Schultheis, Lex W. MD, PhD; Rappaport, Bob A. MD
From the Division of Anesthesia, Analgesia, and Rheumatology Products, Office of Drug Evaluation II, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
Accepted for publication December 27, 2006.
Address correspondence and reprint requests to Bob A. Rappaport, MD, Division of Anesthesia, Analgesia, and Rheumatology Products, Office of Drug Evaluation II, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, Silver Spring, MD 20993. Address e-mail to email@example.com.
A case report in this issue of Anesthesia & Analgesia describes the emergency use of the investigational drug, sugammadex, in a patient not enrolled in a clinical trial (1). At the request of the journal, we have outlined below the regulations that govern emergency use of investigational drugs.
In general, clinical studies of an investigational drug (generally, any drug not approved for marketing) must be performed under an investigational new drug application (IND) and, in almost all cases, after submission of the clinical study protocol for the use to an IRB and to the Food and Drug Administration (FDA). FDA regulations recognize, however, that in an emergency, different rules are needed. Thus, in a medical emergency, an investigational drug may be used outside of an FDA-reviewed clinical trial protocol in accordance with the regulations governing an “Emergency Use” IND. This emergency use could involve a drug already under study in an institution or one not yet being studied at all at the site. In both cases, the use can be allowed, with appropriate reporting to follow. Treatment of a patient in such a setting is unusual in anesthesiology and some other disciplines, but physicians may be confronted with this situation. A physician contemplating the emergency use of an investigational drug should be convinced that the clinical setting dictates this action, and must understand that the treatment may expose the patient to unknown hazards.
The requirement that clinical studies of investigational drugs be performed under an IND is longstanding. It assures appropriate review of studies by IRBs, careful attention to study design and patient monitoring, and review of accumulating data. Emergency use, while important, should not be casual or unmonitored. If the need arises for emergency use of an investigational drug before an IND or IND amendment can be submitted, the FDA should be contacted for authorization and the IND submitted as soon as practicable in accordance with the Federal Code of Regulations (21 CFR 312.36).1 The FDA division managing the development of the investigational drug will review the circumstances of treatment to determine whether evidence supports the proposed use of this product. The FDA also will expect the attending anesthesiologist to provide additional follow-up information regarding the patient after the emergency has passed, in conjunction with submission of the IND. Where the need for a drug in the possession of an investigator is urgent and FDA cannot be reached, the investigator can use the drug and contact FDA afterward, but this is expected to be very unusual.
When using an investigational drug outside of an FDA-reviewed protocol, the anesthesiologist must be certain that the emergency nature of the medical situation is indisputable and must comply with federal regulations that govern the emergency use of an investigational drug. The FDA’s Office of Emergency Operations (301-443-1240) is continuously staffed, even during nonbusiness hours, to facilitate authorization for a specified investigational drug, as appropriate, in advance of submission of an Emergency Use IND. An on-call physician at FDA can be contacted at any time, including nights, weekends, and holidays. If the investigational drug is not available on-site, FDA may authorize shipment of the drug for a specified use in advance of submission of an IND. Authorization may be requested while the anesthesiologist is attempting to obtain access to the investigational drug from the sponsor and to obtain informed consent for the investigational treatment from the patient or the patient’s legally authorized representative.
If it is not possible to obtain informed consent, the patient’s attending anesthesiologist, acting as the clinical investigator under an Emergency Use IND, and an independent physician not otherwise participating in the clinical investigation of the drug, must document the following conditions in accordance with the regulations at 21 CFR 50.23(a)(1)-(4):
1. The human subject is confronted by a life-threatening situation necessitating the use of the test article.
2. Informed consent cannot be obtained from the subject because of an inability to communicate with, or to obtain legally effective consent from, the subject.
3. Time is not sufficient to obtain consent from the subject’s legal representative.
4. There is available no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject.
If, in the investigator’s opinion, immediate use of the investigational drug is required to preserve the life of the patient and time is insufficient for an independent physician to certify the decision before treatment, then the action of the attending anesthesiologist (clinical investigator) must be reviewed and evaluated in writing by an independent physician within five working days after treatment (21 CFR 50.23(b)). The IRB must also be informed of the emergency use of the investigational drug within the same period. Any subsequent use of the investigational drug at the institution is subject to prior IRB review (21 CFR 56.104(c)).
It is essential that an anesthesiologist contemplating emergency use recognize how an investigational drug differs from an approved drug: the investigational drug has not been demonstrated to be safe and effective for any specific indication. In addition to the clinical trials being performed to support particular uses, other evaluations are ongoing to assess the safety of the product, such as short-term and long-term toxicology studies and animal carcinogenicity studies. Clinical development is also staged so that the first individuals who consent to participate in clinical studies are generally healthy volunteers, with subsequent studies gradually progressing to include more vulnerable patients who are likely to be exposed once the drug has been approved for marketing. When an investigational drug is used in an emergency, and outside of an approved protocol, the attending anesthesiologist needs to recognize that the usual review process used to evaluate safety and effectiveness in the clinical setting has not been completed and, therefore, he or she must consider the potential implications of the use of the product.
In summary, the emergency use of an investigational drug is allowed under FDA regulations, but it is a serious decision that must be undertaken thoughtfully. The circumstances precipitating the emergency administration of an investigational drug or biologic product outside of an FDA-reviewed protocol are unusual. When an investigational drug is used outside of an FDA-reviewed protocol, an IND must subsequently be submitted to the FDA, detailing the circumstances that led to the emergency treatment. After the emergency has passed, the medical decision to use the product will be reviewed by the bodies charged with oversight of patient safety in clinical investigations, including the FDA and the institutional IRB.
1. Lenz A, Hill G, White PF. The emergency use of sugammadex after failure of standard reversal drugs. Anesth Analg 2007;104:585–6.
1On December 14, 2006, FDA published a proposed rule on expanded access to investigational drugs for treatment use (71 FR 75147). This proposed rule would, among other things, replace 21 CFR 312.36 with a new regulation at 21 CFR 312.310(d) governing emergency expanded access use for individual patients and provide further clarification regarding sponsor and investigator responsibilities. Cited Here...