LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER IN NEW ORLEANS INSTITUTIONAL REVIEW BOARD (IRB)
APPLICATION FORM / CONSENT FORM INSTRUCTIONS

APPLICATION FORM

INSTRUCTIONS
Complete the application and submit the following to the following to the IRB Office, Resource Center, 433 Bolivar Street, Room 206 E, New Orleans, Louisiana, 70112: an original and one copy of the application form, two copies each of the full protocol or grant proposal describing the research projects and the consent form. Complete all sections of the IRB form. Do not submit documents printed on both sides, with exception of the full protocol or grant proposal. If any section is not applicable to your project, mark (N/A). IRB meetings are held on the third (3rd) Wednesday of every month. The DEADLINE for receipt of applications in the IRB Office is the last working Wednesday of the month prior to the next month's meeting with no exceptions! Only typed applications will be accepted. The application form is also available on the LSUHSC homepage. If you have any questions, call 568-4060.
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If the investigator is applying for exempt or expedited status check the appropriate box in section 10 of the application form.
The types of activities that may qualify for exempt or expedited review status include research such as review of existing records, collection of pathological or diagnostic specimens, survey or interview procedures, educational tests, observation of public behavior, recording of data from subjects and other types of minimal risk studies. The complete list of those activities is contained at the end of these instructions. All research activities that involve human research must be submitted for IRB review and approval. Even if a study qualifies for exempt/expedited review, it must be submitted.

After review of the application, if the IRB determines that the research does not qualify as exempt or expedited, it must then be submitted for full review in accordance with the requirements and deadlines listed above. Although there are no deadlines for exempt or expedited research, it is recommended that these proposals be submitted a few weeks prior to the deadline in the event full review is required.

Guidance involving Human Subject Protection is available from:

The Office for Human Research Protections Website Http://ohrp.osophs.dhhs.gov 

The Food and Drug Administration Office of Health Affairs website Http://www.fda.gov.oc/oha  

The LSUHSC IRB Office 568-4060.

Additional Instructions for Investigators Submitting Clinical Protocols

All applications must contain information regarding the Investigational New Drug (IND) status of any article. The investigator, with IRB concurrence, will determine if the administration of approved or experimental drugs, chemicals, or biological agents is subject to regulations of the FDA. This includes a study involving the use of new combinations of drugs, or new uses of old drugs. The investigator is responsible for obtaining an IND from the FDA, if necessary. Applications from industry sponsored protocols must reference the IND number.

A new application for a medical device must provide additional information. A medical device is defined in part as any health care product that does not achieve its intended purposes by chemical action or by being metabolized. Medical devices include among other things surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts, intraocular lens, and orthopedic pins. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis of disease and other medical conditions such as pregnancy.

During the application process to the IRB the principal investigator must indicate the non-significant risk or significant risk status of the device in the project summary. The IRB determines whether or not a non-significant risk (NSR) device qualifies to be so designated. The IRB uses the same criteria it uses when considering approval of any research involving an FDA product. Any device not of minimal risk as defined as [21CFR 56.110] will be reviewed by the full Board.

The investigation device exemption (IDE) number assigned by the FDA must be included in the application.

If the device does not qualify as a NSR in the opinion of the Board following review, the IRB will notify the investigator, sponsor and the FDA. In this circumstance it does not matter if the sponsor has classified the device as NSR since the IRB has ultimate responsibility for this determination. The applicant must then approach the FDA for proper procedures to change the status of the device and pursue an IDE.

The FDA Office of Health Affairs website http://www.fda.gov/oc/oha has additional guidance and the current phone numbers of contact persons for clarification of research involving investigational therapies, devices, biologics, and other concerns. The LSUHSC IRB office should also be contacted if there are any questions, 568-4060 

LSUHSC CONSENT FORM
GENERAL INSTRUCTIONS

A. Consent Forms may be written in first, second or third person except the signature section, which must be written in the first person (use language provided in the attached sample)

B. When investigational drugs or therapies are used in a study, they must be referred to as investigational drugs or therapies. Include the IND number on the application. If experimental devices are used, an IDE must be included.

C. Consent forms must be written in a manner understandable to someone with 9th grade reading skills. Technical terms and jargon must be reduced to lay language. No scientific or technical symbols can be used without explanation. The style must be similar to that used in popular news magazines and newspapers.

D. "Louisiana State University Health Sciences Center Consent Form" must appear at the top of the first page. "LSUHSC-N.O." and a study identifier must appear at the top of all subsequent pages, which must be numbered consecutively. Use the header format with a smaller size font than the text. Provide a version number or date that will clearly identify that version of the consent form since several revisions may occur over the course of the study. Page numbers must be used on each page. The following format is suggested: "1 of 5, 2 of 5, etc." Footers can also be utilized to provide additional clarification of protocol version, subject's initials, etc. 

