Preparing and Submitting the Protocol and Consent

Preparing The Protocol
Please refer to Appendix II: Protocol Preparation Checklist for a concise list of criteria that is required to be included in the protocol.

Preparing the Consent Document

REQUIRED ELEMENTS OF INFORMED CONSENT

BASIC ELEMENTS OF INFORMED CONSENT:

In seeking informed consent, the following information must be provided to each subject:

1. A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any products which are experimental.
   
   The statement that the study involves research is important because the relationship between patient-physician is different than that between subject-Investigator. Any procedures relating solely to research (e.g., randomization and placebo control) should be explained to the subjects. The procedures subjects will encounter also should be outlined in the consent document.
   
   Consent documents for studies of investigational articles (drugs, devices) should include a statement that a purpose of the study includes an evaluation of the safety of the test article. Statements that test articles are safe or statements that the safety has been established in other studies, are not appropriate when the purpose of the study includes determination of safety. In studies that also evaluate the effectiveness of the test article, consent documents should include that purpose, but should not contain claims of effectiveness.
   
   Include in the description of procedures:
   
   1. The number and frequency of visits to the doctor's office.
      
   2. Any limitation of the subject's activities; e.g., requirements to remain in the doctor's office.
      
   3. A description of all tests that will be performed; e.g., ECG, pulmonary function, blood pressure measurements, blood sampling, etc.
      
   4. A description of dietary requirements.
      
   5. A description of special requirements; e.g., need to chew tablets rather than swallow whole or vice versa.
      
   6. Language to include: "You are eligible to volunteer for a drug research study. This study will determine whether [name of drug] is safe."
      
   7. Language to avoid: "[Name of drug] is a drug used for the treatment" of respiratory infections.
      "[Name of drug] is a drug which has been found to be effective in the treatment of respiratory infections."
      The word "treatment assumes that the drug has been proven effective. Use the term "study treatment."
      
      
2. A description of any reasonably foreseeable risks or discomforts to the subject.
   The risks of procedures relating solely to research should be explained in the consent document. The risks of the tests required in the study protocol should be explained, especially for tests that carry significant risk of morbidity/mortality themselves. The explanation of risks should be reasonable and should not minimize reported adverse effects.
   
   
3. A description of any benefits to the subject or to others which may reasonably be expected from the research.
   
   The description of benefits to the subject should be clear and not overstated. If no direct benefit is anticipated, that should be stated. When benefits may accrue to the Investigator, the sponsor, or others, these benefits may be materially relevant to the subject's decision to participate, and they should be disclosed in the informed consent document.
   
   
4. A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.
   
   To enable a rational choice to participate in the research study, subjects should be made aware of the full range of options available to them. Consent documents should briefly explain any pertinent alternatives to entering the study. While this should be more than just a list of alternatives, a full risk/benefit explanation of alternatives may not be appropriate to include in the written document. The person(s) obtaining the subject's consent, however, should be able to discuss available alternatives and answer questions that the subject may raise about them. As with other required elements, the consent document should contain sufficient information to ensure an informed decision.
   
5. A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that external regulatory agencies, such as the Food and Drug Administration, may inspect the records.
   Study subjects should be informed of the extent to which the institution intends to maintain confidentiality of records identifying the subjects. In addition, they should be informed that external regulatory agencies, such as the FDA, may inspect study records (which include individual medical records). If any other entity, such as the sponsor of the study, may gain access to the study records, the subjects should be so informed.
   
   
6. For research involving more than minimal risk, an explanation as to whether any compensation and/or medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
   
   
7. An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject.
   
   This requirement contains three components, each of which should be specifically addressed. The consent document should provide the name of a specific office or person and the telephone number to contact for answers to questions about:
   • the research subjects' rights
   • the research study itself.
   • research related injuries
     
     
8. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

ADDITIONAL ELEMENTS OF INFORMED CONSENT:

When appropriate, one or more of the following elements of information shall also be provided to each subject:

1. A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.
   
   A statement that there may be unforeseen risks to the embryo or fetus may not be sufficient if animal data are not available to help predict the risk to a human fetus. Investigators should ensure that subjects who agree to enter a study fully understand the potential risks that the study poses. If measures to prevent pregnancy should be taken while in the study, that should be explained.
   
   
2. Anticipated circumstances under which the subject's participation may be terminated by the Investigator without regard to the subject's consent.
   
   When applicable, subjects should be informed of circumstances under which their participation may be terminated by the Investigator without the subject's consent. An unexplained statement that the Investigator and/or sponsor may withdraw subjects at any time, does not adequately inform the subjects of anticipated circumstances for such withdrawal.
   
   A statement that the Investigator may withdraw subjects if they do not "follow study procedures" is not appropriate. Subjects are not in a position to know all the study procedures. Subjects may be informed, however, that they may be withdrawn if they do not follow the instructions given to them by the Investigator.
   
   
3. Any additional costs to the subject that may result from participation in the research.
   If the subjects may incur an expense because they are participating in the research, the costs must be explained in sufficient detail as to prepare the potential subject for such a possibility.
   
