Quality assurance of drugs used in clinical trials: proposal for adapting guidelines

Abstract

Paul Newton and colleagues propose that clinical trial guidelines should include a requirement to assess and state the quality of the drugs and other medical products used 3 4 But they have not been updated since the 1990s so they do not include adequate consideration of the current challenges of the international drug market, where globalised production and insufficient regulatory overview have resulted in variable drug quality. There are many different types of poor quality drugs that could mistakenly be included in clinical trials, including those with no, too little, or too much active pharmaceutical ingredient, those with the wrong active pharmaceutical ingredient, those with inadequate bioavailability, and those that degrade with toxic products or contaminants.1 2 6 7 We argue that clinical trial guidelines (CONSORT, SPIRIT, STARD, and TIDieR) should include statements on the checking and reporting of the quality of drugs and medical products used in clinical research. The WHO and ICH guidelines should also be updated to include such recommendations. Scope of problemWe are aware of several examples of clinical trials that have been conducted or planned using drugs that did not contain what they were stated to contain. Idindili and colleagues conducted a double blind, randomised, two arm study comparing the safety and efficacy of low dose versus high dose vitamin A supplementation in young Tanzanian infants. 8 The vitamin A capsules used were manufactured by companies in Canada and Italy. Samples were checked "regularly" during the trial for vitamin A content. Within 13 months of the trial starting the 50 000 IU capsules had degraded to 32% of the expected amount of vitamin A, despite being stored under appropriate conditions. The analyses were adjusted for this major confounder, and the authors emphasised the need for quality assurance checks of such capsules in clinical trials and routine supplementation programmes.In 2011 a study of the antimalarial drug sulfadoxine-pyrimethamine in pregnant women in six countries in Africa was planned using four locally available brands. These were tested at the US Centers for Disease Control and Prevention, and the sulfadoxine content of one of the brands was found to be below 90% of the manufacturer's stated amount. An emergency request to procure a good quality brand was made and the study proceeded with confidence (F ter Kuile, personal communication, 2015 10-13 Thus, clinical trials using different brands or batches of the same drug may give different results, which makes interpretation difficult and can dilute the power of meta-analyses that underlie many policy recommendations. Sowunmi and colleagues compared the bioavailability of three brands of oral quinine commonly available in Nigeria in a formal, randomised, crossover study in healthy adults.14 Alarmingly they found that one of the brands contained no detectable quinine. This product could well have been used in a clinical trial of the efficacy of quinine as an antimalarial drug in Nigeria.The problem is n...

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