56. IRBs: Models and procedures
S L I D E
IRB model and procedures: Studies of Ocular Complications of AIDS (SOCA) trials80
Parent center: Coordinating Center Parent IRB: IRB of Coordinating Center
Prototype consent forms and related informational documents prepared by Coordinating Center
Protocol and prototype consent forms submitted to parent IRB; distributed to clinics with instructions to submit to local IRBs after approval by parent IRB
Copy of approval letter from local IRB required at Coordinating Center before clearing clinic for enrollment; randomizations not issued absent copy of approval notice from local IRB
Randomizations not released if approval of clinic has expired (copy of renewal notice required in Coordinating Center to resume randomization)
Numbered memos from Coordinating Center used to transmit approved protocol and prototype consent forms and to instruct clinic on local IRB submission process; similar notification process used for protocol amendments
Notice of adverse events communicated to clinics by the Coordinating Center via numbered memos; memos instruct clinics to send notice to local IRBs
R E L AT E D E N T R I E S
IRBs (page 161), Consent: Process (page 185), Critical event path analysis (page 241)
D E F I N I T I O N S
central IRBn- An IRB having review authority over a multicenter study, especially one where approval by such a board is sufficient to allow investigators at study centers to proceed without additional review or approval.rt: commercial IRB, institutional review board, local IRB, parent IRB board
commercial IRB n - A board performing functions similar to an institutional review board on a fee-for-service basis for investigators directed to submit to it by IRB officials of their respective institutions or for investigators not affiliated with institutions having IRBs;
frequently used by investigators in industry-sponsored multicenter trials not at institutions having IRBs. (see http://www.circare.org/info/commercialirb.htm for list)rt: central IRB, independent IRB Usage note: Technically not an institutional review board as defined in the code of federal regulations underlying IRBs.66 The name, as used therein, pertains to a board created to review research arising from investigators at the institution housing the IRB. As a rule, investigators submitting to commercial IRBs are doing so because they are not associated with institutions having IRBs. Usually, investigators of major academic institutions are required to submit to their own respective IRBs.
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independent institutional review boardn- 1. A board performing functions similar to an institutional review board but not housed in institutions from which applications are received; typically from investigators at institutions not having an IRB. 2. commercial institutional review board
institutional review board (IRB)n- A body, set forth in regulations emanating from the United States Public Health Service concerning research involving human beings,47,66 appointed by authorities within a research institution and constituted to review and approve studies to be carried out on human beings by investigators from that institution.
The review focuses on the ethics and legitimacy of the proposed research from the perspective of risk–benefit to those studied and on the adequacy of safeguards for persons put at risk by the research. The risk may be a direct consequence of procedures performed or may be an indirect consequence of being studied (e.g., invasion of privacy or breaches of confidentiality). The review deals with, but is not restricted to, the nature and adequacy of the consent process and related consent statement when there is contact with individuals; in all cases, whether or not there is contact, the review focuses on the adequacy of procedures to preserve privacy and confidentiality. Technically, the regulations apply only to projects funded by the federal government, but most institutions require IRB review and approval of all research involving human beings, regardless of funding source. The name institutional review board arises from the regulations. The name is unfortunate in that it is not suggestive of the functions performed.syn: ethics committee, ethics review board, Helsinki committee, human experimentation committee, human volunteers committee
lead center n - 1. A center in a multicenter study that takes the lead in testing or performing certain procedures or which is otherwise designated to assume a leadership position in a study. 2. The center responsible for disbursing funds to other centers in a study funded via a consortium funding agreement.rt: parent center
local IRB n - 1. The institutional review board of one’s own institution. 2. The IRB serving a particular center in a multicenter study.rt: central IRB, parent IRB
parent centern- 1. A study center that gives rise to or nurtures other centers. 2. A study center that has administrative or operational primacy over other centers. 3. A study center having an affiliate, associate, field, or satellite center.
parent IRB n - 1. The IRB of the institution housing the principal investigator of a multicenter research project involving human beings. 2. The IRB of the parent center in a multicenter trial. 3. The IRB of the coordinating center in a multicenter trial.rt: central IRB, local IRB
N A R R AT I V E
Operationally, IRBs in the United States are created equal. They operate as autonomous units. They are not given to reciprocity arrangements. There is no master IRB. The action of one IRB is not binding on any other IRB. This means, in the case of multicenter trials, that it is possible for a proposal for a trial to sail through one IRB and be rejected by another.
