Author: M.S. Evans, M.D.,
Southern Illinois University School of Medicine,
Springfield, Illinois, USA
Revised: April 21, 1998, March 5, 2001
SCRIHS, the Springfield Committee for Research in Human Subjects, is an Institutional Review Board (IRB) established in order to allow local investigators to comply with Federal regulations regarding the protection of human subjects of research.
The ethical concern for protection of human research subjects is a modern issue, so the fundamental documents in this area are relatively recent. A partial list of the fundamental documents in this area are:
The Belmont Report describes three fundamental principles for the ethical conduct of research in human subjects:
Since much human research is medical research, the Belmont Report distinguishes between medical practice and medical research. The purpose of medical practice is to "provide a diagnosis, preventative treatment or therapy to particular individuals."(1) Unlike medical practice,medical research is "an activity designed to test an hypothesis, permit conclusions to be drawn,and thereby to develop or contribute to generalizable knowledge . . . [and it is] usually described in a formal protocol that sets forth an objective and a set of procedures designed to reach that objective." It is the purpose of the activity, not the tools that are used, that determine whether an activity is "research." An "experimental" (in the sense of unapproved or untested) drug or device may be used in order to help a patient. This is not research. In contrast, if part of the purpose is to gather information about safety or efficacy of the drug or device, the activity is research.
An IRB is a "group that has been formally designated to review and monitor biomedical research involving human subjects . . . .[An] IRB has the authority to approve, require modifications in (to secure approval), or disapprove research."(2) The major function of an IRB "is to review research to assure the protection of the rights and welfare of the human subjects."(3) The purposes, composition, and responsibilities of IRBs are mandated by Federal law.(4) IRB review is required for human studies "conducted, supported or otherwise subject to regulation by any Federal Department or Agency . . . ." Federal Policy concerning research done under the auspices of the National Institutes of Health, Public Health Service, Department of Health and Human Services, and 13 other Federal Agencies are given in the Code of Federal Regulations 45 CFR46. Much human research is done without the support of the Federal government, but is intended to be used to support an application to the Food and Drug Administration (FDA). Regulations concerning human research to be submitted to the FDA are covered in 21 CFR 50, 56 andothers.(5) Although there are minor wording differences, the FDA and Federal guidelines are identical in the functions and responsibilities assigned to IRBs.
An IRB has jurisdiction over research involving human subjects. Research is defined by regulations as "a systematic investigation, including research development, testing and evaluation, designed to contribute to generalizable knowledge."(6) Human subjects include "living individual(s) about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information."(7) Some research on human subjects is exempt from Federal regulations. One example is the use of existing data, documents, or specimens, where no identifying information will be recorded that could link subjects to the data.
Any institution that receives Federal support for research is required to file an "Assurance" with the Office of Human Research Protections (OHRP), an office in the Department of Health and Human Services (DHHS) concerned with implementing regulations on behalf of the Secretary of DHHS.(8) The Assurance certifies that the institution will protect the welfare of human subjects and abide by the ethical principles codified in the Federal Policy. Most institutions, including Southern Illinois University School of Medicine (SIU-SM), Memorial Medical Center, and St. John's Hospital, cite the Belmont Report as the set of principles by which they will abide. The Assurance applies to all research, whether or not the particular research project is supported by a Federal department or agency. In order to fully comply with their assurances, some institutions may enlarge the jurisdiction of their IRBs to include research that would be exempt under Federal guidelines. The FDA regulations are slightly different from the Federal Policy, and compliance with them is monitored by a system of audits and on-site inspections rather than by submission of a formal assurance.
Although an IRB is established (and funded) by a particular local institution, the institution does not control the decision-making of the IRB. Research that has been approved by an IRB may be subject to further institutional review, and possible disapproval, but research that has not been approved by the IRB cannot be approved by the institution. In general, institutions are very concerned that their IRB function correctly and follow Federal Policy, since the IRB is subject to audit by the OHRP and the FDA. Violations found by OHRP may result in suspension or withdrawal of the institution's Federal Assurance, and make the institution ineligible to receive Federal funds. Violations found by the FDA may result in specific sanctions or administrative actions.
