title: Reporting of deaths during pre-approval clinical trials for advanced HIV-infected populations.
abstract: The Division of Antiviral Drug Products of the US FDA has regulatory authority over the investigational new drugs under development by various sponsors to treat HIV-infected populations. The FDA and the sponsors of investigational new drugs use the Code of Federal Regulations to guide the entire drug development process, in order to ensure that safe and efficacious drugs are brought to market. To achieve this goal, diligent monitoring for safety during the pre-approval phase of new drug development is particularly crucial. When deciding what adverse experiences on clinical trials should be expeditiously reported, the Division recommends a conservative interpretation of the Code of Federal Regulations, where an adverse experience in a clinical trial of advanced HIV-infected patients is considered to be 'associated with the use of the drug' when the relationship cannot be ruled out with objective evidence. Fatal adverse experiences for subjects on clinical trials should be especially scrutinised. Safety reporting should be expedited when death occurs during clinical trials of advanced HIV-infected populations. The three components of an expedited reportable death occurrence, namely 'serious', 'unexpected' and 'associated with the drug use' as they relate to advanced HIV-infected populations, are discussed in this article. An occurrence of death is by definition serious. Unexpected experiences are unlisted adverse experiences, but need to be put into the context of specificity and severity. 'Associated with the drug use' has been clarified as 'relationship to the drug cannot be ruled out'. Because death in the advanced HIV-infected/AIDS population is usually a complex event, the possible contribution of the study drug is difficult to rule out. Thus, if the three components of the reporting requirement are met or insufficient information is available to make a firm determination of causality by the seventh day of the reporting period, the Division of Antiviral Drug Products expects expedited death reports on subjects participating in investigational new drug clinical studies.
authors.affiliation: Division of Antiviral Drug Products, Center for Drug Evaluation and Research, The US Food and Drug Administration, Rockville, Maryland 20850, USA. johann.liangr@cder.fda.gov
authors.forename: Rosemary
authors.initials: R
authors.lastname: Johann-Liang
authors.forename: Andrea N
authors.initials: AN
authors.lastname: James
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Behr
authors.forename: Kimberly
authors.initials: K
authors.lastname: Struble
authors.forename: Debra B
authors.initials: DB
authors.lastname: Birnkrant
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000331:legislation & jurisprudence / Q000706:statistics & numerical data; D002986:Clinical Trials as Topic; D016903:Drug Monitoring / Q000379:methods; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000401:mortality*; D006801:Humans; D015996:Survival Rate; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D015507:Drugs, Investigational