The requirements of review apply to all research involving human beings. Research is considered to ‘‘involve’’ human beings as subjects even if it is done without any contact with them. It is considered to ‘‘involve’’ human beings if the research merely involves use of data or materials belonging to persons. Therefore, in the context of trials,
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planners should assume need for IRB approval for all centers in the trial, not just clinical centers.
IRB approval stands in the critical path to initiation of any research involving human beings (see Start-up critical event path analysis, page 241). The time required from initial IRB submission to definitive action will depend on the schedule of the IRB, on the nature and complexity of the research, and on the amount of risk to subjects represented in the research. The review process can stretch over months.
The submission will be as required by local IRBs. It is likely to include any or all of the following for trials:
• Funding proposal (for initial approvals)
• Study protocol
• Investigational new drug (IND) application (in the case of drug trials involving unapproved drugs)
• Investigator’s brochure (in the case of drug trials)
• Consent documents and forms
• Study forms; drafts or finished forms, depending on the IRB
IRBs will likely require disclosures from investigators relating to conflicts of interests and whether they have any proprietary interests in products being tested.
Planners need to specify the minimum requirements for allowing clinics to proceed with patient contact. Theoretically, a clinic can start initiating such contacts once it has IRB approval to do so. The difficultly with such a laissez faire approach is obvious in multicenter trials. It can allow clinics to start before other critical elements needed for starting are in place.
The minimum recommended requirements before allowing any patient contact are:
• Training and certification of clinic personnel
• Clinic certification
• IRB approval of the parent center, necessary resource center to service the trial, and at least one clinic
• Necessary approvals and authorizations from sponsors and regulatory agencies
• Necessary drugs and supplies
• Approved protocol and consent forms
• Necessary data collection forms
Dos and don’ts regarding IRB processes
• Doassume the need for review and approval unless specifically told otherwise by one’s IRB; operationally this means, in the case of multicenter trials, that every center, including resource centers, should assume the need for review and approval.
• Doassume approvals to be time limited (by regulation, approvals granted by IRBs may not be for more than a year; they may be for less time at the discretion of an IRB).
• Doassume the need for revision of consents whenever the protocol is modified.
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• Do assume the need for approval of changes to the study protocol if likely to adversely affect the risk–benefit ratio for study subjects.
• Doassume the need to report all serious adverse events (see Adverse events, page 471;
Adverse event reporting procedures, page 475).
• Do notinitiate patient contact absent IRB approval.
• Do notproceed with a protocol change adversely affecting the risk–benefit ratio to patients, absent IRB approval.
• Do notuse invalid consent forms (many IRBs require use of forms bearing a stamp affixed by the IRB that indicates approval and date approval expires).
• Do not assume that IRBs will not request changes to consent statements after approval (typically, consent statements are reviewed in relation to each renewal of an approval; the review may lead to requests for changes).
Recommended IRB practices for multicenter trials
• Designate a center to serve as the lead center in regard to submissions and approval.
• Regard the IRB of the lead center as the parent IRB.
• Prepare prototype consent form; submit to parent IRB for approval.
• Request that clinics prepare consent documents using approved prototype consent;
allow modifications to conform with local requirements, but require that information imparted not be less than represented in the prototype.
• Require that the lead center distribute documents to be used in local submissions, to include:
❑ Current, dated version of study protocol (typically the one submitted to the parent IRB or an updated version resulting from that review)
❑ Current, dated version of the approved prototype consent
❑ Current, dated version of the investigator’s brochure (in the case of drug trials done under INDs)
❑ Other information needed for submissions, including, but not limited to, information concerning funding sources, details regarding procedures for reporting adverse events, and provisions for treatment effects monitoring
• Require centers to supply copy of local IRB approval to lead center and copy of approved consent form.
• Perform review of consent form for adequacy of content.
• Institute fail safe systems to prevent clinics from initiating contact until approval has been obtained and clinic has been cleared to start by lead center
• Institute procedures to avoid lapses of approvals by lead center keeping track of expiration dates of individual approvals
Note The United States stands apart from many other parts of the world in its review structure. The autonomous nature of IRBs in the United States has made it difficult to centralize reviews. The absence of such a review and approval structure is unfortunate. The current structure is cumbersome and inefficient. The European Union, with its Clinical Trial Directive (2001), avoids the duplication by having created a centralized structure for its member states. It remains to be seen whether similar structures
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will emerge in the United States to streamline review and approvals for multicenter trials.
IRBs are under no obligation to act. Hence, reviews can drag on for months. In Europe there is a 60-day limit for reviews. The reviewing authority is obliged to act within that time period. If there are questions, the clock stops while waiting for answers to the questions.