address ownership of the transferred materials, and ownership of modifications or derivatives made by the recipient from the materials. They also address limits on the use of the materials by the recipient institution, confidentiality of information related to the materials, liability issues, publication rights, and rights to inventions and research results.
Materials that are commonly transferred under MTA’s are culture, cell lines, plasmids, nucleotides, proteins, bacteria, transgenic animals, pharmaceuticals, and other chemicals. Intangible research materials, such as data and software, are generally transferred under Confidentiality Agreements (CDAs and are processed by UAB’s office of Grants and Contracts Administration, unless an Intellectual Property Disclosure (IPD) has been filed with UABRF. If an IPD has been filed, then the Agreement would be processed by UABRF. More information may be found at the following web sites:
www.uab.edu/uabrf/
https://www.uab.edu/research/home/osp
Devices, Inventions and Patent Policy
If the research involves a device or invention developed by the investigator, the investigator should contact the UAB Research Foundation at 934-9911. For more information please visit the UABRF web site at www.uab.edu/uabrf.
Protocol-Specific Approvals
The investigator should also determine which, if any, of the approvals described in the section on Special Approvals apply to the protocol. All special approvals must be obtained and documented as described before the OIRB will issue an Approval Form.
Advertisements
Advertisements should be limited to
- the name and address of the investigator;
- the purpose of the research and a summary of the eligibility criteria;
- a description of the benefits and compensation;
- the location of the research and the person to contact for further information.
The IRB recommends investigators obtain approval of any message text prior to taping to avoid re-taping if reviewers determine that inappropriate wording is used. The advertisements for recruiting into investigational studies should not mislead participants.
- Avoid making claims that the therapy or device is safe and/or effective, or that it is known to be superior or equivalent to some other product.
- Advertisements should not promote the study as providing “free medical treatment” when the intent is to convey that participants will not be charged for participating in the study.
- Advertisements may state that the participants will be paid for their participation, but it should not overemphasize this or the amount by bolding or enlarging the typeface.
Data Safety Monitoring Information
Data and safety monitoring is often required to provide regular reports about the continuing safety of participants, as well as the continuing validity and scientific merit of the project. Data Safety Monitoring Board (DSMBs) and Data Safety Monitoring Plans (DSMPs) may not be necessary or appropriate for many studies when the intervention is low risk. For example, expedited protocols rarely need such monitoring because they are minimal risk studies.
DSMPs
A DSMP is sufficient for many types of studies, such as most Phase I and Phase II trials or investigator-initiated studies conducted at UAB. A DSMP details how the study investigator, along with a colleague or medical monitor, will provide continuous, close monitoring as well as prompt reporting of toxicities to the IRB, FDA, and sponsor, as applicable. The DSMP should include the name of the individual(s) who will be reviewing the data so that the IRB can assess their qualifications and assure there is no conflict of interest.
The DSMP should also describe data “stopping rules,” which include
- if there is clear evidence of harm or harmful side-effects of the intervention(s);
- if there is no or little likelihood of demonstrable benefit; or
- if there is overwhelming evidence of benefit of one intervention or one intervention over the other in comparative trials.
DSMBs
A DSMB is required for federally funded Phase III studies and may be needed for Phase I or II trials that are high-risk, blinded, and/or multi-center. A DSMB may also be needed for protocols that involve, for example, a large study population, a multi-center study, use of high-risk therapies or procedures, study populations with potential for increased rates of mortality or morbidity, or a high probability that the study may be terminated early under the stopping rules. For the IRB to determine whether the members of the DSMB are qualified and appropriate, the investigator must provide the names and the qualifications of the members in the IRB application.
DSMBs are formed under a charter. Their members typically include clinical experts, statisticians, someone knowledgeable about conduct of clinical trials, ethicists, and an advisory panel member (lay member). Each member has a contractual agreement to serve on the board, to declare any relevant conflict of interest, and to sign the appropriate confidentiality agreement(s).
A DSMB has the authority to stop a trial if there is
- clear evidence of harm,
- no likelihood of demonstrating benefit (i.e., futility), or
- overwhelming evidence that the intervention is beneficial or if there is clearly benefit of one intervention over the other.
Under FDA regulations, "emergency use" is defined as the use of a test article (e.g., investigational drug, biologic, or device) on a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval.’
The FDA regulations allow each institution only one exemption from the requirement for prospective IRB review in emergency cases. Multiple uses of this nature would violate FDA regulations; therefore, UAB policy requires prior review and approval in "emergency use" situations if time permits in order to prevent multiple investigators from unknowingly using the same test article in an emergency situation that is the same, or very similar, to one already performed at UAB. The following sections describe the emergency use procedures allowed at UAB and the applicable requirements.
Two categories exist for emergency use of a test article: One-Time Use for Clinical Purposes Only and Treatment Use Prior to Convened IRB Review. Both require prior review and approval by the IRB Chairman whenever time permits. When time does not permit, the UAB IRB has a procedure whereby a health care provider can apply for exemption from prior IRB review and approval after treating a patient with an FDA-unapproved test article. Notably, all these uses require that the investigator obtain the informed consent of the patient or legally authorized representative unless specific conditions apply.
