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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 40-46

Quantitative analysis, cost comparison, physician, and patient perceptions on generic versus branded clopidogrel bisulfate tablets marketed in Kerala, India


Department of Cardiology, Pushpagiri Medical College Hospital, Thiruvalla, Kerala, India

Date of Submission24-Dec-2019
Date of Decision21-Feb-2020
Date of Acceptance03-Mar-2020
Date of Web Publication17-Apr-2020

Correspondence Address:
Varghese George
Department of Cardiology, Pushpagiri Institute of Medical Sciences and Research Center, Thiruvalla, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_82_19

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  Abstract 


Background: Clopidogrel bisulfate is sold in more than 60 advertised brand names (trade names) in the Indian market. Government health sector in India emphasizes on prescribing clopidogrel in its generic form, which refers to the chemical makeup of the drug, rather than to the advertised brand name, to reduce the economic burden. Preference for branded drugs and cost difference with generics are already well established, however physicians are apprehensive regarding the quality of generic drugs and have concerns about their reliability. Objective: We studied perspective of physicians and patients regarding generic versus branded medicines among hospitals in our locality. Cost difference incurred while prescribing various brands and generic clopidogrel tablets were calculated. Percentage purity of generic and branded clopidogrel tablets were analyzed to find if any difference really exists between them. Methodology: Perspective of 150 physicians and patients were studied using questionnaire method. Using ultraviolet spectrophotometer, generic and most commonly prescribed brands of clopidogrel were analyzed for percentage purity. Once analyzed, their costs were compared. Results: Eighty- six percent (n = 129) of physicians and 81% (n = 122) of patients surveyed, preferred branded medicines over generic ones. Among 10 branded clopidogrel tablets, only three complied with the Indian Pharmacopoeia standards of drug percentage purity. Pricing pattern of various brands of clopidogrel ranged from $1.4 to $3.13 per month. Generic clopidogrel tablets are available free of cost for patients from government-run hospitals but did not meet recommended percentage purity standards. Conclusion: Both branded and generic versions of clopidogrel have their merits and demerits. The general notion and doubt regarding difference in quality of generic versus branded version of medicines as evidenced by our perspective evaluation of physician and patients is appropriate in the present scenario. More large scale studies of different cardiovascular drugs are required to ensure their quality. Improved quality of generic medicines has to be ensured prior to marketing in India.

Keywords: Branded, clopidogrel, cost comparison, generic, percentage purity, perception


How to cite this article:
George V, Mullavelil K, Joseph AT, Koshy C, Venugopal KN. Quantitative analysis, cost comparison, physician, and patient perceptions on generic versus branded clopidogrel bisulfate tablets marketed in Kerala, India. J Pract Cardiovasc Sci 2020;6:40-6

How to cite this URL:
George V, Mullavelil K, Joseph AT, Koshy C, Venugopal KN. Quantitative analysis, cost comparison, physician, and patient perceptions on generic versus branded clopidogrel bisulfate tablets marketed in Kerala, India. J Pract Cardiovasc Sci [serial online] 2020 [cited 2020 May 26];6:40-6. Available from: http://www.j-pcs.org/text.asp?2020/6/1/40/282819




  Introduction Top


Medical fraternity and society akin have growing concern regarding prescription of costly branded drugs. Recently, there has been a lot of media propaganda about the much-rumored pharmaceutical nexus involved in the marketing of low-quality medicines with high profit margin. In a developing country like India, the importance of prescribing generics has been stressed, primarily to reduce the economic burden on the patient as well as the state.[1] Generic drugs are “drugs that are usually intended to be interchangeable with an innovator product that is manufactured without a license from the innovator company and marketed after the expiry date of the patent or other exclusive rights.”[2],[3] Generic version of the drugs can be launched by other manufacturers, once the patent drug period expires. They are advantageous economically to patients in both developed and developing countries, and improves health sector by drastically reducing healthcare expenditure by virtue of their substantially lower price than the innovator brands.[4],[5] Promoting generic medicines have provided an opportunity for policymakers to make effective and economically efficient use of these medicines.[6] However, physicians and patients are apprehensive regarding the quality of generic drugs.[7],[8] and have concerns about their reliability as well as interchange of certain drug categories.[9],[10] Although the generic medicines are bio-equivalents of their innovator counterparts and are produced in similar facilities according to good manufacturing practices,[11] these are widely believed as inferior in their therapeutic efficacy and quality to branded products.[12],[13] Manufacturers of branded medicines could also have propagated this belief.[14]