The Springfield Committee for Research in Human Subjects, SCRIHS, is an Institutional Review Board formed in response to the need for a Springfield-area IRB to assure compliance with DHHS and FDA requirements. Southern Illinois University School of Medicine has filed a Multiple Project Assurance of Compliance with DHHS Regulations for Protection of Human Research Subjects with the OHRP. It is part of SIU-SM's assurance that all research in humans conducted by SIU faculty or staff, or conducted using SIU support, must be reviewed by SCRIHS. Through amendments to the primary document, Memorial Medical Center, and St.John's Hospital are covered by the same Assurance, but some research done at these institutions can be reviewed by IRBs other than SCRIHS. Any research supported by Federal funds at any of the three institutions must be reviewed by SCRIHS. Administratively, SCRIHS is part of the Southern Illinois University School of Medicine, Office of the Associate Dean for Research andFaculty Affairs (ADRAF).
SCRIHS has authority to "approve," "require modifications in (for approval)," or "disapprove" studies that are within its jurisdiction. Even if a study is "disapproved," SCRIHS does not have the authority to prevent the investigator from doing the research. However, our institutions are bound to assure that all research at their institutions is performed in compliance with DHHS ethical guidelines, and industry sponsors are obliged to ensure that their research meets equally stringent FDA guidelines. Both sets of guidelines require IRB review. Because of these requirements, institutions and sponsors invariably require IRB approval before an investigator is allowed to begin research using human subjects. For SIU-SM investigators, or for investigators in the Springfield area performing Federally-sponsored research, there is no alternative--prior to beginning the study, all non-exempt human research must be "approved" by SCRIHS.
If you are a faculty or staff member of SIU-SM (anywhere in the world), or if you are in the Springfield area and doing Federally-sponsored research, you specifically must obtain approval from SCRIHS. Some studies to be done at Memorial Medical Center or St. John's Hospital can be submitted to a local commercial IRB named "Triad, Justice, Beneficence, Respect." Non-SIU-SM investigators who do not plan to use the above hospitals during their research may submit their research protocol to any IRB that considers the study within their jurisdiction, including national IRBs.
Are you doing research? If your answer is "no" you do not need SCRIHS approval. SCRIHS does not regulate medical practice, even medical practice using "experimental" or "unapproved" treatments. If the intent of the practitioner is to help an individual patient with an experimental treatment, and there is no intent to collect data to "contribute to generalizable knowledge" (forexample, for publication or to demonstrate safety and efficacy to a third party), then the activity is not research. It should be noted that many institutions require that "experimental" treatments not be used for therapy, except in the setting of an IRB-approved research study. This may be a burden on the clinician who wishes to use an "experimental" treatment, because for SCRIHS approval to be obtained, the activity must be more than a good treatment, it must also be good research.
Will your research use human subjects? If your research uses data obtained by interacting with human beings, or by collecting data or specimens from human beings, you are using "human subjects," according to Federal regulations.
Is your research "exempt" from IRB review? "Exempt" research is defined in detail in 45CRF 46(b). Research may be exempt in several circumstances, for example, "collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available, or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects."(9) It is not possible to give a succinct account of research that may be "exempt"--you must refer to the detailed regulations.
If there is any question about whether you should submit an application to SCRIHS, the easiest, safest, and most practical way to answer the question is to ask the SCRIHS staff or chairman in a formal letter briefly describing your proposed study. You will receive a formal written reply. If you would like to design your study so that it will be exempt from IRB review, the criteria are given in the SCRIHS procedures manual and in the Federal Policy (45 CFR 46).
Is SCRIHS really a pain? Yes, in a way, because it causes investigators to have to do a considerable amount of work merely to get "approval" from the committee. On the other hand, without IRB approval most human research is prohibited by Federal law. Without an effective IRB like SCRIHS to help them fulfill the many requirements of law, Springfield-area investigators could not legally perform research in humans.
Usually yes, but you may not have to if your research can be "expedited." Expedited review is done by a SCRIHS subcommittee of two members and the chairman. It does not require a meeting. If approval is recommended by the subcommittee, the chairman can sign off on your protocol indicating approval. The full committee must be formally notified of studies approved by expedited review, which is accomplished by listing these studies in the committee's minutes. A protocol can be formally "disapproved" only by the full review process, not by the expedited review process. Protocols can be expedited for "certain kinds of research involving no more than minimal risk, and for minor changes in approved research."(10) Again, the list of kinds of research that can be expedited is long, but very specific, and few studies qualify. Examples include research done using voice recordings or "collection of hair and nail clippings in a non-disfiguring manner". Research protocols involving children are not eligible for expedited review.
