FOOD AND DRUG ADMINISTRATION REGULATIONS

In addition to the requirements imposed by DHHS which form the basis of these Guidelines, the Food and Drug Administration also has regulations requiring IRB review, informed consent and protection of human subjects. These regulations apply to all studies of test articles the results of which will be submitted to the FDA. Most of the provisions are identical to those in the DHHS regulations discussed in the general sections of these Guidelines but there are some additional requirements specific to the FDA, e.g. the requirement to report adverse events and provisions for emergency use of investigational drugs or devices.

In some cases, use of "articles" for either research or practice purposes may be covered by FDA regulations even though FDA has approved commercial distribution of the "article." For example, use of an approved drug for an indication or in a population not mentioned on the FDA-approved package label may be subject to FDA regulation such as when data is being developed in connection with the new use of the "article" or to support an application to the FDA for a change in the package label or advertising.

Physicians who plan to use "articles" in ways that differ substantially from those identified on the package label should contact the firm that distributes the "article" to see what the manufacturer would either agree to obtain an IND/IDE or permit the investigator to apply for an IND/IDE.

Even if FDA regulations are not applicable, research involving investigational practices must conform to IRB guidelines.

EMERGENCY EXCEPTION TO THE GENERAL REQUIREMENTS

Section N, page 54, provides a full discussion of requirements for emergency use of a test article to treat a single patient in a life-threatening situation.

CONSENT FORM

When the study is subject to FDA regulations or to the Good Clinical Practices Guidelines, it is necessary to state the number of subjects who will participate in the study. The statement must be an objective statement of fact, such as `A total of X# of subjects will take part in this study.' Statements like `You will be one of X# of subjects...' or `This pivotal study will include X# of subjects from the United States and X# of countries.` are not permitted.

Subjects must be informed that their medical records may be subject to review by agents of the FDA and, in some cases, by agents of the industrial sponsor. WAIVER OF CONSENT NOT PERMITTED BY FDA REGULATIONS

FDA regulations do not have a provision for a waiver or alteration of the informed consent requirements except in emergency situations where the use of the test article would be for emergency treatment (see section N for details) or for research in an emergency room setting, which is subject to special requirements. Please see the guidance at the following web address: http://www.fda.gov/oc/ohrt/irbs/except.html

SUBJECT PRIVACY

To protect the privacy of the subjects, separate research code numbers should be used to identify individual subjects and only the investigators should have the means to link the code numbers to identifiable patients. There are some exceptions to this principle, such as when an implantable device is being tested, the FDA may require the reporting of the subjects' identity and contact information to sponsors. In most circumstances, if the sponsor's data reporting forms include names, initials or other identifiers, the forms should be modified.

DOCUMENTATION

Investigators working on FDA-regulated studies are strongly encouraged to keep all data, notes, and consent forms as "research records" that are separate from the medical records. When FDA personnel arrive to inspect records, they may -- in the interests of protecting the patient's privacy -- be given these records rather than their having to go to the medical chart to find the documentation. While clearly the subjects' medical records need to include information about research participation that would impact clinical decision making, research records should also be maintained.

UTHSCSA record retention policy is that the research records be kept a minimum of six years after the study protocol is inactivated, which satisfies the federal requirements related to the HIPAA privacy rule. FDA regulated study records may have to be kept a longer period. FDA regulations state that an investigator must maintain the records of drug disposition, signed consent documents, case report forms, all correspondence, dates of monitoring visits, and supporting documentation, for a period of two years following the date a New Drug Application is approved or until two years following the notification by the sponsor that the clinical investigations have been discontinued. The investigator may withdraw from the responsibility to maintain records and transfer custody of the records to another faculty or staff person who will accept responsibility for them. Notice of a transfer must be given to the FDA not later than 10 working days after the transfer occurs. A copy of that notice should also be sent to the IRB.

