The central government’s thrust on prescribing generic drugs to provide affordable health care to patients, although laudable, continues to be a major concern for physicians. Clinicians hesitate to prescribe generics as they are not convinced about their effectiveness. In contrast to innovator drugs – original drugs discovered by a company – robust clinical trial evidence is not required by health authorities (HA) for approving generic drugs. Comparative
data on in-vitro dissolution studies and bioequivalence (BE) studies are considered adequate for getting marketing approval for a generic drug.
For formulations composed of highly soluble substances and excipients known not to affect dissolution, stability and absorption processes, similarities in in-vitro dissolution profiles of innovator drugs and generics suggest that the generic drug is unlikely to have any bioavailability problems. However, for generic drugs with low solubility, BE studies are a must.
In BE studies, innovator drugs and generic products are considered bioequivalent if their bio-availabilities – the rate and the extent of absorption – after administration in the same molar dose lie within acceptable predefined limits. HAs consider the products to be bioequivalent if pharmacokinetic parameters — mean maximum concentration (Cmax), time to reach maximum concentration (Tmax ), and the area under concentration-time curve (AUC) — for the generic product falls within 80%–125% of the innovator product.
As BE studies are conducted in healthy adult volunteers, the data generated are not reflective of any variations in drug response seen in patients due to disease, gender and age, and the innovator and generic product can’t be considered therapeutic equivalent in case of variations. Generic substitution may be accompanied by a risk of therapeutic failure or an increase in the incidence of adverse events for a) critical drugs with a narrow therapeutic index or a long half-life, e.g. carbamazepine, theophylline and warfarin; b) critical patients, e.g. paediatric, elderly and those suffering from multiple diseases, and c) critical diseases, e.g. epilepsy, bronchial asthma, congestive heart failure, renal transplant and severe infections. Whenever a patient fails to show a clinical response or develops an adverse outcome, the physician should consider bioavailability problems of the prescribed drug and consider using a good quality brand.
The effectiveness of a generic drug can be assessed only in clinical study settings. For products of local use, e.g. oral, inhalation and dermal, which are intended to act without systemic absorption, therapeutic equivalence clinical trials are necessary. This approach could also help establish efficacy of orally absorbed generics. However, such trials would be expensive and time-consuming. Newer real-world studies, e.g. registry or retrospective analysis of routinely collected clinical practice data, would be useful alternatives to judge the effectiveness of a drug in clinical practice.
Recently, Desai et al (PLOS Medicine Mar 2019) analysed data of more than 3.5 million patients from 2 large US commercial insurance databases and showed that the use of generics provided clinical outcomes comparable to those of the brand-name products for diabetes, hypertension, osteoporosis, depression and anxiety.
Ayushman Bharat provides the government with an opportunity for evaluating the effectiveness of generics in the Indian population. Such robust real-world evidence would also boost physician confidence in prescribing generics.
Writer is a consultant on clinical research & development from Mumbai.