"Compassionate use" studies are research, and must be submitted for IRB review. In these studies the design is usually simple, but it undergoes full board review, and requires a formal informed consent.
"Emergency" use is the use of a test article (e.g., drug) on a human subject in a life-threatening situation in which no standard treatment is available, and in which there is insufficient time to obtain IRB approval for the use. The FDA exempts a single emergency use from IRB review as long as the occurrence is reported to the IRB within five working days.(11) When SCRIHS receives a report of emergency use, the committee is obliged to investigate thecase carefully and ensure that emergency use was indeed justified. The use will not be justified if the problem is less than life-threatening or if a standard treatment was available. An investigator's belief that an experimental article is better than standard treatment is not sufficient to justify emergency use.
Emergency use requires informed consent, except in certain very specific circumstances defined by regulation.(12) There is a new category of research called "emergency research" applying to particular research situations in which it is not possible to obtain effective informed consent.(13) The regulations are meant to begin to allow research in conditions under which obtaining informed consent may be impossible, such as in the acute treatment of severe head trauma. The regulations concerning emergency research are specific and complex. It would be best to contact the SCRIHS office before designing or accepting such a study.
All ethical guidelines emphasize the importance of informed consent. In the Belmont Report, which is the ethical basis for IRBs, informed consent is the main component of the principle of "respect for persons." This respect requires "that subjects . . . choose what shall or shall not happen to them." Proper informed consent requires three elements: information, comprehension,and voluntariness. These elements are codified in Federal Policy. SCRIHS insists on a standard informed consent format whose design ensures that the minimum information necessary in an informed consent is routinely imparted.
The standard informed consent is supplied as a template, and is, for the most part, self-explanatory. If clarification is needed, please refer to the document "Helpful Hints for Preparing a Consent Form" (available from the SCRIHS office). Please be aware that the SCRIHS staff cannot write your consent form for you, but can be of great help in advising how to complete it or in proofreading it before submission to the full committee.
SCRIHS is primarily concerned with the welfare of human subjects of research, not with the research per se. The committee has members with expertise in medicine, law, behavioral medicine, and includes members of the community with expertise in still other areas. Each new protocol is assigned a primary and secondary reviewer, who review their protocols closely. These two reviewers also receive a copy of the investigator's manual, if one is available. The members examine each application carefully to determine whether the study procedures appear safe and reasonable. The members will make an assessment of risk and benefit for participating in the study, with the purpose of determining whether a "reasonable person" would participate in the study. In order to make this assessment, the protocol and investigator's manual should carefully describe what is known about the test article. If a drug is being tested, the protocol and investigator's manual should describe previous animal studies and their results, as well as previous human studies and the known effects and side effects of the drug in animals and humans.
Research studies reviewed by SCRIHS are scientific studies. Some SCRIHS members, but not the majority, have scientific expertise. Nevertheless, "scientific merit" is a concern of the committee. The purpose of scientific research is to contribute to "generalizable knowledge," and to do so the research should be designed in such a way that its results will be reliable and valid. If the research proposal uses the scientific method so poorly that it cannot answer the questions it proposes, it will not contribute to generalizable knowledge. This is poor science, and poor science, when done on human beings, is not ethical. Some studies reviewed by SCRIHS are problematical. If the committee's concern is about scientific merit, the committee may table the protocol and ask for a review by an expert in the field, ask the principal investigator for clarification, ask the principal investigator to rewrite or amend the protocol, or direct it to the Associate Dean for Research and Faculty Affairs, who will convene an ad hoc committee of scientific reviewers for the protocol.
