A physician not connected with the research and who, by virtue of his relationship to the prospective subject, had the best interests

of the prospective subject in mind would be called upon to determine that:

a) The patient's physical and psychological condition were such that he was not likely to be unduly threatened or harmed by the consent negoti- ations, and

b) the patient's cognitive function had not been impaired to the ex- tent that he could not understand the information.

The physician assigned responsibility to make these determinations was to be the one who had most recently examined the patient sufficiently thoroughly to make these determinations. When possible this would be the patient's personal physician who had established a physician-patient re- lationship prior to the onset of the current illness. When no such re- lationship existed or when the physician meeting this description was un- available, the physician called upon for this judgment would be the resident physician in the coronary care unit. In the event the personal physician was also a member of the research team, he would be disqualified as a third party scrutinizer.

In this case, the investigators were cardiologists who are highly skilled and experienced not only in catheterizations of the heart but also in the management of patients with myocardial infarction in the coronary care unit. Thus, it was judged unnecessary to have any other physicians in attendance during the process of negotiating for informed

consent or during the brief period during which the research maneuver was performed. In the event the subject wanted to see his own physician during this period his access to that physician would be no more limited than it would ordinarily be in the usual conduct of activities on a

coronary care unit. The circumstances of the research were such that it would not be in the scientific interests of the investigators to continue the research if something “went wrong”.

Other examples of research in which a requirement for third party scrutiny of all or part of the negotiations for informed consent can be provided should the Commission wish them. It is the view of the author that regulations for third party scrutiny of negotiations for informed consent should impose on the IRB the requirement for determining when it will be necessary and what form it should take. Regulations that attempt to prescribe the form and substance of third party scrutiny may deprive the IRB of the flexibility necessary to meet the needs of particular re- search proposals and particular prospective subjects.

Documentation of informed consent

DHEW regulations prescribe in section 46.10 the forms in which in- formed consent must be documented. Three possible forms are described (5):

"(a) Provision of a written consent document embodying all of the basic elements of informed consent. This may be read to the subject or to his legally authorized representative, but in any event he or his legally authorized representative must be given an adequate opportunity to read it. This document is to be signed by the subject or his legally authorized representative. Sample copies of the consent form as approved by the Board (IRB) are to be retained in its records.

"(b) Provision of a "short form" written consent document in- dicating that the basic elements of informed consent have been presented orally to the subject or his legally authorized representative. Written summaries of what is to be said to the patient are to be approved by the Board. The short form is to be signed by the subject or his legally authorized representative and by an auditor witness to the oral presen- tation and to the subject's signature. A copy of the approved summary, annotated to show any additions, is to be signed by the persons offic- ially obtaining the consent and by the auditor witness. Sample copies of the consent form and of the summaries as approved by the Board are to be retained in its records."

The third "form" is, in fact, not a form; it reads in part as follows:

"(c) Modification of either of the primary procedures outlined in paragraphs (a) and (b) of this section. Granting of permission to use modified procedures imposes additional responsibility upon the Board and the institution to establish: (1) That the risk to any subject is mini- mal, (2) that the use of either of the primary procedures for obtaining informed consent would surely invalidate objectives of considerable im- mediate importance, and (3) that any reasonable alternative means for attaining these objectives would be less advantageous to the subjects."

The regulations go on to require that the reasons for permitting the use of modified procedures must be individually and specifically docu- mented and made a matter of permanent record.

Careful reading of the quoted portion of paragraph (c) will indicate that--since all three criteria must be met--modified procedures may

virtually never be used. If the word "and" preceding "(3)" were changed to "or", some flexibility might be permitted by this paragraph.

It is difficult to understand the implications of these regulations without an awareness of how they are implemented by DHEW officials having such authority. Thus, an illustrative example is provided:

Since these rules and regulations were promulgated it has been NIH policy to require informed consent documented as specified in either paragraph (a) or (b) to use tissues or fluids removed at either surgery or autopsy for research purposes (25). This requirement is imposed even

though the autopsy or surgical procedures are done in accord with customary medical practice, where there is no removal or retention

of additional tissues or fluids for research purposes (beyond the amount required by the medical needs of the patient or next of kin), and where the procedures themselves are authorized by consent (of the sort usually used in the medical practice context) to remove, retain, and dispose of tissues. Further, this requirement is imposed even if there is no way to link the information that might be developed through the research to the name of the individual from whom the tissue or fluid was removed. Thus, it is asserted that current DHEW regulations--although they seem to permit reasonable flexibility--actually permit very little. The consequences of this sort of interpretation of the regulations will be analyzed subsequently (Conditions under which consent negotiations may be less elaborate).