E. Consent forms must be in the format provided, with section headings numbered and capitalized and in the order presented. If a section is not applicable to your study, indicate this by marking (N/A). A software disk is available with instructions from the IRB office.

F. Translations (for non-English speaking) subjects should be submitted after IRB approval of the final version of the English consent. The non-English version of the consent form must be accompanied by a legally notarized statement from the investigator certifying that it is the true translation of the LSUHSC approved consent form.

G. The IRB may for some or all subjects, waive the requirement that the subject or the subject's legally authorized representative sign a written consent form if it finds that the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context. The exception to the informed consent process or a request to alter some or all of the elements must meet all the federal requirements for such exception or waiver. An investigator planning to request such an exception should contact the IRB office prior to submission of the application. LSUHSC does not participate in studies that require a waiver of informed consent for planned emergency research.

FORMAT INSTRUCTIONS

LSUHSC in New Orleans Informed Consent 

1. STUDY TITLE: The complete title of the study must be used and must be identical to the research protocol. Indicate the protocol number and IND and/or IDE number if applicable.

2. PERFORMANCE SITES: The names of all institutions where LSUHSC personnel will enroll subjects in the study must be given. 

3. NAMES AND TELEPHONE NUMBERS OF INVESTIGATORS: All investigators involved in the study, as well as their department, school, and telephone numbers must be listed. Designate a 24 hour phone number and label it as such. Beeper use must be explained.

4. PURPOSE OF THE STUDY:
The first sentence must clearly state that this is a research study. There must be a clear statement that describes what the difference is between being a research subject and a person not involved in this study. State clearly what the study is designed to investigate. Provide the FDA status of any drug(s) or devices. Provide a rationale that explains why this therapy, research, survey, etc. is being done. Include a description of the type of subject that would be included; i.e. adult diabetics with hypertension. This section is a critical portion of the informed consent since this should convey the essence of what is being studied and why. The importance of the research should not be overstated or exaggerated. It should inform the subject if the study is being done just locally or on a larger scale e.g. city-wide, state-wide, nationally or internationally. The number of local and national subjects must be provided.


5. DESCRIPTION OF STUDY PROCEDURES: This section must contain a complete description of the procedures that are necessary to complete the study. All experimental procedures must be described and any related but non-experimental procedures must be stated. The subject's time commitment must be explained in terms of the length of study, visits required and any other activities e.g. diaries, telephone follow-up, etc. that is required for completion. Use lists, tables and charts to show complex schedules and study designs. Provide the subject with the sequence of events that will occur during the study. This should be a chronology of the events that will take place from the subject's point of view. Describe the procedures to be followed, including their purpose, duration, frequency, and recovery time, if applicable. All drugs and/or devices must be described. The total number of subjects to be entered locally and nationally must be included. Procedures for randomization of subjects should be explained, if applicable; this must include the chances of being assigned to a particular arm or strategy. The term placebo must be defined in lay terms. If a placebo is to be administered to a group or to all of the subjects at anytime, this information must be included, though individual subjects need not be informed as to whether they will actually receive the placebo. Quantities of specimens, such as blood, should be stated in terms familiar to the subject, such as teaspoons. If audio/visual taping of the subject is part of the study, insert a statement permitting the subject to review and edit. Define permitted usages and detail disposition of such material at the end of the study. The use of lay language is essential. The subject and the family must be able to get an overall picture of what will happen during the study, when it will happen and how long they will be involved.

6. BENEFITS TO SUBJECT: A fair, reasonably detailed and understandable description of any potential benefits that might result from the research should be simply stated. Usually there is only a possibility of benefit or no benefit. If the subject will receive no direct benefit, this should be explicitly stated. Benefits to others is permitted. It is also permissible to state that a project may yield results that could possibly benefit a sub-population (e.g. HIV/AIDS patients, low-birth weight babies, etc.).

7. RISKS TO THE SUBJECT: This section must include a sufficient description of the risks to enable subjects and their families the opportunity to decide if they are willing to participate. Provide a fair, reasonably detailed and understandable description of any physical, psychological, and/or social risks or discomforts that might occur to the subjects as result of the study. Potential behavioral and psychological risks such as evoking memories, finding out about a disabling condition, etc. must be listed. 

Legal and social risks need to be stated as well as risks to confidentiality or privacy, especially if special results such as HIV testing , genetic testing or confirmation of other health status are required for entry or as part of the study. 

For clinical drug studies, the side effects of each drug, device and procedure must be listed separately with the medical consequences of such an effect, e.g. lowering of white blood cell count that may result in an increase of infections. All known side effects must be listed. It must also be pointed out that there is always the risk of previously unknown side effects occurring. 

