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• W1494543804 abstract "A senior vice president at a major pharmaceutical company suggested that the Food and Drug Administration (FDA) does not really care about the risks of drugs given by anesthesiologists, saying “If you can safely give muscle relaxants, you can safely give anything.” He was exaggerating, of course, but his point was that regulatory agencies, including the FDA, do not get particularly anxious about excessive sedation, ventilatory depression, hemodynamic depression, and many other serious consequences of drugs when the patient is in the hands of an anesthesiologist. What we call “induction of anesthesia” would be called “code blue” anywhere else in the hospital. We are continuously with the patient, have our drugs and tools out and ready, and treat muscle paralysis, hypotension, hypoventilation, and airway obstruction as expected consequences of anesthetic drug administration. Our sangfroid with highly potent and toxic drugs may limit our appreciation of their potential for unanticipated toxicity. How else can we explain our tendency to inject drugs into the epidural and intrathecal spaces, around nerves, or into children, in the absence of reassuring toxicity studies and FDA approval? We are all interested in knowing if our drugs work in these settings, but shouldn't there be a standard to ensure patient safety before undertaking such studies? Anesthesia & Analgesia has published many human clinical studies describing the use of nonapproved drugs used in the intrathecal space, including papers on intrathecal midazolam (1,2), sufentanil (3–5), meperidine (5), nalbuphine (6), morphine-6-glucuronide (7), magnesium (8), neostigmine (9–11), sameridine (12), and multiple studies of intrathecal chloroprocaine (13). Some of these studies have provoked strong reactions. The articles on midazolam (1,2) prompted a critical manuscript by Yaksh and Allen stating that “One could reasonably assert that every one of the 800 patients reported to have received midazolam, not to mention those not reported, was a true experiment presenting a scenario entailing needless risk to the patient” (14). In an accompanying editorial, Michael Cousins and Ron Miller discussed the ethical dilemma of publishing manuscripts describing clinical trials demonstrating apparently safe and effective intrathecal drug delivery, and justifying publication of these studies because it would “bring more benefit to patients than any perceived harm resulting from a process of investigation that was less than ideal ” (15). In a concurrent editorial, Yaksh and Allen pleaded with human studies committees and journal editors to cast suspect studies aside (16). Subsequent letters supported (17) and condemned (18) the decision to publish the studies. This uproar over intrathecal midazolam mirrored a similar set of concerns that were raised by Eisenach et al. (19) in response to publication in Anesthesia & Analgesia of a study of epidural administration of isoproterenol (20) and verapamil (21), also with little or no animal toxicology data to support neuraxial safety. The Eisenach et al. Letter to the Editor stated bluntly “we believe that before human administration, screening for potential neurotoxicity of novel drugs for epidural-spinal administration is ethically mandatory.” However, the letter could have been left blank, because the title said it all: “primum non nocere.” There are similar issues for pediatric use of drugs. Anesthesia & Analgesia recently published a series of articles on the unapproved use of dexmedetomidine in children (22–25). An accompanying editorial examined the ethical implications of studying drugs in children without adequate, supporting animal toxicity data (26), while the FDA shared their perspective of the importance of regulatory oversight of pediatric trials (27). The issues of neuraxial and pediatric drug delivery are exactly the same: What is the correct balance between our noble aspirations to improve patient therapy through the novel use of drugs, and our duty to our patients to ensure their safety? Shouldn't the fundamental principle be “primum non nocere,” as advocated by Eisenach et al. (19)? The editorials and letters in response to the intrathecal midazolam and epidural verapamil and isoproterenol articles suggest that journal editors and reviewers have a responsibility to examine the preclinical toxicology data in deciding whether a study should be published or not. Is this a reasonable standard? Very few anesthesiologists are also trained in toxicology. How is Anesthesia & Analgesia supposed to differentiate studies supported by adequate preclinical toxicology from studies without adequate supporting toxicology data? After much deliberation, we have