The regulations of the Food and Drug Administration do permit some flexibility (26).

Section 310.102 (a) specifies that "...the use of investigational new drugs on humans shall impose the condition that investigators "obtain the consent of such human beings or their representatives, except where they deem it not feasible or, in their professional judgment, contrary to the best interests of such human beings."

"(b) This means that the consent of such humans (or the consent of their representatives) to whom investigational drugs are administered primarily for the accumulation of scientific knowledge, for such purposes as studying drug behavior, body processes, or the course of a disease, must be obtained in all cases, and, in all but exceptional cases, the consent of patients under treatment with investigational drugs or the consent of their representatives must be obtained."

(d) Defines exceptional cases as "...those relatively rare cases in which it is not feasible to obtain the patient's consent or the consent of his representative, or in which as a matter of professional judgment ex- ercised in the best interest of a particular patient under the investigator's care, it would be contrary to that patient's welfare to obtain his consent."

"(g) "Contrary to the best interests of such human beings" applies when the communication of information to obtain consent would seriously affect the patient's well-being and the physician has exercised a pro-

fessional judgment that under the particular circumstances of this patient's case, the patient's best interests would suffer if consent were sought."

This section goes on to specify that consent to receive an investi- gational new drug in Phase I and Phase II shall be in writing. When con- sent is necessary under such rules in Phase III investigations, it is the responsibility of investigators, taking into consideration the physical and mental state of the patient, to decide when it is necessary or preferable to obtain consent in other than written form. When such written consent is not obtained, the investigator must obtain oral consent and record that fact in the medical record of the person receiving the drug.

These quotes from FDA regulations indicate that this agency is willing to permit more flexibility than is DHEW not only in the documentation of but also in the nature of the negotiations for informed consent. These re- gulations might be criticized on grounds that they leave too much to the judgment of the physician (investigator). However, section 312.1 imposes the necessity for an "institutional review committee" (analogous to the IRB) which is assigned responsibility for, among other things, imposing group judgment on the plans for negotiations for and documentation of in- formed consent.

The provision in FDA regulations that in exceptional cases, it might be appropriate to conduct phase III drug trials according to reduced standards of consent recognizes that in some situations according to the judgment of the physician-investigator, negotiating informed consent might be contrary to the welfare of a particular patient. In general, this pro- vision is meant to recognize two sorts of contingencies. The first is the

situation in which a Phase III drug must be administered immediately in order to have optimal effect. If time is taken to negotiate informed consent, the patient-subject might sustain irreversible injury as a consequence of the delay. It is not extraordinary that physician-inves- tigators ask of the IRB permission to proceed with sufficient flexibility

and receive from

to accommodate the demands of an emergency situation.

The second is the situation in which the patient-subject might for various reasons not wish to know some of the facts enumerated as elements of information. Most commonly, this calls to mind the patient with some dread disease who might be harmed psychologically by inappropriately pre- mature full disclosure of the diagnosis. However, there might be many other points of material information with which the patient-subject might not wish to be bothered. As Louisell and Williams have observed in the context of medical practice (27, at p. 594.63): "...Some patients do prefer not to know the details, including the risks, of proposed pro- cedures. Their attitude frankly is: "Doctor, I engaged you because of my confidence in your judgment and skill. I cannot understand all the implications of what you propose to do, and I do not wish to try. Because of my confidence in you, and my own ignorance and fears, I ask you to bear on your shoulders not only the medical burden of the procedure, but the moral one of the decision." If that is the true attitude of the patient, and he clearly conveys it, there is no reason in law, morals, or public policy why the physician normally should not abide it, if he is willing to do so."