The risk of blood draws, including pain, bruising, at the site where the blood is taken can occur. It must also be stated that some people feel lightheaded and may even faint. There is also a slight risk of infection.
Subjects must be warned that their condition may not improve and may worsen even with participation in the study. If differences exist in risk between the treatment groups, these risks must be explained to all subjects. A statement must be included that participation in the study may involve unforseen risks.

8. ALTERNATIVES TO PARTICIPATION IN THE STUDY: Describe the alternative procedures or treatments that are available to individuals if they choose not to participate. Any standard treatment that is available must be disclosed, with its relative risks and benefits. The "option of no treatment" must be candidly presented when the research protocol is hazardous, unpleasant, or may cause the quality of prolonged life to worsen. If no alternative treatment is available, the specifics of such must be stated. If a drug or device is available outside of the proposed protocol that must be stated. 



For studies that propose non-clinical protocols, state if there are other alternative actions such as private weight loss clinics, private counseling, special courses, etc. 


9. SUBJECT REMOVAL: Subjects must be informed about the circumstances under which they would be removed from the study against their wishes. This includes but is not limited to:
1. The subject's condition worsening or if the doctor feels that staying in the study is not in the best interest of the subject.
2. The subject is unable to keep appointments for study visits
3. Failure of the subject to complete study activities e.g. keeping study diaries
4. The study is canceled by the investigator or by the company, etc. 


If subjects are put at special risks by removal, they must be informed about those risks. This is particularly important in studies where discontinuation of therapy will probably result in continuation and progression of the disease.

10. SUBJECT'S RIGHT TO REFUSE TO PARTICIPATE OR WITHDRAW: The following language is suggested, "Study subjects may refuse to participate or withdraw from the study at anytime without jeopardizing, in any way, their medical treatment in this institution in the present or future. Should significant new findings develop during the course of the research which may relate to the subject's willingness to continue participation, that information will be provided to the subject." Study subjects are free to withdraw at any time and cannot be required to provide a reason. They cannot be required to come for follow up visits. They should be informed that a reasonable effort will be made to contact them for a "close-out visit" for safety reasons. If subjects are put at special risks by withdrawing, they must be informed of the risks.


11. SUBJECT'S RIGHT TO PRIVACY: The following language is suggested: "The results of the study may be released to the funding agency. (Provide the name of the funding agency, if known.) The results of the study may be published. The privacy of subjects will be protected and they will not be identified in any way." If the study includes photography, video taping, audio recording, or other media the subject must be told how long the information will be kept, who might see it, how the identity of the subject will be protected, etc.

12 RELEASE OF INFORMATION: The following language is suggested, "The medical records related to the study are available to the sponsoring agency ,the Food and Drug Administration and the LSUHSC IRB. (Provide the name of the sponsoring agency, if known.) While every effort will be made to maintain your privacy, absolute confidentiality cannot be guaranteed. Records will be kept private to the extent allowed by law.

13. FINANCIAL INFORMATION:
A. If additional costs are to be incurred by participation in the study, the subject must be informed. If not, the following language is suggested, "Participation in this study will not result in any extra charges above and beyond those routinely incurred by patients with similar conditions.

B. The subject must be informed as to who is responsible for all costs which include drugs, visits, procedures, and complications both related to and unrelated to participation in the study. If the sponsor is responsible for providing study drugs and will pay for office visits and procedures, this should be clearly stated. If applicable, the following language is suggested:
"The costs of all drugs, visits, procedures and study related and unforseen complications must be met by the subject. The principal investigator will arrange for medical care for any emergency medical problem that you may experience as a direct result of your participation in this research. This will be provided on a fee-for-service basis. There is no other financial aid available for damages such lost wages, etc."

C. If subjects are to be paid for their participation or reimbursed for expenses, the amount, and conditions for payment. Payments must be made in equal amounts at each visit during the course of the study. Payment must be based on a prorated system. Since subjects can withdraw from a study at any time they cannot be required to complete the study to receive a payment. Payment must not constitute an undue inducement to participation.


14. SIGNATURES: The section must be submitted in the format provided on the sample consent form without exception. A copy of the signed consent form must be given to the subject according to federal regulations. A legal guardian must give informed consent for minors. Particular attention must be paid to obtaining assent from children. The following must be adhered to: 1) the investigator is required to obtain assent from children 12 years of age or older; 2) the investigator must make every attempt to obtain assent of children 7 years to 12 years of age; 3) the investigator is not required to obtain assent of children below 7 years of age, however, it is recommended as good practice whenever possible; 4) documentation of required assent by children will be by signature of the child, whenever practical, or by signature of the parent, legal guardian, attesting to such assent; 5) if a decision is made to include children in a study without their assent, the reasons must be documented and constitute proper justification for such action. The signature section must include the person who should be contacted for additional information regarding the study and for injuries. This is usually the principal investigator. 

All questions regarding the subject's rights as a research subject must be answered by the Chancellor. The specific language regarding this is provided in the sample consent form.


