Compliance Analysis as Additional Evidence for Efficacy in Clinical Trials: Perspectives of the Swedish Medical Products
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Compliance Analysis as Additional Evidence for Efficacy in Clinical Trials: Perspectives of the Swedish Medical Products Agency
Karin Hrdrnmolm, MD, PhD Clinical Assessor, Clinical Trial Unit, Medical Products Agency, Uppsala, Sweden; Department of Clinical Pharmacology, Uppsala University, Uppsala, Sweden
Ginior Alvon, MD Professor, formerly General Director, Medical Products Agency. Uppsala. Sweden
Kay Words Adherence; Compliance; Clinical trials: Learning versus confirming; Phase 3
Corrrspondrncr Address Karin Hedenmalm. Medical Products Agency. Box 26, 751 03 Uppsala. Sweden (email: Karin. [email protected]). Presented at DIA Workshop. Improving Drug Development Using Patient Adherence Data in Clinical Trials, May 6-7.2008. University of California, Washington Center, Washington, DC.
Dejicient adhmce to trial protocols induding dosing errors in6vduccs uncertainty about the reZiabiZity of dinical trial d t s . Tdtional ways of meuswing compliance have been chdlenged since studies using efectronicmonitoring to mgister opening of medication containers have mded that patient rcpoptingand residual tabZet countingtend to Oyemtimatecompliance with dosing mgimens. Applicationto the Medical products Agency for approval of all clinical trials pcrfonned in Sweden on medicines invdving human subjects has been obligatorysince 1984. The number of applications has ranged from 394 to 675 peryear.Among over I ,OOO clinical trial applications between May 2004 and February 2008, compliance or adherence was mentioned in the study objectives of onZy two applications. Clinical trial applications that combine adherence infmation with dinical outcome are
STUDIES O F COMPLIANCE Compliance is understood as the degree of correspondence between instructions given to the patient, especially regarding the dosing schedule, and actual patient performance. Among the earlier studies that had the purpose of capturing objective information related to patient compliance through electronic means, Norell investigated three-times-daily administration of pilocarpine eye drops in Swedish patients with glaucoma (1,2). A monitor recorded the date and hour each time the medication bottle was opened. Examples of such monitoring in two patients over a period of 20 days are presented in Figure 1 (3).It was noted that patients tended to miss the noon dose more often compared with the morning or evening doses (1). Furthermore, a decrease in compliance during a 20-day peri-
still m in Sweden. Phase 3 dinical trials are designedto pravide sufficient evidenceof efficacy to slcpport marketing authorization. Patients are typicuUy anaiyzed according to ass@ed groocp (intention to treat principle) mther than according to a d d treatment received in order to ensure that an identified treatment effect is due to the tmtment itself and not a d t of ptmndomization bias. Taln'ng account of complianceinfnqmation is thaeforc mainly considered as support*veevidenceexceptfor noninfm'm*iydinical trials. Hawever, dcctronic capiuring of compZiance infmation in clinical
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