Branded medicines in India are manufactured by multinational companies in their larger factories with more sophisticated equipment, which they advertise and try to push through physicians. In addition to the innovator product, Indian market can have the same molecule marketed under several brand (trade) names for which they have to obtain a license during the patent period. Generics on the other hand are manufactured by smaller units with good manufacturing practices and are not advertised to be sold.[15]

Clopidogrel bisulfate belongs to the class of P2Y12 Adenosine Di Phosphate receptor inhibitor.[16] Dual antiplatelet therapy with clopidogrel and aspirin is vital in the treatment of patients with coronary artery disease (CAD).[17],[18],[19] Even with newer P2Y12 inhibitors, clopidogrel continues to be the most popular drug in the antiplatelet regimen, of patients undergoing percutaneous transluminal coronary angioplasty and stenting.[20] The wide acceptability of clopidogrel among physicians is mostly because of its easy availability at low cost. In this era, when interventional cardiology and neurology have reached an unprecedented level of sophistication, role of clopidogrel in addition to aspirin has been accepted by all international societies as their Class I guideline-directed medical therapy in CAD and cerebrovascular accident (CVA) patients.

Clopidogrel is a prodrug and without direct antiplatelet activity of its own. It has variable absorption with approximately 50% bioavailability when taken orally.[21] Majority of clopidogrel thus absorbed, i.e., around 85%, is extensively hydrolyzed by esterase to its inactive metabolite[22] In the liver, clopidogrel is metabolized in a two-step process by CYP3A4/3A5 to a very short-lived active metabolite which is responsible for its effect on platelet aggregation.[23] This metabolism of clopidogrel has significant interpatient variability,[24] and suggests a genetic basis for the much discussed topic of clopidogrel resistance.[25]

Inadequate serum clopidogrel concentration may complicate coronary procedures with stent thrombosis and recurrent ischemia. In addition, about 4%–30% of patients treated with conventional dose of clopidogrel fail to show an adequate antiplatelet response, making the situation even more complex.[26] Higher quantities of drug can result in more bleeding events, especially in elderly and frail patients. Hence, it becomes extremely crucial to ensure that patients receive precise dose of the drug.

It is surprising to find that more than 60 brands of the drug clopidogrel are available in the Indian market at different costs. The brand that a patient takes will depend on factors such as physician preference, patient preference, and of course, pharmacist preference. Facts about the metabolism of the drug and its active molecule being short-lived emphasize the magnitude of importance of ensuring high quality of these brands to prevent a major cardiac and neurological event among patients with CAD and CVA. Brands need to be compared on therapeutic efficacy,[27] cost-effectiveness, compliance with label claim before being prescribed. There is a lot of confusion prevailing among physicians and patients regarding generic and branded drugs.

This dilemma prompted us to find a scientific basis to these apprehensions of physician and patient population regarding the quality of branded and generic drugs by estimating the percentage purity and comparing the cost of commonly prescribed commercial clopidogrel brands and generic ones.

The aim was to determine and compare the percentage purity of standard generic and branded clopidogrel tablets marketed in India to estimate the cost difference when prescribing generic versus branded drug and to understand the perspective of patients and physicians regarding generic versus branded medicines.


