In the United States, the United Kingdom and Australia, more than 80% of prescriptions filled are for generic medicines. According to Mediscor research, the use of generics in South Africa increased to 56.3% between 2012 and 2017. We spoke to three experts about common misconceptions about generics.
According to Dr Jacques Snyman, CEO of Medical Specialist Holdings, and a clinical pharmacologist, prescriber ignorance about the efficacy and safety of generics, and aggressive marketing by some pharmaceutical companies are two of the major stumbling blocks to increased generic use in the country.
All generic medication registered in South Africa is deemed to be interchangeable with the brand-name originals. This is the basis of registration, stressed Andy Gray, senior lecturer in the Department of Pharmacology at the University of KwaZulu-Natal. Dr Snyman agreed, saying that the quality and efficacy of generics is above reproach.
Generic’s bioavalability (concentration in blood) usually vary less than 3% from that of the originator brand and may often err on the upside rather than the down side of the bioequivalence curve (time concentration curve during testing). Having said this, all generics need to demonstrate noninferiority regarding basic pharmaceutical principles.
All generics have to show the same bioequivalence, safety, efficacy and quality as their brand-name counterparts, said Dr Snyman. Stringent measures are in place to ensure that generics meet these requirements. Similar to brand-name products, generic manufacturing plants are regularly inspected by the appropriate authorities such as the European Medicine Agency and the American Food and Drug Agency.
Locally, generics have to be approved by the South African Health Products Regulatory Authority (SAHPRA). Similar to brand-name products, small therapeutic index variables are allowed (1%) in various generic batches. Batches that do not meet the variability criteria are destroyed, explained Dr Snyman.
South Africa represents 1% of the world medicine market. No company would take the risk of manufacturing and distributing inferior products, he pointed out. “If you prescribe a generic for eg hypertension and find that the patient’s condition does not improve, this might be a side-effect, rather than inferior efficacy,” he added. Clinicians are obligated to report such instances to SAHPRA for further investigation.
Dr André Marais, a senior lecturer and clinical pharmacologist at the University of Pretoria, agreed that most prescribers are of the opinion that generics are inferior to their brand-name counterparts. This is a myth, he said, adding that it is prescriber’s personal preference to prescribe brand-name products rather than a generic.
Approximately 95% of brand-name products have a generic counterpart. Generics cost between 20% and 90% less than brand-name products. Healthcare professionals should not be asking whether or not to prescribe generics, but rather what is in the best interest of the patient, said Dr Snyman.
The World Health Organization (WHO) estimates that about 30% of the world’s population lacks regular access to essential medicines, and the figure increases to 50% in the poorest countries of Africa and Asia. One of the most important barriers to access to medicine is their high cost, said the WHO.
WHAT DOES THE LAW SAY ABOUT GENERICS?
South Africa is the only country in the world that includes regulations regarding generic substitution in its medicine act. Other countries’ recommendations regarding generic substitution is taken up in guidelines, said Dr Snyman.
Section 22F of the South African Medicines and Related Substances Act (1965), states that generic substitution is allowed, unless expressly forbidden by the patient to do so.
According to Gray, there are a number of other circumstances where substitution is also allowed. These are:
Pharmacists are also ethically bound by the rules of Good Pharmacy Practice to offer patient’s a generic substitution, based on sound judgement and professional expertise to ensure the maximum safety and efficacy of the prescribed treatment.
In South Africa, consumers’ right to choose is protected under the Consumer Protection Act (CPA). According to Chapter 2 of the CPA, consumers have the right to: ‘Equality in marketing, to privacy, to choose, disclosure and information, fair and responsible marketing, fair and honest dealings, fair and just terms and conditions, value, quality and safety and supplier’s accountability’. Therefore, a patient who presents a prescription at a pharmacy, have the right to request generic substitution.
There seems to be uncertainty about Schedule 6 generic substitution among healthcare professionals. But according to Dr Snyman, the South African Medicines and Related Substances Act allows for Schedule 6 substitution. The uncertainty might be related to the fact that the Act expresses concern about the risk of misuse, he added.