Good scientific research uses the scientific method. Good research contains a clearly stated hypothesis and a clearly stated means for gathering information regarding the hypothesis (i.e., experimental design and methods). A number of different kinds of studies may be valid and ethical--everything from purely descriptive or epidemiological studies, to large multicenter randomized double-blind placebo-controlled clinical trials. No matter what the study design, it should be able to answer the questions it poses. Common scientific mistakes include: 1) not clearly stating an hypothesis; 2) stating an hypothesis that is poorly justified by previous studies or by accepted medical or scientific theory; 3) giving study methods, but not giving a study design; 4) designing a study that cannot test the hypothesis; or 5) testing too few patients or testing too many (a statistical method called power analysis should usually be done to determine the number of subjects that are likely to be needed). Please note that good experimental design can still be an ethical mistake, such as having an untreated placebo group when an efficacious and accepted therapy is available.
The principal investigator should be qualified by virtue of training and experience to do the study proposed. At present, SCRIHS deals almost exclusively with protocols submitted by physicians or other investigators with whom the committee is familiar. Because of this, SCRIHS does not yet require the investigator to submit or have on file a curriculum vitae or other evidence of qualifications. However, the committee may ask for a documentation of the qualifications of the principal investigator or co-investigators. If the study is on a subject not known by the committee to be obviously within the expertise of the investigator, the investigator should submit a cover letter explaining the situation, with his or her qualifications to do the study. For example, if a cardiac surgeon submits a protocol to study hypertension, a cover letter explaining the principal investigator's qualifications to do the study--either experience or training--should be submitted. In other cases, it might be most practical to include a person with obvious expertise as a co-investigator. For example, if a medical oncologist submits a study involving radiation therapy, it may be most practical to include a radiation oncologist as a co-investigator. If documentation of expertise is lacking, SCRIHS may table the protocol until it is received, or approve the protocol conditional on receiving such documentation.
This is an issue commonly debated by SCRIHS members. The most important ethical guidelines deal with this issue very little. The Belmont Report, which is the ethical basis of IRBs in this country, does not deal with it at all. In general, charging patients for research done on them is considered unethical. The reasoning is simple--the patient is being subjected to a treatment of unknown efficacy, perhaps no efficacy, or perhaps the therapy is even harmful. Although the patient may benefit, the primary purpose of research is not to benefit the subjects, but to benefit others, and the subject is participating for humanitarian reasons. Hence, charging the subject for research is unethical. However, there are two exceptions sanctioned by Federallaw--cancer protocols and medical device protocols.
Cancer is unique among diseases in having an entire NIH Institute devoted to it, the National Cancer Institute (NCI). In oncology, there is a strong tradition of clinical research designed to improve outcomes in cancer treatment. Nationwide multicenter protocols conceived of and distributed by national clinical research groups such as the Southwest Oncology Group (SWOG),Gynecologic Oncology Group (GOG), Radiation Therapy Oncology Group (RTOG) and others, are performed by numerous local oncologists and oncology groups. This research is all performed at considerable expense to the patient. Some protocols may have a test drug provided free of charge by a manufacturer or by the NCI, but most protocols charge for everything including drugs. The cost of the study may then be very expensive to the patient, sometimes even hundreds of thousands of dollars. Although such studies are sanctioned by the Federal government, they frequently raise questions related to The Belmont Report principles of beneficence and justice. The question regarding beneficence is: is it harmful to charge patients for treatment with agents of unknown efficacy? The question of justice is: if a research treatment is of such high value that persons with financial means would pay dearly for it, is it just to withhold it from others who cannot pay?
A second kind of protocol in which the subject is often charged for research is in the development of medical devices. The FDA regulates medical drugs, biologics, and devices. With respect to drugs and biologics, charging for the drug or biologic is ordinarily not allowed by theFDA. An investigational drug or biologic in clinical trials under Investigational New Drug (IND) regulations cannot be charged for without prior written approval from the FDA.(14) To allow such charges, the FDA requires specific evidence from the sponsor "explaining why providing the product without charge should not be considered part of the normal cost of conducting a clinical trial." Nevertheless, such approval does not guarantee that it will be accepted by local IRBs--"when charges are authorized by FDA, whether they are passed on to subjects of research is a matter that clinical investigators and IRBs should carefully consider."(15) The FDA does notprohibit charging for already-marketed products that are used in clinical investigations.