Informed Consent for Emergency Use
Even for an emergency use, the investigator is required to obtain informed consent of the subject or the subject's legally authorized representative unless both the investigator and a physician who is not otherwise participating in the clinical investigation certify all of the following Before the test article is administered, the investigator and a physician unrelated to the investigation must certify in writing to the following four elements:
- Subject is confronted with a life-threatening situation necessitating immediate use of the test article (drug or device);
- Subject is unable to communicate or legally effective informed consent cannot be obtained;
- Time is not sufficient to obtain informed consent from the subject’s LAR; and
- No available alternative method or approved or generally recognized therapy exists that provides an equal or greater likelihood of saving the subject’s life.
If, in the opinion of the investigator, immediate use of the test article is required and there is not sufficient time to obtain the certification of an independent physician in advance of use of the test article, the investigator:
- Certifies in writing the four elements listed above; and
- Has an independent physician review and evaluate the decision in writing within 5 working days after the use of the test article.
One-Time Use for Clinical Purposes Only
This category of emergency use is defined as "Administration of an investigational article in an emergency use situation to one patient with no plans for subsequent use of the test article at this institution." Before administering the investigational drug/device, prior review and d approval by the IRB Chairman is required. The Chairman of the IRB will review the request and respond with an approval or request for revisions. The following information should be submitted to the OIRB:
- Letter of explanation which specifies justification for administration of the test article (see Informed Consent and Emergency Use, above).
- Copy of the informed consent document.
- Any additional information from the manufacturer regarding use of the test article.
Note: If sufficient time is not available to prepare the above documents, telephone approval may be obtained by contacting the IRB Chairman, Dr. Ferdinand Urthaler, at 934-4622 or the OIRB at 934-3789. The above materials must be submitted to the OIRB within 5 days.
If the IRB, during retrospective review, finds that a given test article is used in justifiable emergency situations by several investigators, or if further justifiable emergency situations are anticipated, the IRB will request that a protocol be developed for prospective IRB review, listing all investigators who may use the article in the institution in the future. By reviewing and approving this protocol prospectively, subsequent use of the test article would not be subject to the emergency use provision for those investigators.
Treatment Use Prior to Convened IRB Review
This category of emergency use is defined as "Administration of an investigational drug/device
- to one patient in an “emergency use” situation that was unforeseeable and
- in which there are plans to subsequently submit an application for convened IRB review so that patients may be entered into a research protocol."
Review by the IRB Chair is required before the test article is administered to the patient. The Chair will review the request and respond in writing. The following information should be submitted to the Chair for this review:
- Letter of explanation which specifies justification for administration of the test article (see Informed Consent and Emergency Use, above) and which clearly indicates that a full IRB review application will be submitted at a later date;
- Copy of the informed consent document; and
- Copy of the sponsor's protocol and/or information concerning the test article.
Exemption from Prior Review and Approval by the UAB IRB
In an emergent situation, there may be circumstances under which a health care provider may wish to use an unapproved device to save the life of a patient or to prevent irreversible morbidity when there exists no other alternative therapy. In such a case, within 5 working days of the emergency use, the investigator submits information to the IRB to qualify for exemption from prior IRB review and approval. The submission must include the following information:
- The date the information is being submitted to the IRB
- A description of the life-threatening situation that required immediate intervention with the use of the test article;
- The known or foreseeable risks of the intervention and the anticipated benefits of the intervention;
- A copy of the signed informed consent document if consent was obtained or, if obtaining consent was not feasible, copies of the certifications addressing the items noted above;
- The name of the investigational drug, agent, biologic, or device used;
- A description of the treatment plan in sufficient detail for IRB review;
- Any reportable problems described under POL006 UAB Policy to Ensure Prompt Reporting of Unanticipated Problems Involving Risks to Subjects or Others to the IRB;
- The outcome of the emergency-use intervention, if known.
- An assessment of the likelihood of a similar need for the investigational or unlicensed test article and, if likely, immediately initiates the process to obtain an IND or IDE and convened IRB approval;
- Note that data obtained about a recipient of emergency medical care with an FDA-unapproved test article cannot be used for a prospectively conducted research activity.
- A copy of the notification to be sent to designated officials at performance sites, as applicable.
Treatment IND and Emergency Use IND Protocols
Under the FDA regulations, an IND sponsor may apply for a Treatment IND. If the FDA grants the Treatment IND, the investigational drug may be used to treat patients with serious or immediately life-threatening diseases for whom no comparable or satisfactory alternative drug or therapy is available.
FDA policy specifies that "the provision for emergency use would almost never apply to a treatment protocol or a Treatment IND because these are planned uses of the test article and sufficient time is available to obtain prospective convened IRB review and approval." However, in the rare cases in which emergency use does apply, the procedures outlined above for "One Time Use for Clinical Purposes Only" or "Treatment Use Prior to Convened IRB Review" should be followed.
Although the FDA may waive the requirement for IRB review, the UAB IRB policy specifies that prior review and approval by the Chairman is required. Procedures described above under "Prior Treatment Use" must be followed with two additions:
- The phrase "Treatment IND" must be included in the title.
- The letter of explanation must include the Treatment IND number assigned by FDA.
Under the Federal Food, Drug and Cosmetic Act, the FDA has the authority to inspect clinical investigators, IRBs, sponsors, monitors, contract research organizations, and any other entities that submit to the FDA clinical data or information in applications for approval to market investigational drugs, devices or other test articles.
If you are contacted by the FDA regarding an inspection, you should contact the OIRB by phone and follow up with a written notification to the IRB giving the Principal Investigator and title of the study to be inspected.
Any report regarding the audit should be forwarded to the OIRB within 2 weeks of receipt by the investigator and/or study coordinator.