EXPEDITED AND EXEMPTED CRITERIA

Use the following criteria to determine whether your study might be expedited or exempted from full board review. Fill in the numbers of all categories that apply to your study in the appropriate section of the application form. All research, regardless of whether it meets one of the conditions for expedited IRB review, must conform to the applicable requirements for obtaining and documenting informed consent. Informed consent must be obtained and documented unless the research meets one of the conditions for waiving, excepting or otherwise altering the informed consent requirements that are set forth in 45 CFR 46.116 and 46.117 and 21 CFR 50.23, 50.24 and 56.109(c).

Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) Through an Expedited Review Procedure.

EXPEDITED 45 CFR 46.110 and 21 CFR 56.110
[Revised November 9, 1998 as published in the Federal Register Vol. 63 no. 216] 

Applicability
(A) Research activities that (1) present no more than minimal risk to human subjects, and (2) involve only procedures listed in one or more of the following categories, may be reviewed by the IRB through the expedited review procedure authorized by 45 CFR 46.110 and 21 CFR 56.110. The activities listed should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on this list merely means that the activity is eligible for review through the expedited review procedures when the specific circumstances of the proposed research involve no more than minimal risk to human subjects.

(B) The categories in this list apply regardless of the age of subjects, except as noted. 

(C)The expedited review procedure may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal.

(D) The expedited review procedure may not be used for classified research involving human subjects.

(E) IRBs are reminded that the standard requirements for informed consent (or its waiver, alteration, or exception) apply regardless of the type of review--expedited or convened--utilized by the IRB.

(F) Categories one (1) through seven (7) pertain to both initial and continuing IRB review.

Research Categories

(1) Clinical studies of drugs and medical devices only when condition (a) or (b) is met.

(a) Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required. (Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.)
(b) Research on medical devices for which (I) an investigational device exemption application (21 CFR) Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.

(2) Collection of blood samples by finger stick, heel stick, or venipuncture as follows:
(a) from healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550ml in an 8 week period and collection may not occur more frequently than 2 times per week; or

(b) from other adults and children considering the age, weight and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week.

(3)Prospective collection of biological specimens for research purposes by noninvasive means.
Examples: (a) hair and nail clippings in a nondisfiguring manner; (b) deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction; (c)permanent teeth if routine patient care indicates a need for extraction; (d)excreta and external secretions (including sweat); (e) uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue; (f) placenta removed at delivery; (g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; (h) supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques; (I) mucosal and skin cells collected by buccal scraping or swab, or mouth washings; (j) sputum collected after saline mist nebulization.

(4)Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.)

Examples: (a)physical sensors that are applied either to the surface of the body or at a distance an do not involve input of significant amounts of energy into the subject or an invasion of the subject's privacy; (b) weighing or testing sensory acuity; © magnetic resonance imaging; (d)electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography; (e) moderate exercise, muscular strength testing where appropriate given the age, weight and health of the individual.

(5)Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis). (NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(4). This listing refers only to research that is not exempt).

(6)Collection of data from voice, video, digital or image recordings made for research purposes.

(7) Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. (NOTE: some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.

(8) Continuing review of research previously approved by the convened IRB as follows:
(a)where (I) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii)the research remains active only for long term follow-up of subjects; or
(b) where no subjects have been enrolled and no additional risks have been identified: or
© where the remaining research activities are limited to data analysis

(9) Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight(8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.


1 An expedited review procedure consists of a review of research involving human subjects by the IRB chairperson or by one or more experienced reviewers designated by the chairperson from among members of the IRB in accordance with the requirements set forth in 45 CFR 46.110.

2 Children are defined in the HHS regulations as "persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted." 45 CFR 46.402(a).


Code of Federal Regulations
45 CFR 46
Subpart A Federal Policy for the Protection of Human Subjects (Basic DHHS Policy for Protection of Human Research Subjects)

(B) Unless otherwise required by Department or Agency heads, research activities in which the only involvement of human subjects will be in one or more of the following categories are exempt from this policy: 

EXEMPT CATEGORIES as Defined by 
45 CFR 46.101(b)

(1) Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as (I) research on regular and special education instructional strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.
(2) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless (I) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to subjects' financial standing, employability, or reputation.
(3) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (b)(2) of this section, if:
(i)the human subjects are elected or appointed public officials or candidates for public office; or (ii) federal stature(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.
(4) Research involving the 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 through identifiers linked to the subjects.
(5) Research and demonstration projects which are conducted by or subject to the approval of the department or agency heads, and which are designed to study, evaluate, or otherwise examine (I) public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs, (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs.
(6) Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) if a food is consumed that includes a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

**Exemptions at 45 CFR 46.101 (b) do not apply to research involving prisoners, fetuses, pregnant women, or human in vitro fertilization, subparts B and C. The exemptions at 45 CFR 46.101(b)(2), for research involving survey or interview procedures or observation of public behavior, does not apply to research with children, subpart D, except for research involving observation of public behavior when the investigator(s) do not participate in the activities being observed.