INSPECTIONS

Various federal agencies such as the FDA, the NCI and others have the authority to inspect medical records of patients or subjects involved in research studies in which these agencies have an interest. The Director of Internal Audit is responsible for coordinating the activities of all external auditors. If a department is contacted by an external audit agency, the agency should be referred to the Director who will contact the appropriate levels of Health Science Center management to schedule the external auditor's visit.

Investigators should also contact the President's Office and the IRB as soon as they receive notice of an inspection or audit by a federal agency.

FDA Defined Expanded Access to Investigational Drugs

Investigational products are sometimes used for treatment of serious or life-threatening conditions either for a single subject or for a group of subjects. The procedures that have evolved for an investigational new drug (IND) used for these purposes reflect the recognition by the Food and Drug Administration (FDA) that, when no satisfactory alternative treatment exists, subjects are generally willing to accept greater risks from test articles that may treat life-threatening and debilitating illnesses. The following mechanisms expand access to promising therapeutic agents without compromising the protection afforded to human subjects or the thoroughness and scientific integrity of product development and marketing approval.

OPEN LABEL PROTOCOL OR OPEN PROTOCOL IND

These are usually uncontrolled studies, carried out to obtain additional safety data (Phase 3 studies). They are typically used when the controlled trial has ended and treatment is continued so that the subjects and the controls may continue to receive the benefits of the investigational drug until marketing approval is obtained. These studies require prospective Institutional Review Board (IRB) review and informed consent.

TREATMENT IND

The treatment IND [21 CFR 312.34 and 312.35] is a mechanism for providing eligible subjects with investigational drugs for the treatment of serious and life-threatening illnesses for which there are no satisfactory alternative treatments. A treatment IND may be granted after sufficient data have been collected to show that the drug "may be effective" and does not have unreasonable risks. Because data related to safety and side effects are collected, treatment INDs also serve to expand the body of knowledge about the drug.

There are four requirements that must be met before a treatment IND can be issued: 1) the drug is intended to treat a serious or immediately life-threatening disease; 2) there is no satisfactory alternative treatment available; 3) the drug is already under investigation, or trials have been completed; and 4) the trial sponsor is actively pursuing marketing approval.

Treatment IND studies require prospective IRB review and informed consent. A sponsor may apply for a waiver of local IRB review under a treatment IND if it can be shown to be in the best interest of the subjects, and if a satisfactory alternate mechanism for assuring the protection of human subjects is available, e.g., review by a central IRB. Such a waiver does not apply to the informed consent requirement. An IRB may still opt to review a study even if FDA has granted a waiver.

GROUP C TREATMENT IND

The "Group C" treatment IND was established by agreement between FDA and the National Cancer Institute (NCI). The Group C program is a means for the distribution of investigational agents to oncologists for the treatment of cancer under protocols outside the controlled clinical trial. Group C drugs are generally Phase 3 study drugs that have shown evidence of relative and reproducible efficacy in a specific tumor type. They can generally be administered by properly trained physicians without the need for specialized supportive care facilities. Group C drugs are distributed only by the National Institutes of Health under NCI protocols. Although treatment is the primary objective and patients treated under Group C guidelines are not part of a clinical trial, safety and effectiveness data are collected. Because administration of Group C drugs is not done with research intent, FDA has generally granted a waiver from the IRB review requirements [21 CFR 56.105]. Even though FDA has granted a waiver for these drugs, an IRB may still choose to conduct a review under its policies and procedures. The usage of a Group C drug is described in its accompanying "Guideline Protocol" document. The Guideline Protocol contains an FDA-approved informed consent document which must be used if there has been no local IRB review.

PARALLEL TRACK

The Agency's Parallel Track policy [57 FR 13250] permits wider access to promising new drugs for AIDS/HIV related diseases under a separate "expanded access" protocol that "parallels" the controlled clinical trials that are essential to establish the safety and effectiveness of new drugs. It provides an administrative system that expands the availability of drugs for treating AIDS/HIV. These studies require prospective IRB review and informed consent.