Determination of the underlying cause of death in three multicenter international HIV clinical trials

TY - JOUR

T1 - Determination of the underlying cause of death in three multicenter international HIV clinical trials

AU - Lifson, Alan R

AU - INSIGHT Cause of Death Writing Group

AU - Lundgren, Jens

AU - Belloso, Waldo H

AU - Carey, Cate

AU - Davey, Richard T

AU - Duprez, Daniel

AU - El-Sadr, Wafaa M

AU - Gatell, Jose M

AU - Gey, Daniela C

AU - Hoy, Jennifer F

AU - Krum, Eric A

AU - Nelson, Ray

AU - Nixon, Daniel E

AU - Paton, Nick

AU - Pedersen, Court

AU - Perez, George

AU - Price, Richard W

AU - Prineas, Ronald J

AU - Rhame, Frank S

AU - Sampson, James

AU - Worley, John

N1 - Keywords: Adult; Anti-HIV Agents; Anti-Retroviral Agents; Cause of Death; Clinical Trials as Topic; Female; HIV Infections; Humans; International Cooperation; Male; Middle Aged; Multicenter Studies as Topic

PY - 2008

Y1 - 2008

N2 - PURPOSE: Describe processes and challenges for an Endpoint Review Committee (ERC) in determining and adjudicating underlying causes of death in HIV clinical trials. METHOD: Three randomized HIV trials (two evaluating interleukin-2 and one treatment interruption) enrolled 11,593 persons from 36 countries during 1999-2008. Three ERC members independently reviewed each death report and supporting source documentation to assign underlying cause of death; differences of opinion were adjudicated. RESULTS: Of 453 deaths reported through January 14, 2008, underlying causes were as follows: 10% AIDS-defining diseases, 21% non-AIDS malignancies, 9% cardiac diseases, 9% liver disease, 8% non-AIDS-defining infections, 5% suicides, 5% other traumatic events/accidents, 4% drug overdoses/acute intoxications, 11% other causes, and 18% unknown. Major reasons for unknown classification were inadequate clinical information or supporting documentation to determine cause of death. Half (51%) of deaths reviewed by the ERC required follow-up adjudication; consensus was eventually always reached. CONCLUSION: ERCs can successfully provide blinded, independent, and systematic determinations of underlying cause of death in HIV clinical trials. Committees should include those familiar with AIDS and non-AIDS-defining diseases and have processes for adjudicating differences of opinion. Training for local investigators and procedure manuals should emphasize obtaining maximum possible documentation and follow-up information on all trial deaths.

AB - PURPOSE: Describe processes and challenges for an Endpoint Review Committee (ERC) in determining and adjudicating underlying causes of death in HIV clinical trials. METHOD: Three randomized HIV trials (two evaluating interleukin-2 and one treatment interruption) enrolled 11,593 persons from 36 countries during 1999-2008. Three ERC members independently reviewed each death report and supporting source documentation to assign underlying cause of death; differences of opinion were adjudicated. RESULTS: Of 453 deaths reported through January 14, 2008, underlying causes were as follows: 10% AIDS-defining diseases, 21% non-AIDS malignancies, 9% cardiac diseases, 9% liver disease, 8% non-AIDS-defining infections, 5% suicides, 5% other traumatic events/accidents, 4% drug overdoses/acute intoxications, 11% other causes, and 18% unknown. Major reasons for unknown classification were inadequate clinical information or supporting documentation to determine cause of death. Half (51%) of deaths reviewed by the ERC required follow-up adjudication; consensus was eventually always reached. CONCLUSION: ERCs can successfully provide blinded, independent, and systematic determinations of underlying cause of death in HIV clinical trials. Committees should include those familiar with AIDS and non-AIDS-defining diseases and have processes for adjudicating differences of opinion. Training for local investigators and procedure manuals should emphasize obtaining maximum possible documentation and follow-up information on all trial deaths.

U2 - 10.1310/hct0903-177

DO - 10.1310/hct0903-177

M3 - Journal article

C2 - 18547904

SN - 1528-4336

VL - 9

SP - 177

EP - 185

JO - HIV Clinical Trials

JF - HIV Clinical Trials

IS - 3

ER -