Thus, in the context of medical practice, it seems to be the right

as discussed elsewhere, the subject ordinarily should be much more cautious about delegating decision-making responsibility to the in- vestigator. The author can recall no proposal by an investigator to the IRB at Yale University School of Medicine to withhold information from a prospective subject because--in the judgment of his physician-- full disclosure (particularly of the diagnosis) would be contrary to his best interest (except, as noted earlier, in cases of emergency).

The consent form

In almost every research activity involving consequential risk or inconvenience to the subject it is most appropriate to document in writing the fact that appropriate negotiations for informed consent

have been conducted. Exceptions will be specified in subsequent sections.

In the experience of the author, the consent form used by virtually every investigator is of the sort specified in section 46.10 (a) of the DHEW rules and regulations. The view prevails among investigators that the "short form" prescribed in 46.10 (b) offers no advantage to either investigator or subject. If the same quality and quantity of information is to be presented to the subject in form (b) as in form (a), and if all this information is to be committed to paper no matter which form is used, there seems no advantage to not giving the subject a copy of that paper to read, sign and--as discussed subsequently--keep. The author recalls no case in which an investigator proposed to the Yale Medical School IRB to use a "short form" as described in the regulations. Through the Commission's IRB study it will be seen if this experience is shared by

most or all other IRBs.

In general, it should be kept in mind by all concerned--but parti- cularly the investigator and members of the IRB--that the consent form can almost never be so constructed as to anticipate all of any parti- cular prospective subject's wishes to be informed. The consent form is most effective when it is viewed by the investigator as an instru- ment designed to guide him in his negotiations with the prospective sub- ject. The consent form should contain at least the minimum amount of information and advice that should be presented during the negotiations for informed consent. If any substantive new understandings are developed in the process of the negotiations which have any bearing on the prospective subject's willingness to participate these should be added to the consent form signed by that particular individual.

The consent form should present an adequate coverage of each of the eleven elements of information (section on Informing) that are germane to the particular proposed research activity. The fact that the consent form is considered a guide to the negotiations should be specifically reflected as indicated in element number 8 calling for an offer to answer any in- quiries concerning the procedures. It should be made clear that this offer to respond to inquiries is, in fact, an offer to elaborate on any of the eleven elements of information to the extent that the prospective subject wishes.

The use of general consent forms designed to document consent for research generally or even for several categorically related research protocols should be discouraged. At the very least, a consent form should

be designed to meet the specifications of a particular research proposal.

A fully satisfactory document designed to meet the needs of one particular protocol may, as discussed above, undergo further modification to reflect alterations in the negotiations that occur as a consequence of discussing the proposed research with individual subjects. At times it is necessary to design more than one consent form for use in a single research protocol.

Thus, for example, when a protocol is designed to conduct the same maneuvers on two distinctly different populations of subjects--eg, diabetics and healthy volunteers--it is ordinarily appropriate to have separate consent forms for each class of subject. Many of the elements of information pre- sented to the diabetics will differ from those presented to the healthy

volunteers. Thus, for example, element number 3 would contain very different information as to why the prospective subject has been selected. It might also contain very different sorts of information regarding "pretests" to determine eligibility and the consequences of "failure to pass" these exam- inations. Further, the nature of the benefits to be derived is likely to be very different.

Many institutions have guidelines prescribing the type of language that ought to be used in the consent form. Most commonly it is suggested that the form be worded in language that the "average lay person" should be expected to understand. This suggestion has provoked considerable controversy. For example, what is an average lay person? And what can he be expected to understand? Many protocols are designed to involve subjects that depart in some substantial way from "average". For example, some studies are designed to involve subjects who have serious chronic diseases in whom "standard and accepted" therapeutic measures have failed.

Commonly, such individuals have a highly sophisticated understanding of the technical language used to describe their disease, various means of diagnosis and therapy, and the harms that may occur as a consequence of therapy or of not being treated. On the other hand, some protocols are designed to involve naive subjects who might have little schooling, who might have primary languages other than English, and so on. Thus, it seems more appropriate to suggest in guidelines that the consent form should be presented in language that the prospective subject might be expected to understand. Protocols in which it is planned to draw upon diverse populations for subjects might require more than one con- sent form.