WHAT SCIENCE SAYS ABOUT THE EFFICACY AND SAFETY OF GENERICS
According to the FDA, it is important to note that generics and brand-name products have the same active ingredients as well as proven safety, efficacy, strength, quality and benefit profiles. The only difference is that they may look somewhat different in terms of size, shape, and colour, which do not impact how generics work.
The World Medical Association’s viewpoint is that if generic products are available on the market, practitioners should ensure that quality assurance procedures are in place to confirm their lot-to-lot bioequivalence and their chemical and therapeutic equivalence.
The British National Institute for Health and Care Excellence, states that generic prescribing allows for any suitable drug, rather than a particular brand of drug, to be dispensed. This can lead to cost savings because cheaper alternatives can be prescribed.
According to Gray, comparison studies between brand-name and generic medication are unnecessary, and potentially unethical. In addition, to detect the very small differences that could be present, they would need to be enormous in order to be sufficiently powered. The science is clear – what is needed in most cases is bioequivalence data not clinical comparisons. In some cases, biowaivers are warranted and in vitro data can be relied upon. In others – especially with intravenous injections – only an assurance that the APIs and excipients are the same is needed. In a few circumstances, in vivo data other than bioequivalence are needed, such as skin blanching studies with topical steroids.”
It is generally agreed that a bioequivalence study is the most appropriate approach for demonstrating therapeutic equivalence between two drug products. However, said Gray, this only applies to products that have an absorption phase for example when administered orally or intramuscularly. In addition, he added, for some products, which are highly soluble and rapidly absorbed, the most appropriate is an in vitro dissolution study.
In a review incorporating 12 years of data, the American Food and Drug Administration report (Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration, 2009) evaluated how well the bioequivalence measures of generic drugs compare with those of their corresponding brand-name counterparts.
Bioequivalence measures evaluated were drug peak plasma concentration (Cmax) and area under the plasma drug concentration versus time curve (AUC), representing drug rate and extent of absorption, respectively.
The generic/innovator Cmax and AUC geometric mean ratios (GMRs) were determined from each of the bioequivalence studies, which used from 12 to 170 subjects. The GMRs from the 2 070 included studies were then averaged. In addition, the distribution of differences between generic means and innovator means was determined for both C(max) and AUC.
They found that the mean +/- significant difference of the GMRs from the studies was 1.00 +/- 0.06 for C(max) and 1.00 +/- 0.04 for AUC. The average difference in Cmax and AUC between generic and innovator products was 4.35% and 3.56%, respectively.
In addition, in nearly 98% of the bioequivalence studies conducted during this period, the generic product AUC differed from that of the brand-name product by less than 10%.
They concluded that generic and brand-name medications produce similar clinical outcomes. Nonetheless, differences in shape, colour, taste, and name can lead to patient, and sometimes to clinician confusion.
Over the past decade, a number of studies have confirmed the efficacy of generic drugs when compared to brand-name drugs – most notably in cardiovascular disease (CVD).
Kesselheim et al. summarised clinical evidence comparing generic and brand-name drugs used in CVD and to assess the perspectives of editorialists on this issue. Studies comparing generic and brand-name CV drugs using clinical efficacy and safety endpoints were included.
Clinical equivalence was noted in all seven randomised clinical trials (RCTs) of beta-blockers, 10 of 11 RCTs (91%) of diuretics, five of seven RCTs (71%) of calcium channel blockers, all three RCTs of antiplatelet agents, both RCTs of statins, one RCT of angiotensin-converting enzyme inhibitors, and one RCT of alpha-blockers.
Among so-called ‘narrow therapeutic index drugs’, clinical equivalence was reported in one of one RCT of class 1 antiarrhythmic agents and in all five RCTs of warfarin. Aggregate effect size (n = 837) was -0.03, indicating no evidence of superiority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a negative view of generic drug substitution.
The researchers concluded that evidence does not support the notion that brand-name drugs used in CVD are superior to generic drugs, but that a substantial number of editorials counsel against the interchangeability of generic drugs. They did not explore the reasons why.