decided to punt this question to an agency that knows how to distinguish adequate from inadequate preclinical safety data: the United States FDA (or the equivalent agency for papers submitted from other countries). This issue of Anesthesia & Analgesia contains a remarkable document: the 2007 Anesthesia & Analgesia Guide for Authors (28). Our editorial board spent over a year preparing this guide. It will shape the Journal for many years. The guide is very explicit about investigational drug use based on three clear criteria, first suggested to me by James Eisenach, MD, Editor-in-Chief of Anesthesiology, with regard to neuraxial administration: Is the drug approved by the FDA for this indication? If the drug is not approved, is it widely used off-label (e.g., in tens of thousands of patients)? Our editorial board concluded that if multiple textbooks indicated that the drug could be safely used in a given manner, this was a suitable surrogate demonstration that the drug was widely used for the indication. If neither 1 nor 2 applies, was the study performed with an “Investigator Investigational New Drug (IND)” from the FDA or an equivalent regulatory authority? These are described in greater detail in the Guide for Authors (28). The new guidelines state the obvious conclusion that IRB approval alone may not be adequate for clinical studies to be considered for publication. The requirement for an Investigator IND if the drug is not approved, and not widely used for the indication off-label, places the burden of assessing the adequacy of preclinical toxicology data where it belongs: on the FDA. The process of obtaining an investigator IND is simple. There is a two-page form to complete, which can be found at http://www.fda.gov/Cder/about/smallbiz/clinical_investigator.htm (Form 1571). In this issue of the Journal, Lee and Lee describe the antipruritic and antiemetic effects of epidural droperidol (29). Their study does not meet our criteria for neuraxial drug administration. Why did we publish it? As Cousins and Miller observed (15) editorial decisions are often a balance. In this case, we struggled to balance fairness to authors with our need for unambiguous standards for neuraxial drug delivery. The manuscript by Drs. Lee and Lee had undergone four revisions when we settled on our new policy in September, 2006. We elected to proceed with publication of their manuscript to be fair to the authors. Additionally, one could contend that the many published papers on epidural droperidol administration without adverse events (30–38) adequately document neuraxial safety, although extrapyramidal reactions have been reported (39–41). After the decision to continue with Lee and Lee's paper, approximately a dozen subsequent submissions were rejected for inadequate preclinical toxicology. The paper by Drs. Lee and Lee brings to an end a series of rigorous studies pursued by ethical investigators and published in Anesthesia & Analgesia. The same issue of the journal introduces a new standard. This issue provides two bookends for Journal policies on the use of investigational drugs. Standards evolve over time. I do not question the decision of investigators to study intrathecal midazolam, epidural verapamil and isoproterenol, or dexmedetomidine in children. I do not question the decision to publish these studies. No patients have been hurt, to the best of our knowledge. We have learned from this research. The investigators followed the then-accepted standards for clinical research, and the Journal followed the then-accepted standards for publication. However, I am proud to be associated with a journal that struggled openly with the ethical dilemmas involved in publishing these studies, and invited thoughtful editorials critical of the Journal to present both sides of the issue. I can only hope to be as candid and forthright as my predecessor, Dr. Miller, in handling ethical issues. I acknowledge the assistance of James Eisenach, the Francis M. James III Professor of Anesthesiology and Vice-Chair for Research at the Wake Forest Medical Center and Editor-in-Chief of Anesthesiology, in discussing these issues. The editorial board of Anesthesiology has reached the same conclusion about clinical studies involving neuraxial and pediatric drug administration. I also acknowledge the ongoing contributions of Tony Yaksh, Professor of Anesthesiology at the University of California at San Diego, and the journal's Section Editor for Pain Mechanisms, in establishing practical and reasonable guidelines for investigators." @default.
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• W1494543804 title "Anesthesia & Analgesia's Policy on Off-Label Drug Administration in Clinical Trials" @default.
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