  Methodology Top


The perceptions of physicians[28],[29] and cohort of population[30],[31] on the use of generic and branded medications were sought using a written questionnaire. The domains of the questionnaire to physicians were regarding efficacy, safety, percentage purity, confidence in prescribing, and their opinion regarding patient satisfaction in prescribing generic drugs. Questionnaire to patients were concerning the efficacy, percentage purity, preference, and perceived safety. To have a better understanding about the physician and patient perspective on generic versus branded drugs, we began by doing a survey based on two different questionnaires for physicians and patients separately. One hundred and fifty patients were randomly selected from the cardiology, neurology, and general medicine outpatient departments and were asked to answer a printed questionnaire containing four questions. Similarly, 150 physicians in our locality were asked to fill a questionnaire having five questions [Table 1] and [Table 2].
Table 1: Physician Perspective on Generic and Branded Medicines Questionnaire

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Table 2: Patient Perspective on Generic and Branded Medicines Questionnaire

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To analyze the percentage purity, generic clopidogrel bisulfate, and commonly prescribed brands of the same available in Kerala were randomly selected, and codenamed as brands A– K from two batches and quantitatively analyzed, using ultraviolet (UV) spectrophotometer as high-performance liquid chromatography (HPLC) Literature survey revealed several spectrophotometric[32],[33],[34] and few HPLC methods for estimation of clopidogrel bisulfate. Hence, we selected UV spectrophotometry method because of its availability and for economic feasibility of this study in our setting. The costs of different brands were estimated from their maximum retail price obtained from pharmacies. Generic medicines were obtained from government hospital, free of cost.

Since the study did not involve the recruitment of human subjects, ethical committee clearance was not required as per our institution guidelines (IEC NO.: ECR/878/InsuKLI20|16).

Apparatus: UV spectrophotometer-JASCO UV, model: V-630

General procedure

Determination of percentage purity of clopidogrel bisulfate tablets




  Determination of λ Max Top


  • Accurately weighed 10 mg of clopidogrel bisulfate is transferred into a 100 ml volumetric flask and dissolved in 30 ml of 0.1 N HCl. It was then sonicated for 10 min and made up to the mark with 0.1 N HCl to give a stock solution having 100 μg/ml concentrations. This solution was subjected to scanning between 200–400 nm and absorption maxima at 220 nm were determined. The effect of dilution maxima was studied by diluting the above solution to 20 μg/ml and scanned from 200 to 400 nm.



  Analysis of Marketed Tablet Formulation Top


  • To determine the content of clopidogrel bisulfate in conventional tablets (label claim: 75 mg Clopidogrel per tablet), 20 tablets were weighed.


Their mean weight was determined, they were finely powdered, and powder equivalent to 100 mg of clopidogrel bisulfate was weighed and transferred into a 10 ml volumetric flask containing 10 ml 0.1 N HCl, sonicated for 10 min and the resulting sample solution was then filtered through Whatman filter paper (No. 41). The filtrate was further diluted to obtain the final concentration of 1000 μg/ml. Appropriate dilutions of Clopidogrel bisulfate were made, and the resultant solution was measured at wavelength 218 nm to obtain the absorbance. The obtained absorbance was substituted in the formula for the determination of percentage purity, and the same was determined.[32],[33]


  Results and Discussion Top


The results [Table 1], [Table 2] and [Figure 1] of this survey showed that only 19% (n = 28) of population preferred generic drugs over branded ones, and only as little as 28% (n = 42), 23% (n = 35), and 30% (n = 45) of the patient population believed that generic and branded drugs have equal efficacy, percentage purity, and safety, respectively.
Figure 1: Patient perspective on generic and branded medicines.

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This result shows that the majority of the patient population are still not prepared to accept generic brands as their preferred drug. From this survey, the main reason that can be projected for low acceptance of generic medicines is the apprehension that the patient population has regarding the efficacy and safety of these generic drugs. In Kerala, with well-advanced health-care system comparable to most of the well-developed western countries, the general population is knowledgeable and well aware of their health and understands the importance of good quality drugs, especially for heart disease. The patient population of Kerala prefers branded drugs to generic drugs due to this belief of expensive medicine being better in quality. This adds on to the economic burden of the patient as most of them will be on treatment for multiple comorbidities.

Kerala has a better doctor to patient ratio compared to many states in India. Most of the patients from urban areas consult physicians from private sector whereas rural population rely on government-run hospitals. From physician's point of view [Figure 2], only 16% (n = 24) of believe that generic and branded drugs have same efficacy and 22% (n = 33) believe that either categories are equally safe. Majority (96%) of physicians doubt the percentage purity of generic drugs and hence only 14% (n = 21) show a confidence in prescribing the same. When it comes to patient satisfaction, only 28% physicians think that their patients are satisfied of being prescribed with generic drugs.
Figure 2: Physician perspective on generic and branded drugs.