In their 7 863 propensity‐matched pairs (15 726 patients) study, Jackevicius et al., found that 17.7% of those prescribed generic atorvastatin and 17.7% of those prescribed Lipitor experienced death or recurrent acute coronary syndrome (ACS).
Among older adults discharged alive after ACS hospitalisation, the researchers found no significant difference in cardiovascular outcomes or serious, infrequent side-effects in patient’s prescribed generic atorvastatin compared with those prescribed Lipitor (the branded product) at one year.
They concluded that their findings support the use of generic atorvastatin in ACS, which could lead to substantial cost savings for patients and healthcare plans without diminishing population clinical effectiveness.
According to Gagne et al, the aim of their observational cohort study was to determine whether patients are more adherent to generic statins versus brand-name statins (lovastatin, pravastatin, or simvastatin) and whether greater adherence improves health outcomes.
A total of 90 111 patients who initiated a statin during the study was identified of which 83 731 (93%) initiated a generic drug, and 6 380 (7%) initiated a brand-name drug. The mean age of patients was 75.6 years, and most (61%) were female.
The average proportion of days covered was 77% for patients in the generic group and 71% for those in the brand-name group (P<0.001). An 8% reduction in the rate of the clinical outcome was observed among patients in the generic group versus those in the brand-name group.
They concluded that compared with those initiating brand-name statins, patients initiating generic statins were more likely to adhere and had a lower rate of a composite clinical outcome.
Corrao et al also compared patients treated with generic and brand-name statins in terms of therapeutic interruption and CV outcomes. More than 13 700 participants, treated with generics or brand-name simvastatin were part in the study. Endpoints were therapeutic discontinuation and hospitalisation for CV events.
They found that patients who started on a generic did not experience a different risk of discontinuation nor of CV outcomes from those starting on a brand-name drug. Patients who spent >75% of the time of follow-up with a statin available on generics did not experience a different risk of discontinuation, nor of CV outcomes compared with those who mainly or only used brand-name statin. They concluded that generics are not inferior to brand-name statins.
HEALTHCARE PROVIDER AND PATIENT PERSPECTIVES OF GENERICS
An American study by Shrank et al, published in 2009, showed that only 36.7% of respondents indicated that they would switch to a generic. They also found that 70% agreed that generics are better value for money than brand-name drug and only a few patients reported concerns about safety or side-effects and efficacy. The reasons why so few people were willing to switch to a generic are unclear.
The outcomes of their follow-up study might shed some light on this. In this study Shrank et al explored physician perceptions about generic drugs. They found that 23% and 50% of physicians respectively had negative perceptions about the efficacy of generic drugs and the quality. More than 25% indicated that they do not prefer to use generics as first-line medications for themselves or for their families.
In addition, the researchers found that physicians over the age of 55 years were 3.3 times more likely to report negative perceptions about generic quality, 5.8 times more likely to report that they would not use generics themselves, and 7.5 times more likely to state that they would not recommend generics for family members. Physicians reported that pharmaceutical company representatives are the most common (75%) source of information about market entry of a generic drug.
Desai et al explored whether or not changes in the physical appearance of a drug product, including its shape, colour, and size, might influence negative perceptions about switching from a brand-name drug to a generic.
Among patients switched from brand-name to generic drugs, the rates of switching back to brand-name drug products are reported to be in the range of 12% to 65% for many drug classes including antiepileptics, antipsychotics and beta-blockers.
The researchers analysed data from a large American commercial health insurance database (2004-2013). They screened 22 drug products that had marketed authorised generics. The following eight products were included in their study: alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets.
The researchers found that:
- Eight out of every 100 patients taking brand-name drug products who switched to a generic, switched back to the brand-name drug product within a year
- Patients who switched to generic drug products, which have the same active ingredients, appearance, and excipients, had lower rates of switchbacks compared with patients who switched to generic drug products, which may have a different appearance and excipients compared with the branded drug product.
They concluded that changes in drug product appearance, which may induce the nocebo effect, drive patients’ negative perceptions about the treatment efficacy or tolerability of generics.
The experts agreed that gaps in healthcare providers and patients’ knowledge about the safety, efficacy and quality of generics should be addressed.