21 CFR 56.104 Exemptions from IRB Requirement

The following categories of clinical investigations are exempt from the requirements of this part for IRB review:

(a) Any investigation which commenced before July 27, 1981 and was subject to requirements for IRB review under FDA regulations before that date, provided that the investigations remains subject to review of an IRB which meets the FDA requirements in effect before July 27, 1981.

(b) Any investigation commenced before July 27, 1981 and was not otherwise subject to requirements for IRB review under Food and Drug Administration regulations before that date.

(c) Emergency use of a test article, provided that such emergency use is reported to the IRB within 5 working days. Any subsequent use of the test article at the institution is subject to IRB review.

(d) Taste and food quality evaluations and consumer acceptance studies, if wholesome foods without additives are consumed or if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural, chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

[46 FR 8975, Jan.27 1981, as amended at 56 FR 28028, June 18, 1991.]


Belmont Report

Ethical Principles and Guidelines for Research Involving Human Subjects

Scientific research has produced substantial social benefits. It has also posed some troubling ethical questions. Public attention was drawn to these questions by reported abuses of human subjects in biomedical experiments, especially during the Second World War. During the Nuremberg War Crime Trials, the Nuremberg code was drafted as a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners. This code became the prototype of many later codes intended to assure that research involving human subjects would be carried out in an ethical manner.
The codes consist of rules, some general, others specific, that guide the investigators or the reviewers of research in their work. Such rules often are inadequate to cover complex situations; at times they come into conflict, and they are frequently difficult to interpret or apply. Broader ethical principles will provide a basis on which specific rules may be formulated, criticized and interpreted.
Three principles, or general prescriptive judgments, that are relevant to research involving human subjects are identified in this statement. Other principles may also be relevant.
These three are stated at a level of generalization that should assist scientists, subjects, reviewers and interested citizens to understand the ethical issues inherent in research involving human subjects. These principles cannot always to applied so as to resolve beyond dispute particular ethical problems. The objective is to provide an analytical framework that will guide the resolution of ethical problems arising from research involving human subjects.

This statement consists of a distinction between research and practice, a discussion of the three basic ethical principles, and remarks about the application of these principles.

A. Boundaries Between Practice and Research

It is important to distinguish between biomedical and behavioral research, on the one hand, and the practice of accepted therapy on the other, in order to know what activities ought to undergo review for the protection of human subjects of research. The distinction between research and practice is blurred partly because both often occur together (as in research designed to evaluate a therapy) and partly because notable departures from standard practice are often called "experimental" when the terms "experimental" when the terms "experimental" and "research" are not carefully defined.
For the most part, the term "practice" refers to interventions that are designed to solely enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy to particular individuals. By contrast, 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.
When a clinician departs in a significant way from standard or accepted practice, the innovation does not, in and of itself, constitute research. The fact that a procedure is "experimental," in the sense of new, untested or different, does not automatically place it in the category of research. Radically new procedures of this description should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project. 
Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy. This need not cause any confusion regarding whether or not the activity requires review; the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects.

B. Basic Ethical Principles

The expression "basic ethical principles" refers to those general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of human actions. Three basic principles, among those generally accepted in our cultural tradition, are particularly relevant to the ethics of research involving human subjects: the principles of respect for persons, beneficence and justice.

2. Respect for persons - Respect for persons incorporates at least two ethical convictions:
first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.
An autonomous person is an individual capable of deliberation about personal goals and of 
acting under the direction of such deliberation. To respect autonomy is to give weight to autonomous persons' considered opinions and choices while refraining from obstructing their actions unless they are clearly detrimental to others. To show lack of respect for an autonomous agent is to repudiate that person's considered judgments, or to withhold information necessary to make a considered judgment, when there are no compelling reasons to do so.
However, not every human being is capable of self-determination. The capacity for self- determination matures during an individual's life, and some individuals lose this capacity wholly or in part because of illness, mental disability, or circumstances that severely restrict liberty. Respect for the immature and the incapacitated may require protecting them as they mature or while they are incapacitated.
Some persons are in need of extensive protection, even to the point of excluding them from activities which may harm them; other persons require little protection beyond making sure they undertake activities freely and with awareness of possible adverse consequences. 
The extent of protection afforded should depend upon the risk of harm and the likelihood of benefit. The judgment that any individual lacks autonomy should be periodically reevaluated and will vary in different situations.
In most cases of research involving human subjects, respect for persons demands that subjects enter into the research voluntarily and with adequate information. In some situations, however, application of the principle is not obvious. The involvement of prisoners as subjects of research provides an instructive example. On the one hand, it would seem that the principle of respect for persons requires that prisoners not be deprived of the opportunity to volunteer for research provides an instructive example. On the other hand, it would seem that the principle of respect for persons requires that prisoners not be deprived of the opportunity to volunteer for research. On the other hand, under prison conditions they may be subtly coerced or unduly influenced to engage in research activities for which they would not otherwise volunteer. Respect for persons would then dictate that prisoners be protected. Whether to allow prisoners to "volunteer" or to "protect" them presents a dilemma. Respecting persons, in most hard cases, is often a matter of balancing competing claims urged by the principle of respect itself.