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After analyzing the physician preference, it is clear that physicians too prefer branded drugs than generic ones. This is in a scenario when the government is trying its best to implement laws prohibiting physicians from prescribing branded drugs. This adds to the dilemma of physician, especially in government sector when he/she has to prescribe a generic medicine without his/her and patients satisfaction.

As per the Indian Pharmacopoeia (IP), the standard percentage purity of clopidogrel bisulfate must be between 97% and 101.5% (amount of drug: 72.75–76.12 mg). The absorbance of samples was measured at 218 nm [Figure 3].
Figure 3: Wavelength determination of clopidogrel standard.

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The quantitative analysis of different brands and generic drugs [Table 3] showed that out of 10 chosen clopidogrel brands – 3 brands were compliant with the IP standards [Figure 4]. These 3 brands coded as A, B, and C had the recommended amount of clopidogrel between 74 and 75.82 mg and percentage purity ranging 98.7% to 101.1%. Costs of these drugs, when compared, showed a variation from Rs. 162.9 ($2.97) per month to Rs. 218.86 ($3.13) per month [Figure 5]. This shows that drugs with the same percentage purity had a price variation of Rs. 56 per month for reasons not specified.
Table 3: Percentage purity and cost/month of different commercial clopidogrel brands and clopidogrel generic

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Figure 4: Percentage purity of different clopidogrel tablets (n = 11).

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Figure 5: Cost/month of different marketed clopidogrel brands.

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The percentage purity of seven brands coded D–K was not complying with recommended standards. Brand E showed below recommended standard amount of drug (71.6 mg) and low percentage purity of 95.5% which is not acceptable as per IP standards. The same brand E costed Rs. 219 per month ($3.14) which is surprisingly the highest cost among all brands compared. This is an example to prove that a medicine if costly need not be meeting its recommended quality criteria [Figure 6]. There are brands cheaper than this brand with better percentage purity available in the market. This finding may help us in improving our confidence in prescribing better brands at a lower rate. Prescribing clopidogrel with lower quality may result in increased events of stent thrombosis and reduced efficacy of secondary prevention thereby failing in its primary intended usefulness
Figure 6: Cost and percentage purity of different clopidogrel brands The cost of different clopidogrel brands were compared and the results showed substantial variations in drug price, ranging from Rs. 97.5/month ($1.4) to Rs. 218.86/month($3.13) for different brands of same strength of clopidogrel. This discrepancy may reflect the lack of proper drug price control in the country.

Click here to view


Interestingly, six brands (D, F–K) had excess amount of drug in the formulation than recommended. Range varied from 79.8 to 88.05 mg of clopidogrel. Individual quantity is as per mentioned in the table. This increase in amount of clopidogrel even though appears to be a slight increase may result in higher incidence of bleeding among patients who have high risk of bleeding. Elderly and patients with multiple comorbidities are at higher risk of developing bleeding complications that range from minor to severe life-threatening gastrointestinal and central nervous system (CNS) bleeds.

Out of the ten brands, three brands (B, C, F) showed batch to batch variation in the percentage purity.

The percentage purity of generic drug purchased from government hospital was also determined, and the amount was found to be deficient than the recommended IP standards. This finding in the context of our research question is significant. On the contrary, since we had tested only drug procured from single center and the same batch, the result cannot be extrapolated into the general scenario. Hence, more detailed studies comprising multiple batches of clopidogrel from various centers are necessary before coming to a conclusion.

However, in the light of the above-mentioned finding, it is imperative to consider more security measures and strict vigilance of pharmaceutical companies to ensure good quality generic medications are being brought into the market.

Quantitative and qualitative analysis of drug samples is essential to ensure the right quantity of drug, its efficacy[35],[36],[37] and safety to the consumer. Lack of standardized quantitative analysis procedure protocol can result in the manufacture of substandard drugs lacking the intended efficacy and drugs with excess amount resulting in unwanted drug effect, both of which can directly cause great harm to the consumers raising uncertainty in the prescription.

