Logistic planning and drug formularies : considerations for clinically effective drug substitution

Abstract

Drug substitution is mainly economically not medically-driven; it can benefit healthcare services but does not directly benefit individual patients. Many healthcare providers have been promoting drug substitution in an attempt to contain their costs. This practice has been approved and supported on the basis of the presumption that the cheaper drug is not inferior to the more expensive one and the premise that any saving that does not compromise the quality of care is essentially appropriate. However, substitutions become problematic when the cheaper drug is known to have different effects and side effects, or even when there is just uncertainty about such effects. This thesis explores issues surrounding generic and therapeutic substitution from the ethical, patients’ and physicians’ point of view and from the potential differences in formulations between the branded and generic medicines. A series of studies such as a review of the ethical issues in drug substitution, multicentre surveys to explore patients’ and physicians’ views on drug substitution and other in-vitro and in-vivo comparisons between the actual formulations of the branded medicines and their generic counterparts were included in this thesis. The main objective was to encourage safe and effective generic and therapeutic substitution by validating the appropriateness and the potential impact of these substitutions on patients’ clinical outcomes and thus to promote high quality strategic logistic planning and effective management of drug formularies in hospitals. It was confirmed in this thesis that promoting generic and therapeutic substitution on economic grounds alone is unethical because it can be potentially harmful to patients and is incompatible with patient-centred medicine. As a consequence, multicentre surveys were conducted to assess patients’ views on generic substitution in hospital settings. A total of 163 renal transplant patients were surveyed using 36 multiple-choice questions at Barts and The London Renal Transplant Clinic, in the UK. This group of patients was specified because they may be particularly affected by drug substitution. Any small changes in the medicinal effect of this group of patients can negatively impact their clinical outcome. It was revealed in this survey that 84% of participating patients felt that generic medicines were not equivalent or only equivalent sometimes and they were uncertain that generics had the same quality as branded medicines. In addition, many patients admitted that they would refuse the generic substitution of ciclosporin when it became available in the UK. Another multicentre survey in the United Arab Emirates (UAE) using 188 renal patients revealed that 68% of participating patients felt that generics were not equivalent or only equivalent sometimes, and they were uncertain that generics had the same quality as branded medicines. Therefore, many patients admitted that they would refuse the generic substitution of ciclosporin when become available. These beliefs were highly marked in patients with less education, less communication with healthcare professionals and who suspected that the cheaper drug substitution was implemented only to save costs. In another prescription based survey in the UAE, a random sampling of 1000 written prescriptions was analysed to determine physicians’ attitudes towards generic medicines and prescribing. It was explored in this study that prescribers were not yet ready to promote appropriate generic substitution. They were still prescribing generic medicines on occasions where health complications may occur as well as increase healthcare expenditure. As a result, improving awareness and education among physicians is compulsory to implement appropriate generic prescribing and substitution. In-vitro dissolution study was also conducted in this thesis to detect any potential differences in dissolution behaviour between the branded medicines and their generic counterparts. A total of 37 medicines (13 innovator medicines and 24 generic counterparts) were collected locally and internationally and tested according to the British Pharmacopeia, European Pharmacopeia and the US Pharmacopeia with the rate of dissolution determined by ultra-violet Spectrophotometer. It was marked in this study that some generic medicines showed significant differences in dissolution rate at 60 and 120 minutes compared to their branded counterparts. Other generics violated the EMA and the FDA guidelines for industry when they failed to achieve 85% dissolution at 60 minutes and to keep the same dosage form as their branded counterparts. Moreover, a bioequivalence study was carried out in this thesis using 24 healthy volunteers under fasting conditions to compare Resclar 500 mg (Neopharma, UAE) with its branded Klacid® 500 mg (Abbott Laboratories Ltd, England), both are macrolide antibiotics contain 500 mg clarithromycin per tablet. It was confirmed in this study that Resclar 500 mg met the regulatory definition of bioequivalence with Klacid® 500 mg as the innovator product based on a single dose comparative bioavailability study under fasting conditions in the selected healthy volunteers. Therefore, Resclar 500 mg could provide an acceptable prescribable alternative to Klacic® 500 mg. In conclusion, the results presented in this thesis suggested that randomly and economically-driven drug substitution can be potentially deleterious to patients and should not be promoted. Factors such as physicians and patients education, monitoring, severity of the disease and efficacy of generic medicines are essential to promote safe and effective drug substitution. Thus, to achieve excellent strategic logistic planning and effective management of drug formularies in hospitals, generic and therapeutic substitution should be solely based on providing patients with the best possible care and quality medicines.