   
4. The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject.
   
   When withdrawal from a research study may have deleterious effects on the subject's health or welfare, the informed consent should explain any withdrawal procedures that are necessary for the subject's safety and specifically state why they are important to the subject's welfare. An unexplained statement that the subject will be asked to submit to tests prior to withdrawal, does not adequately inform the subjects why the tests are necessary for the subject's welfare.
   
   
5. A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject.
   When it is anticipated that significant new findings that would be pertinent to subject's continued participation are likely, the Institutional Review Board should determine that a system, or a reasonable plan, exists to make such notification to subjects.
   
   
6. The approximate number of subjects involved in the study.
   
   If the numbers of subjects in a study is material to the subject's decision to participate, the subjects should be told not only the approximate number of subjects involved in the study, but also why the number of participants is important (e.g., a small number may compromise confidentiality).

INVESTIGATIONAL DEVICES AND IDE REQUIREMENTS

DEFINITION:

An investigational device is a medical device (for use inside or outside the body) which is the subject of a clinical study designed to evaluate its effectiveness and/or safety.

IDE REGULATIONS:

Clinical investigations undertaken to develop safety and effectiveness data for medical devices must be conducted according to the requirements of the IDE regulations [21 CFR part 812].

EXEMPTIONS:

Certain clinical investigations of devices (e.g., certain studies of lawfully marketed devices) may be exempt from the IDE regulations [21 CFR 812.2(c)].

CATEGORIES:

Unless exempt from IDE regulations, an investigational device must be categorized as either "significant risk" (SR) or nonsignificant risk" (NSR). The determination that a device presents significant or nonsignificant risk is initially made by the sponsor, although any local Institutional Review Board reviewing the study protocol must concur (see examples of significant and nonsignificant risk devices below).

SIGNIFICANT RISK (SR) STUDIES:

Significant Risk device studies must be conducted in accordance with the full IDE requirements of the US Food and Drug Administration, and may not commence until 30 days following the sponsor's submission of an IDE application to the FDA.

NON-SIGNIFICANT RISK (NSR) STUDIES:

In contrast, nonsignificant risk studies do not require submission of an IDE application to the FDA. Instead, the sponsor is required to conduct the study in accordance with the "abbreviated requirements" of the IDE regulations [21 CFR 812.2 (b)]. Unless otherwise notified by the FDA, an NSR study is considered to have an approved IDE if the sponsor fulfills the abbreviated requirements.

INSTITUTIONAL REVIEW BOARD APPROVAL:

Once the SR/NSR determination has been made, the Institutional Review Board must consider whether the study should be approved. The fact that the FDA may not object to a particular IDE application does not mean that the Institutional Review Board must approve a study. The FDA relies on local IRBs to ensure the safety and welfare of its local subject population.

EXAMPLES OF RISK CATEGORIES

INVESTIGATIONAL NEW DRUGS/BIOLOGICS AND IND REQUIREMENTS

Before a new drug or biologic may be tested on humans, the sponsor (usually a pharmaceutical firm, but sometimes an individual) must submit a Notice of Claimed Investigational Exemption for a New Drug (IND) to the US Food and Drug Administration (FDA). Current regulations at 21 CFR 312.22 and 312.23 contain the general principles underlying the IND submission and the general requirements for an IND's content and format.

WAITING PERIOD:

After the sponsor submits an IND, there is a 30-day waiting period during which the FDA reviews the protocol to make certain subjects are not exposed to any unwarranted risks. If, after 30 days, the FDA has not raised any objections or placed the IND on a clinical hold, the study may proceed. Of course, local Institutional Review Board approval is also required prior to initiation of any drug study. Frequently, Investigators submit protocols to the Institutional Review Board for review during the 30-day waiting period. If the Institutional Review Board finds the protocol acceptable, approval is issued after the 30-day waiting period has elapsed.

PHASES:

IND studies are generally conducted in three phases, numbered I, II and III. Phase I pharmacology studies are used to determine toxicity, metabolism absorption and safe dosage range. These studies involve a small number of subjects and are conducted under carefully controlled circumstances. Phase II initial trials are conducted on a limited number of patients for a specific disease treatment or prevention. Additional pharmacological studies performed on animals may be necessary to indicate safety. Phase III studies are extensive clinical trials intended to assess a drug's safety, effectiveness, and most desirable dosage in treating a specific disease. Sometimes Phase IV is used to describe a pre-marketing period for a drug that is pending FDA approval.

RADIATION SAFETY COMMITTEE

Protocols involving radioactive materials or any radiation-producing equipment (e.g., CT Scans, PET Scans, X-Rays) may require separate approval from the Radiation Safety Committee. For more information about Radiation Safety Committee requirements, call the chairman for the Radiation Safety Committee at your institution.

INSTITUTIONAL BIOSAFETY COMMITTEE

Protocols involving gene therapy, gene transfer or any genetic manipulation requires separate approval from the Institutional Biosafety Committee. For more information about Institutional Biosafety Committee requirements, call the chairman at your institution.

For more information on submitting and preparing the protocol and informed consent, see Appendix I-IV.