Generic drugs are found to be cost-effective, but its therapeutic efficacy, drug percentage purity is also to be taken into consideration. In an Indian study[38] conducted which compared the percentage purity of generic and branded marketed tablets of various class and it was found that the formulations - both generic and branded drugs showed compliance with percentage purity as per the IP standards.

Medicine pricing is an important matter to be taken into consideration. This becomes further complicated as more number of brands are being introduced into market day-by-day.[39] Even though the government has undertaken steps by to standardize the cost of medicines, cost variations[40],[41] are evident in the present scenario[42] However, it was found in various studies that the prices vary considerably between different brands of the same drug. The price variation can be due to different factors such as cost of the ingredients, methods used in preparation of drug, procurement mechanisms in public and private pharmacies. In the government sector, procurement is made directly from pharmaceutical manufacturers recognized by the government or from government established manufacturing facilities, whereas in the private sector there is multi-layered procurement mechanism leading to increase in cost of medicine brought by the consumer (patient).[42],[43],[44]

Limitations

This study compared drug quality and cost variation of a single drug, clopidogrel bisulfate. This was mainly due to the technical and logistical difficulty of procuring methanol for analyzing other groups of cardiac drugs. This limitation could be overcome by conducting large multicenter trials where a central drug laboratory can procure reagents and methanol necessary for analyzing multiple cardiac drugs. We could analyze a single batch of various clopidogrel brands and multiple batches need to be studied for finding batch to batch variation in quality of these brands. HPLC technique is the recommended method for quantitative analysis of drugs such as clopidogrel. Our study was performed using validated UV spectrophotometric technique taking into consideration the cost and technical limitations.

This study was conducted in the southern state of India, Kerala, where patients have higher literacy, better health awareness and purchasing power compared to rest of the country. India is a vast country with a wide variation in economy and medical facilities available for patients belonging to different strata of the society. Perceptions of patients from other states could be different from our results. However, the urban population of other states may have a similar preference of commercial brands over generic brands and needs to be studied by large, multi-centers, and this study may be taken as a pilot study for many larger studies with more number of drugs and patient–physician surveys to be conducted in India.


  Conclusion Top


To the best of our knowledge, this is the first study from our part of the world to compare the purity of drug in branded versus generic clopidogrel drug. This study is a small but a very significant step toward answering the million-dollar question of whether one should prescribe a branded medicine or accept generic medicine with the same confidence we have for a well-known brand. As an initial attempt, we analyzed only one drug clopidogrel, which is in fact most important drug in secondary prevention of an acute event in CAD and CVA patients. We found that being a costly brand need not necessarily be a high purity drug. Generic medicines are the need of the hour for countries like India. Large studies involving more drugs and brands are needed to improve physician confidence in prescribing and patient compliance in taking a particular medicine. Moreover, improved quality of generic medicines will go a long way in reducing the economic burden on the patient and government thereby ensuring a better health and improved quality of life of the patient in developing countries.

Lack of proper quality assurance policy and appropriate price control order for these life-saving and long-term use drugs will impose unnecessary financial burden on patients which can result in noncompliance. Hence, necessary strategies are to be undertaken for the same. In addition, it is to be assured that necessary quantitative and qualitative analyses are being performed before a batch of drug is being dispatched into the market. An effective strategy has to be undertaken by the government to rule out the uncertainty in drug pricing. Furthermore, necessary standard protocols are to be implemented on the quantitative as well as qualitative analysis of drug samples before these are being made available in the market for consumption. The officials must also ensure that these practices are being followed and each batch is being screened thoroughly before being dispatched.

Ethics clearance

Since the study did not involve the recruitment of human subjects, ethical committee clearance was not required as per our institution guidelines (IEC NO.: ECR/878/InsuKLI20|16).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Nass SJ, Madhavan G, Augustine NR. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Care Services; Committee on Ensuring Patient Access to Affordable Drug Therapies; Making Medicines Affordable: A National Imperative. Washington (DC): National Academies Press (US); 2017. p. 3.  Back to cited text no. 44
    


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