2. Beneficence. - Persons are treated in an ethical manner not only by respecting
their decisions and protecting them from harm, but also by making efforts to secure their well-being. Such treatment falls under the principle of beneficence is understood in a stronger sense, as an obligation. Two general rules have been formulated as complementary expressions of beneficent actions in this sense:(1) do not harm and (2) maximize possible benefits and minimize possible harms.

The Hippocratic maxim "do no harm" has long been a fundamental principle of medical ethics. Claude Bernard extended it to the realm of research, saying that one should not injure one person regardless of the benefits that might come to others. However, even, avoiding harm requires learning what is harmful; and, in the process of obtaining this information, persons may be exposed to risk harm. Further, the Hippocratic Oath requires physicians to benefit their patients "according to their best judgment." Learning what will in fact benefit may require exposing persons to risk. The problem posed by these justifiable to seek certain benefits despite the risks involved, and when the benefits should be foregone because of the risks.
The obligation of beneficence affect both individual investigators and society at large, because they extend both to particular research projects and to the entire enterprise of research. In the case of particular projects, investigators and members of their institutions are obliged to give forethought to the maximization of benefits and the reduction of risk that might occur from the research investigation. In the case of scientific research in general, members of the larger society are obliged to recognize the longer term benefits and risks that may result from the improvement of knowledge and from the development of novel medical, psychotherapeutic, and social procedures.
The principle of beneficence often occupies a well-defined justifying role in many areas of research involving human subjects. An example is found in research involving children. Effective ways of treating childhood diseases and fostering healthy development are benefits that serve to justify research involving children - even when individual research subjects are not direct beneficiaries. Research also makes is possible to avoid the harm that may result from the application of previously accepted routine turn out to be dangerous. But the role of the principle of beneficence is not always to unambiguous. A difficult ethical problem remains, for example about research that presents more than minimal risk without immediate prospect of direct benefit to the children involved. Some have argued that such research is inadmissible, while others have pointed out that this limit would rule out much research promising great benefit to children in the future. Here again, as with all hard cases, the different claims covered by the principle of beneficence may come into conflict and force difficult choices.


C. Justice - who ought to receive the benefits of research and bear its burdens? This 
is a question of justice, in the sense of "fairness in distribution" or "what is deserved." An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. Another way of conceiving the principle of justice is that equals ought to be treated equally. However, this statement requires explication. Who is equal and who is unequal? What considerations justify departure from equal distribution? Almost all commentators allow that distinctions based on experience, age, deprivation, competence, merit and position do sometimes constitute criteria justifying differential treatment for certain purposes. It is necessary, then, to explain in what respects people should be treated equally. There are several widely accepted formulations of just ways to distribute burdens and benefits. Each formulation mentions some relevant property on the basis of which burdens and benefits should be distributed. These formulations are (1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.

Questions of justice have long been associated with social practices such as punishment, taxation an political representation. Until recently these questions have not generally been associated with scientific research. However, they are foreshadowed even in the earliest reflections on the ethics of research involving human subjects. For example, during the 19th and early 20th centuries the burdens of serving as research subjects fell largely upon poor ward patients, while the benefits of improved medical care flowed primarily to private patients. Subsequently, the exploitation of unwilling prisoners as research subjects in Nazi concentration camps was condemned as a particularly flagrant injustice. In this country, in the 1940's, the Tuskegee syphilis study used disadvantaged, rural black men to study the untreated course of a disease that is by no means confined to that population. These subjects were deprived of demonstrably effective treatment in order not to interrupt the project, long after such treatment became generally available. 

Against this historical background, it can be seen how conceptions of justice are relevant to research involving human subjects. For example, the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial an ethnic minorities, or persons confined to institutions) are being systemically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied. Finally, whenever research supported by public funds leads to the development of therapeutic devices an procedures, justice demands both that these not provide advantages only to those who can afford them and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research.

C. Applications

Applications of the general principles to the conduct of research leads to consideration of the following requirements: informed consent, risk/benefit assessment, and the selection of subjects of research.

