New FDA regulations provide investigational new drug (IND) applicants clearer guidance on whether to report adverse events that might not have been related to a clinical trial, according to a perspective published June 8 by theNew England Journal of Medicine (NEJM).
Rachel Behrman Sherman, MD, MPH, and colleagues, argued that the new rule—published last September and made effective March 28—clarifies the responsibilities of clinical investigators and IND sponsors in reporting unexpected events. The regulations will put more responsibility in the hands of the IND sponsor, as opposed to leaving judgments up to clinical investigators, according to the perspective.
The FDA’s previous safety-reporting requirements did not clearly specify whether an adverse event was deemed reportable, according to the authors, and often resulted in IND sponsors submitting substantial numbers of adverse event reports that may not have had any relationship to the clinical trial.
“For example, an investigator might report a single case of Myocardial Infarction or stroke in a trial enrolling an elderly population,” the authors offered. “Under these circumstances, it is impossible to determine whether drug exposure is causally related to the event. Large numbers of such uninterpretable single case reports can distract clinical investigators, the FDA, and IRBs [institutional review boards] from recognizing genuine drug-safety problems.”
IND sponsors are still required to promptly report unexpected serious adverse events in clinical trials. If an event has a reasonable possibility of having been caused by a drug, it must be reported within 15 days, or within seven days if the event was fatal. However, the new rule provides guidance on causality, according to the perspective.
“Unlike a Myocardial Infarction in an elderly subject, a single occurrence of Stevens–Johnson Syndrome (SJS) would reach this threshold. Not only is SJS unexpected and serious, it is known to be strongly associated with drug exposure,” Sherman and colleagues wrote.
*Bloggers Note On SJS; From Incivek-telaprevir Warnings & Precautions
Serious Skin Reactions
Serious skin reactions, including Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome (SJS) were reported in less than 1 % of subjects
*(or three cases of SJS)
who received INCIVEK combination treatment compared to none who received peginterferon alfa and ribavirin alone. These serious skin reactions required hospitalization, and all patients recovered. The presenting signs of DRESS may include rash, fever, facial edema, and evidence of internal organ involvement (e.g., hepatitis, nephritis). Eosinophilia may or may not be present. The presenting signs of SJS may include fever, target lesions, and mucosal erosions or ulcerations (e.g., conjunctivae, lips).
Rash
Rash developed in 56% of subjects who received INCIVEK combination treatment [see ADVERSE REACTIONS]. Severe rash (e.g., a generalized rash or rash with vesicles or bullae or ulcerations other than SJS) was reported in 4% of subjects who received INCIVEK combination treatment compared to less than 1% who received peginterferon alfa and ribavirin alone. The severe rash may have a prominent eczematous component.
Patients with mild to moderate rashes should be followed for progression of rash or development of systemic symptoms. If rash progresses and becomes severe or if systemic symptoms develop, INCIVEK should be discontinued. Peginterferon alfa and ribavirin may be continued. If improvement is not observed within 7 days of INCIVEK discontinuation, sequential or simultaneous interruption or discontinuation of ribavirin and/or peginterferon alfa should be considered. If medically indicated, earlier interruption or discontinuation of ribavirin and peginterferon alfa should be considered. Patients should be monitored until the rash has resolved. INCIVEK must not be reduced or restarted if discontinued due to rash. Treatment of rash with oral antihistamines and/or topical corticosteroids may provide symptomatic relief but effectiveness of these measures has not been established. Treatment of rash with systemic corticosteroids is not recommended [see DRUG INTERACTIONS].
If a serious skin reaction occurs, all components of INCIVEK combination treatment must be discontinued immediately and the patient should be promptly referred for urgent medical care.
The authors opined that the new regulations put a certain amount of responsibility back into the hands of the IND sponsors, as opposed to clinical investigators that may not have access to an entire safety database. “Therefore, causality of adverse events is best evaluated in the aggregate by the sponsor.”
Clinical investigators were previously directed to make a judgment as to whether an event was drug-related. Now they are required to report all serious adverse events to the sponsors, who then make the call. Sponsors must now analyze the events that are not interpretable as single cases, and compare the drug-treatment group with the control group to determine if events were caused by the tested drug. The changes, the writers argue, ensure that the IND sponsors have a better understanding of the drug and will result in fewer reports of uninterpretable events.
“Ultimately, this new rule will increase the interpretability and usefulness of safety data available to the clinical investigators, IRBs and the FDA. These groups will receive fewer individual reports, and the reports should be more complete and meaningful. Thus, the rule will enhance patient protection, ensure regular and thorough evaluation of serious adverse events, and therefore generate better data to support clinical decision making,” Sherman et al concluded.
Click here to read the full perspective.
http://www.cardiovascularbusiness.com/index.php?option=com_articles&view=article&id=28572
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