Various institutions have developed further recommendations on the language of the consent form. Some institutions have policies requiring that the entire consent form be worded in the first person. Thus, the various elements of information each begin: "I understand that the purpose of the study is to..."or "I hereby agree to have Dr. Jones draw 10 cc (2 teaspoons) of blood...". Other institutions recommend that consent forms be worded in the second person. For example: "You are invited to participate in a research project designed to... (accomplish some purpose)." "If you agree to participate there is a small possibility that you might develop a rash." "The purpose of this research is not to bring direct benefit to you but rather to develop information which might help us design better diagnostic methods for persons like you in the future."

The preference of the author is for consent forms that present the elements of information in the second person. After the elements of in-

formation have been presented there may be a statement worded in the first person entitled " Authorization : I have read the above and de- cide that... (name of subject) will participate in the project as des- cribed above. Its general purposes, the particulars of involvement, and possible hazards and inconveniences have been explained to my satisfaction. My signature also indicates that I have received a copy of this consent form."

In the view of the author, the presentation of the information in the second person followed by an authorization written in the first person best conveys the sense of negotiation (of give and take) in- volved. However, the author is not aware of any documentation that one style of language is to be preferred to another.

At the conclusion of the consent form there should be a line pro- vided for the signature of the consentor. There should further be some means of specifying how the consentor is related to the subject (self, parent, guardian, and so on). It should also specify the date on which the form was signed. Some individuals may wish to also record the date on which the form was first presented to the prospective subject if it differs from that on which it was signed. In cases where proxy consent is obtained a space may be provided for the signature of the actual subject if appropriate. This signature may indicate, depending upon the situation, the actual subject's consent (which may or may not be legally valid), his assent, or, perhaps, merely his awareness that somebody is consenting to something on his behalf.

Also on the consent form there should be a space provided for the signature of the individual who has conducted negotiations for consent.

His telephone number should be provided in the event the prospective subject

(or subject) has any wish to discuss the project further. In cases where a third party scrutinizer has participated in the consent process, a space should be provided for his signature as well. In addition, it might be of value in some consent negotiations to provide the names and telephone numbers of other individuals who might be consulted by the prospective subject or his agents for further information. The most common situation in which it is advantageous to list the name(s) and telephone number(s) of other individuals is when consent for a complex research activity is obtained by someone other than the professional who is responsible for

the conduct of the activity (cf, Who should negotiate for informed consent?) Prohibition of exculpatory clauses

DHEW regulations (5) require under section 46.9 that: "No...informed consent, oral or written,...shall include any exculpatory language through which the subject is made to waive, or appear to waive, any of his legal rights, including any release of the institution or its agents from lia- bility for negligence." The author finds no cause to elaborate, modify, or challenge this requirement as being applicable to all negotiations for informed consent.

Who keeps records of informed consent ?

There seems to be general agreement that the IRB should keep copies of the general consent forms offered to each prospective subject of any particular activity. A copy of the consent form (or the various consent forms) used to document the negotiations for informed consent is made part of the permanent record of each protocol that is retained by the IRB.

There have been various proposals that the IRB should also keep copies of the consent forms signed by each subject. The author suggests that this

would in some cases be detrimental to the best interests of the sub- jects; the reasons for this suggestion are the same as those presented for avoiding having the signed consent forms made a part of the permanent records of the institution ( infra ).

The investigator should ordinarily assume the responsibility to retain the consent forms signed by the individual subjects. It should be his responsibility to safeguard the confidentiality of these forms when appropriate and to the extent necessary. To some extent the mere fact that an individual has agreed to serve as a subject of a particular research activity will reveal information about that subject that he might not wish to have generally known. Thus, for example, the consent form might specify: "You are invited to participate in this research project because you have cirrhosis of the liver." Various rules and regulations specify how long the investigator ought to retain these consent forms in his files. Since one of the purposes of documentation of informed consent is to protect the investigator from inappropriate litigation for failure to provide "full disclosure" it is recommended that the signed consent form be held for a period of time slightly greater than the statute of limitations for such actions in his juris- diction. Ordinarily, signed forms should be retained for a sufficient period of time longer than the statute of limitations as usually ad- vised for physicians who are concerned with potential malpractice liti- gations; this is usually about six months but, in states having "dis- covery statutes", it may be forever (7, at p. 322).