The situation is different for medical devices. The Investigational Device Exemption (IDE) regulations allow a charge for the device, "however, the charge should not exceed an amount necessary to recover the costs of manufacture, research, development, and handling of the investigational device."(16) Charges in excess of this may in effect constitute premature commercialization of the product. Generally, the FDA allows charging subjects for investigational medical devices tested on them. Although the FDA allows it, SCRIHS committee members usually have concerns about the ethics of such protocols. In some cases, the investigational product is merely a slightly updated "model" of a product already approved for use. In fact, it may be so similar to an approved product that Medicare will reimburse for the device (Medicare "Non-experimental/investigational, Category B"). SCRIHS generally allows charges for such devices. In other cases, the product is radically new or different. Investigators should be aware that SCRIHS may disapprove studies attempting to charge for such investigational devices, even if such charges have been approved by the FDA.
Investigators should realize that "charges" include not only charges for the test product itself, but also for other items made necessary by the study, including blood work, radiologic tests, hospitalization, and others. In general, studies should cover the costs of all of these items. The study may not necessarily cover the costs for medical care that is "routine" or "standard of care" even if it is given during the study. However, what is "routine" or "standard of care" to one physician may not be to another. SCRIHS committee members look closely at any protocol that requires a certain treatment protocol for which the patient is charged merely because it is, in the opinion of the investigator or sponsor, "the standard of care." Although seldom disapproved, such studies may be tabled pending a detailed justification from the investigator. The investigator may facilitate consideration of his or her protocol by anticipating this problem and providing the justification with the initial submission.
In all cases, whether the study is a cancer protocol, a device protocol, or another kind of study, the basic principles of informed consent require that charges to patients should be clearly spelled out in the written informed consent document. The fact that the subject of the research will be responsible for charges should be clearly stated, in totally unambiguous, simple language. SCRIHS policy in this matter is not clearly settled at this time, but the recommendations of this author (an ex-chairman of SCRIHS) are for the informed consent document to highlight the language disclosing costs, and to provide numerical figures for exact cost of the device, and at least approximate costs for other items required by the study.
It's probably true that the hardest part is over, but the process has only started with the initial approval. SCRIHS approval is contingent on the study being conducted in exactly the manner stated in the approved protocol and informed consent. If the study is not conducted in the manner stated, approval may be suspended or withdrawn. Suspension or withdrawal of approval requires a report to the OHRP, to the sponsoring institutions, and to the FDA if the study is on an investigational device or drug. Any change in the protocol and/or informed consent requires formal IRB approval. If changes are needed, an amendment should be submitted to SCRIHS. If the amendment is minor, such as adding the name of a co-investigator to the protocol or a change in the telephone number of the principal investigator, the amendment will be reviewed and approved by the chairman. For more complicated amendments, review by a SCRIHS subcommittee or by the full committee is often required.
In addition, adverse events occurring in the study must be reported. Study sponsors generally report all adverse events to every site participating in the study. A report of these adverse events should be submitted to SCRIHS.
Any advertising necessary for recruiting subjects for the study must be reviewed by SCRIHS prior to publication. There are specific regulations covering advertising, which are summarized in the SCRIHS Procedures Manual.
Even if a study does not require amendment, does not need advertising, and has no adverse events, SCRIHS must perform a periodic continuing review of each study. Currently, SCRIHS requires the investigator to fill out a one-page form containing information about the progress of the study. Continuing review is performed at least yearly but more often for some studies. The length of time before continuing review is determined at the time of initial approval.
Eventually, a study will be terminated and the SCRIHS office should be formally notified.
Current forms for these procedures are available from the SCRIHS office:
Investigators planning to do studies involving children, fetuses, pregnant women, prisoners, mentally retarded persons, or in vitro fertilization should be aware that there are special Federalregulations regarding these subjects. Please contact the SCRIHS office if you have questions.
Procedures Manual for the Springfield Committee for Research Involving Human Subjects(SCRIHS) (1996). This manual contains advice on every practical topic, from criteria for IRB review to preparing a consent form. It is highly recommended reading for the investigator planning to submit protocols to SCRIHS. On request, the SCRIHS office will provide a "New Investigators Packet", which includes the procedures manual, current versions of SCRIHS forms, and other materials. Another useful reference is the OHRP home page at http://ohrp.osophs.dhhs.gov/