1. Informed Consent. - Respect for persons requires that subjects, to the degree that 
they are capable, be given the opportunity to choose what shall or shall not happen to them. This opportunity is provided when adequate standards for informed consent are satisfied.
While the importance of informed consent is unquestioned, controversy prevails over the nature an possibility of an informed consent. Nonetheless, there is widespread agreement that the consent process can be analyzed as containing three elements: information, comprehension an voluntariness.
Information. Most codes of research establish specific items for disclosure intended to assure that subjects are given sufficient information. These items generally include: the research procedure, their purposes, risks an anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any time from the research. Additional items have been proposed, including how subjects are selected, the person responsible for the research, etc.
However, a simple listing of items does not answer the question of what the standard should be for judging how much and what sort of information should be provided by practitioners in the field or in the locale, is inadequate since research takes place precisely when a common understanding does not exist. Another standard, currently popular in malpractice law, requires the practitioner to reveal the information that reasonable persons would wish to know in order to make a decision regarding their care. This, too, seems insufficient since the research subject, being in essence a volunteer, may wish to know considerably more about risks gratuitously undertaken then do patients who deliver themselves into the hand of a clinician for needed care. It may be that a standard of the reasonable "volunteer" should be proposed: the extent and nature of information should be such that persons, knowing that the procedure is neither necessary for their care not perhaps fully understood, can decide whether they wish to participate in the furthering of knowledge. Even when some direct benefit to them is anticipated, the subjects should understand clearly the range of risk and the voluntary nature of participation.
A special problem of consent arises where informing subjects of some pertinent aspect of the research is likely to impair the validity of the research. In many cases, it is sufficient to indicate to subjects that they are being invited to participate in research of which some features will not be revealed until the research is concluded. In all cases of research involving incomplete disclosure, such research is justified only if it is clear that (1) incomplete disclosure is truly necessary to accomplish the goals of the research,(2) there are no undisclosed risks to subjects that are more than minimal, an (3) there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them. Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects, and truthful answers should always be given to direct questions about the research. Care should be taken to distinguish cases in which disclosure would destroy or invalidate the research from cases in which disclosure would simply inconvenience the investigator.
Comprehension. The manner and context in which information is conveyed is as important as the information itself. For example, presenting information in a disorganized and rapid fashion, allowing too little time for consideration or curtailing opportunities for questioning, all may adversely affect a subject's ability to understand is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of the information to the subject's capacities. Investigators are responsible for ascertaining that the subject has comprehended the information. While there is always an obligation to ascertain that the information about risk to subjects is complete and adequately comprehended, when the risks are more serious, that obligation increases. On occasion, it may be suitable to give some oral or written tests of comprehension.
Special provision may need to be made when comprehension is severely limited - for example, by conditions of immaturity or mental disability. Each class of subjects that one might consider as incompetent (e.g., infants and young children, mentally disabled patients, the terminally ill and the comatose) should be considered on its own terms. Even for these persons, however, respect requires giving them the opportunity to choose to the extent they are able, whether or not to participate in research. The objections of these subjects to involvement should be honored, unless the research entails providing them a therapy unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to protect the subjects from harm. Such persons are thus respected both by acknowledging their own wishes and by the use of third parties to protect them from harm.
The third parties chosen should be those who are most likely to understand the incompetent subject's situation and to act in that person's best interest. The person authorized to act on behalf of the subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the subject from the research, if such action appears in the subject's best interest.
Voluntariness. An agreement to participate in research constitutes a valid consent only if voluntarily given. This element of informed consent requires conditions free of coercion and undue influence. Coercion occurs when an overt threat of harm is intentionally presented by one person to another in order to obtain compliance. Undue influence, by contrast, occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance. Also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.
Unjustifiable pressures usually occur when persons in positions of authority or commanding influence-especially where possible sanctions are involved - urge a course of action for a subject. A continuum of which influencing factors exists, however, and it is impossible to state precisely where justifiable persuasion ends and undue influence would include actions such as manipulating a person's choice through the controlling influence of a close relative and threatening to withdraw health services to which an individual would otherwise be entitled.

