NDAs SHOULD CONTAIN NARRATIVE DESCRIPTIONS OF DEATHS AND SERIOUS ADVERSE EVENTS OCCURRING IN CLINICAL TRIALS, FDA's GUIDELINE FOR CLINICAL DATA IN AN NDA SAYS

NDA submissions should include narrative descriptions of deaths and serious adverse events that occur in clinical trials, according to FDA's recently released rules for clinical data submissions. The rules are explained in a document called the "Draft Guideline for the Format and Content of the Clinical Data Section of an Application," which is now avaiable from FDA. The guideline states that "for all deaths and all potentially serious adverse experiences, there should be a brief narrative describing each event and assessing the likelihood that the drug was responsible." The guideline explains that "whether an adverse experience is potentially serious is a matter of judgment, and the basis for the judgment should be explained." It states that the significance "of the fatalities and adverse drop-outs should be assessed, particularly with respect to whether any of these events may represent a previously unsuspected important adverse effect of the drug." FDA's new draft guideline describes how clinical data in an NDA should be organized and submitted. The document includes information on FDA's requirements for clinical pharmacology studies, controlled and uncontrolled clinical trials, integrated summaries on effectiveness and safety, individual study reports, risk benefit analysis, and case report tabulations. The guideline also states that similar adverse reactions should be grouped together. "It is important, in presenting adverse events, both to display the original terms used by the investigator and to attempt to group related reactions (i.e., events that probably represent the same phenomena) so that occurrence rate is not obscured." The guideline recommends that "the individual study report. . . emphasize the reported terminology" and that the integrated summary of safety data use a "standard adverse reaction dictionary" for grouping of adverse events. Common Adverse Events Should Be Examined For Relationship To Dosage, Treatment Duration FDA does not recommend the exact terms for a standard dictionary. The agency says that "experience at this time is too limited to recommend a particular one for this purpose." The agency explains, however, that "in general, the individual study report should emphasize the reported terminology, leaving use of a standard dictionary for the integrated summary of safety data." Synonymous reactions, FDA said, "should be grouped (e.g., heartburn, indigestion, or dyspepsia)." In addition to a "basic display of adverse event rates," the guideline states that "the more common adverse events that seem to be drug related should be examined for relationship to dosage (corrected to a mg/kg dose, if possible), duration of treatment, total dose, demographic characteristics, such as age, or other baseline features, such as renal status, and to blood level, if data are available." The guideline notes that "it is not intended that every adverse event be subjected to rigorous statistical evaluation. It may be apparent from initial display and inspection that a significant relation to demographic or other baseline features is not present." Discussing effectiveness criteria, the guideline states that "ordinarily, the clinical trials submitted in an application will not be regarded as adequate support of a claim unless they include studies by more than one independent investigator who maintains adequate case histories of an adequate number of subjects." In general, the document adds, "a study for which case reports are not available will not be relied upon as a critical well-controlled study contributing to substantial effectiveness." The draft guideline specifies those requirements for the clinical data section of an NDA mandated under the NDA rewrite. The introduction of the document states that the "guideline supplement and expands the general outline provided in the regulations. Because it must remain broad enough to apply to all drug classes, it deals with the topics that should be considered by any applicant, and how to organize them rather than with the specific data requirements for approval of a specific kind of drug." For guidance regarding specific data requirements, the guideline suggests referring to "the 'General Considerations for the Clinical Evaluation of Drugs' and the many guidelines dealing with the evaluation of individual drug classes." The draft guideline notes that an NDA submission should contain "reference to existing FDA drug-class clinical guidelines, and the General Considerations guideline, explaining any important differences between guideline recommendations and the actual study plan." One of the major changes in FDA policy on NDA submission requirements under the NDA rewrite is the requirement that an application discuss all studies on a compound. Addressing this point, the guideline states: "All controlled clinical studies, including incomplete or abandoned studies, and all pertinent data, whether developed with support of the sponsor or obtained from any other source should be presented in this section. In most cases the discussion of each study should include a full report but in others a brief report will be sufficient." FDA is requesting written comments on its draft guideline by April 17. Copies of the document can be obtained by calling (301) 443-6060. The draft is recorded as Docket 85D-0467.