Substandard anticancer medications in clinical care settings and private pharmacies in sub-Saharan Africa: a systematic pharmaceutical investigation.

BACKGROUND: The quality of anticancer drugs is crucial for good patient outcomes, but quality surveillance in low-income and middle-income countries (LMICs) has been deterred by the high toxicity of the drugs. Despite worrisome reports about substandard or falsified products, no systematic studies of anticancer drug quality across multiple LMICs have been reported. METHODS: Between April 6, 2023, and Feb 12, 2024, cisplatin, oxaliplatin, methotrexate, doxorubicin, cyclophosphamide, ifosfamide, and leucovorin dosage forms were collected both covertly and overtly from 12 hospitals and 25 private or community pharmacies in Ethiopia, Kenya, Malawi, and Cameroon, with the goal of obtaining ten different brands and lot numbers of each type of active pharmaceutical ingredient (API). Each product was visually inspected. The percentage of active pharmaceutical ingredient relative to the stated API content was assayed with high-performance liquid chromatography (HPLC). Assay values were compared with US Pharmacopoeia acceptance criteria for different APIs and dosage forms. Samples with assay values that failed to meet the appropriate acceptance criteria were categorised as having failed HPLC assay, samples with assay values that fell within the allowed acceptance criteria were categorised as having passed HPLC assay, and samples with assay values that fell within the 2% margin of error of the acceptance criteria were categorised as inconclusive. Critical failure rates were calculated with 95% CIs and significance testing was done for differences between failure rates. For the comparison of visual inspection with HPLC results, sensitivity was calculated as the number of lots that failed both HPLC assay and visual inspection divided by the total number of lots that failed HPLC assay. Specificity was calculated as the number of lots that passed both HPLC assay and visual inspection divided by the total number of lots that passed HPLC assay. FINDINGS: 251 samples of chemotherapy drugs (dosage forms) were collected between April 6, 2023, and Feb 12, 2024, and 191 unique brands and lot numbers were obtained. Products from eight of 191 (4%) unique lot numbers (collected in countries coded as W, X, and Y) failed visual inspection. Active pharmaceutical ingredient contents ranged from 28% to 120% of stated contents, and failure rates ranged from 14% to 24% across the different countries; these rates were not significantly different at the 95% CI. Nearly a quarter of the products (59 [24%] of 251) had expired before analysis, some by nearly a year, but the expired products did not fail HPLC assay at a higher rate than the non-expired products. Ten of the 59 post-expiry products failed assay (ie, a 17% failure rate), whereas 38 of the 189 pre-expiry samples failed assay (ie, a 20% failure rate); these rates were not different at the 95% CI. Failing products were found in all four countries and in both major hospitals and private pharmacies (with no difference in failure rates at the 95% CI). The sensitivity of visual inspection for the detection of products failing HPLC assay was 9% (three of 32 lots) and the specificity was 97% (155 of 159 lots). The sensitivity of visual inspection is low because many quality defects, such as a shortage of an uncoloured active pharmaceutical ingredient, are not visually apparent. INTERPRETATION: Oncology practitioners and health systems in sub-Saharan Africa need to be aware of the possible presence of substandard anticancer products when designing care protocols and evaluating patient outcomes, and regulatory system strengthening is needed to provide better surveillance of this crucial class of medicines. FUNDING: US National Cancer Institute of the National Institutes of Health.