1. Assessment of Risks and Benefits. - The assessment of risks and benefits requires a
careful arrayal of relevant data, including, in some cases alternative ways of obtaining the benefits sought in the research. Thus, the assessment presents both an opportunity and a responsibility to gather systematic and comprehensive information about proposed research is properly designed. For prospective subjects, the assessment will assist the determination whether or not to participate.
The Nature and Scope of Risks and Benefits. The requirement that research be justified on the basis of a favorable risk/benefit assessment bears a close relation to the principle of beneficence, just as the moral requirement that informed consent be obtained is derived primarily from the principle of respect for persons. The term "risk" to a possibility that harm may occur. However, when expressions such as "small risk" or "high risk" are used, they usually refer(often ambiguously) both to the chance (probability) of experiencing a harm and the severity (magnitude) of the envisioned harm.
The term "benefit" is used in the research context to refer to something of positive value related to health or welfare. Unlike "risk," "benefit" is not a term that expresses probabilities. Risk is properly contrasted to probability of benefits and benefits are properly contrasted with harms rather than risks of harm. Accordingly, so-called risk/benefit assessments are concerned with the probabilities and magnitudes of possible harms and anticipated benefits. While the most likely types of harms to research subjects are those of psychological or physical pain or injury, other possible kinds should not be overlooked..
Risks and benefits of research may affect the individual subjects, the families of the individual subjects, and society at large (or special groups of subjects in society). Previous codes and Federal regulations have required that risks to subjects be outweighed by the sum of both the anticipated benefit to society in the form of knowledge to be gained from the research. In balancing these different elements, the risks and benefits affecting the immediate research subject will normally carry special weight. On the other hand, interests other than those of the subject may on some occasions be sufficient by themselves to justify the risks involved in the research, so long as the subjects' rights have been protected. Beneficence thus requires that we protect against risk of harm to subjects and also that we be concerned about the loss of the substantial benefits that might be gained from research.
The Systematic Assessment of Risks and Benefits. It is commonly said that benefits and risks must be "balance" and shown to be " in a favorable ratio." The metaphorical character of these terms draws attention to the difficulty of making precise judgements. Only on rare occasions will quantitative techniques be available for the scrutiny of research protocols. However, the idea of systematic, nonarbitrary analysis of risks and benefits should be emulated insofar as possible. This ideal requires those making decisions about the justifiability of research to be thorough in the accumulation and assessment of information about all aspects of research, and to consider alternatives systematically. This procedure renders the assessment of research more rigorous and precise, while making communication between review board members and investigators less subject to misinterpretation, misinformation and conflicting judgments. Thus, there should first be a determination of validity of the presuppositions of the research; then the nature, probability and magnitude of risk should be distinguished with as much clarity as possible. The methods of ascertaining risks should be explicit, especially where there is no alternative to the use of such vague categories as small or slight risk. It should also be determined whether an investigators estimates of the probability of harm or benefits are reasonable, as judged by known facts or other available studies. 
Finally, assessment of the justifiability of research should reflect at least the following considerations: (I) Brutal or inhumane treatment of human subjects is never morally justified. (ii) Risks should be reduced to those necessary to achieve the research objective. It should be determined whether it is in fact necessary to use human subjects at all. Risk can perhaps never be entirely eliminated, but it can often be reduced by careful attention to alternative procedures. (iii) When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk (looking usually to the likelihood of benefit to the subject-or, in some rare cases, to the manifest voluntariness of the participation). (iv) When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated. A number of variables go into such judgements, including the nature and degree of risk, the condition of the particular population involved, and the nature and level of the anticipated benefits. (v) Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process.
3. Selection of Subjects.-Just as the principle of respect for persons finds expression in the requirements for consent, and the principle of beneficence in risk/benefit assessment, the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the selections of research subjects.
Justice is relevant to the selection of subjects of research at two levels: the social and the individual. Individual justice in the selection of subjects would require that researchers exhibit fairness: thus, they should not offer potentially beneficial research only to some patients who are in their favor or select only "undesirable" persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kin of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing further burdens on already burdened persons. Thus, it can be considered a matter of social justice that there is an order of preference in the selection of classes of subjects (e.g., adults before children) and that some classes of potential subjects (e.g., the institutionalize mentally infirm or prisoners) may be involved as research subjects, if at all, only on certain conditions.
Injustice may appear in the selection of subjects, even if individual subjects are selected fairly by investigators and treated fairly in the course of research. Thus injustice arises from social, racial, sexual and cultural biases institutionalized in society. Thus, even if individual researchers are treating their research subjects fairly, an even if IRBs are taking care to assure that subjects are selected fairly within a particular institution, unjust social patterns may nevertheless appear in the overall distribution of the burdens and benefits of research. Although individual institutions or investigators may not be able to resolve a problem that is pervasive in their social setting, they can consider distributive justice in selecting research subjects. 
Some populations, especially institutionalized ones, are already burdened in many ways by their infirmities and environments. When research is proposed that involves risks and does not include a therapeutic component, other less burdened classes of persons should be called upon first to accept these risks of research, except where the research is directly related to the specific conditions of the class involved. Also, even though public funds for research may often follow in the same directions as public funds for health care, it seems unfair that populations dependent on public health care constitute a pool of preferred research subjects if more advantaged populations are likely to be the recipients of the benefits.
One special instance of injustice results from the involvement of vulnerable subjects. Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability of settings where research is conducted. Given their dependent status and their frequently compromised capacity for free consent, they should be protect against the danger of being involved in research solely for administrative conveniences, or because they are easy to manipulate as a result of their illness or socioeconomic condition.

[FR Doc. 79-12065 Filed 4-17-79; 8:45 am]