The clinical and Practice Dilemma of Frequent Switching Among Generic Medications: Magnitude and Patient Safety Prospective

Abstract

Objective: To assess the magnitude of generic-generic and brand-generic medication switching and its impact on patients’ understanding and the potential risk of medication errors. Methods: The study composed of 2 parts. The first part is a retrospective study to measure the frequency of medications switching in King Faisal Specialist Hospital and Research Centre (KFSH&RC), from 1^st of January 2015 to the 31^st of December, 2020. Brand medications that were switched to generic medications, generic medications that were switched to brand medications and generic medications that were switched to other generic medications were included. Medications that were switched before or after the study period were excluded. The primary outcomes are the total percentage of switching from brand to generic of all medications in KFSH&RC drug formulary, frequency of generic-generic medications switching and percentage of switching back from generic to brand medications. The second part is a cross sectional survey-based study to assess patients’ understanding of their medications and the potential for medication errors by assessing their ability to identify the discrepancies and duplications utilizing a validated questionnaire. Results: Over 5 years, the number of generic medications increased from 553 (35.5%) to 640 (41.1%) out of the 1554 formulary items. Percentage of switching from brand to generic over that 5-year period was 15.9%. Percentage of switching back from generic to brand was 12.8%. Total number of generic medications that had been switched to other generic medications was 256 (16.5%). Out of the 218 patients who had been switched from generic to generic medication, only 43 patients (19.7%) knew the indication for the generic medication they were taking. One hundred forty-six patients (67%) knew the indication of generic medications exclusively by their physical “trademark” characteristics, with 11.5% unrecognized duplication. Conclusion: There is a clear tendency to switch brand medications to generics and to switch between generics. We found the percentage of subsequent switching back to branded products is alarming. Frequent switching between medications negatively impacted patient comprehension and resulted in medication duplication. There is a crucial need for appropriate medication counseling and medication use ecosystem redesign.

Introduction

Intellectual property is the basis through which drug companies protect their newly manufactured medications. Once the patent on a brand name medication expires, generic versions of that medicine are allowed to be produced and marketed.^1,2 Generic products are considered to be interchangeable with the brand name product when they demonstrate the same qualitative and quantitative composition in active substances, as well as, the same pharmaceutical form and bioequivalence with the reference product after a single dose. ³ According to the United Sates Food and Drug Administration (US-FDA), generic drugs contain the same active ingredient and work the same way as brand name drugs work. So, patients will get similar clinical benefits and face comparable risks during use. Generic drugs will not receive US-FDA approval unless these drugs undergo a rigorous review process to ensure the bioequivalence between generic and brand medicine. For bioequivalence, the US-FDA requires that the population mean values for the area under the curve (AUC) and the peak concentration of the generic drug in the blood (C_max) to be not less than 20% or greater than 25% of the population mean values of the original product. For bioequivalence study approval, a 90% confidence interval (CI) must be calculated for the pharmacokinetic parameters, such as the C_max and AUC, and the results have to be within the range of 80% to 125%. ³

Interestingly, there is a batch to batch variability for the same medication from the same manufacturer. Therefore, manufacturers conduct bioequivalence tests on batches to assure batch-to-batch uniformity. The acceptance criteria of expected active ingredient quantity are 90% to 110% (mean of individual test results) and a relative standard deviation (RSD) of no more than 5% is recommended between batches. ⁴

Generic to generic medication switching is becoming common practice in health care systems in many countries, including Saudi Arabia. The evidence supporting brand to generic switching is very well established. However, there are limited bioequivalence data to prove interchangeability among generic medications. Additionally, the frequency of generic-generic medication switching and its impact on patients’ understanding of their medications and consequent risk of potential errors are not known yet. This study sought to assess the magnitude of brand-generic and generic-generic medication switching in a tertiary care hospital over 5-year period and to evaluate its impact on patients’ understating of their medications and the potential risk of medication misadventure.

Methods

The study was composed of 2 parts. The first part was a retrospective study to measure the frequency of medication switching at a 1086-bed tertiary care hospital from January 2015 through December 2020. Instances in which brand medications that were switched to generic medications, generic medications that were switched to brand medications, and generic medications that were switched to another generic medication were included. Medications that were switched before or after the study period were excluded. The primary outcome was the percentage of switching between medications; switching from brand to generic among all included medications, generic-generic medication switching, and switching back from generic to brand medications. Data regarding medication switching were collected from an in-house system (ie, ORACLE^®). The second part of the study was a cross sectional assessment of patients’ understanding of their medications and the potential for patient medication errors by assessing their ability to identify discrepancies and duplications in their medications utilizing a newly created and internally validated tool. The discrepancy of medications was assessed by the pharmacist. Surveyors reviewed the medications with the patient and monitored his/her ability to identify duplications. Discrepancy was reported if there was a difference between what the patient recognized and what the patient could not recognize among the different generic products with the same active ingredient, strength, and dosage form. Adult patients (ie, ≥18 years old) who had a total of 5 medications or more (as per polypharmacy definition ⁵ ) with at least 1 generic medication were included. Pediatric patients, those who did not bring their medication bag as requested, and those who had less than 5 medications or were not on generic medications were excluded. Patients were randomly selected with a balanced distribution between different Cardiology clinics. The first 50 patients from each month were enrolled after obtaining the institutional review board (IRB) approval, until the required sample was completed. Screening was carried out using integrated clinical information system (ICIS) PowerChart, from Cerner^®. Eligible patients were reminded 1 day before their clinic visit to bring their medications’ bag (standard of practice). Upon agreement to take part in the study, patients gave their consents in the clinic. Each participant was given a “study card” during his or her clinic visit, then he or she underwent the regular process of medication dispensing. The “study card” was handed by the patient to the pharmacist at the dispensing window, where the pharmacist communicated with the study investigator to conduct the assessment. After medication dispensing, participants were told to proceed to the counseling area where the survey was carried out.

The study patient assessment tool was reviewed by experts who understood the research idea. A pilot study was carried out on a small sample of intended patients (20 patients). After conducting the pilot study, data were entered into a spreadsheet. The internal consistency (reliability) of questions was measured by calculating the Cronbach’s Alpha (α = .75).

The study was conducted in accordance with the Institutional Review Board guidelines in our organization. Verbal patient consent was obtained, and patients had the right not to participate in the study without affecting the care they received. Details on the study were provided to participants on the first page of the questionnaire and patient confidentiality was assured.

Statistical Analysis

The primary aim of the first part of the study was to measure the frequency of medication switching by counting the number of switches per each item. Subsequently, the total percentage (TP) of switching from brand to generic of all medications was calculated as follows:

$TP=\frac{\begin{array}{l}Numberofbrandproductsthat\\ havebeenswitchedtogeneric\end{array}}{\begin{array}{l}Totalnumberofbrandproduct\\ inthehospitaldrugformulary\end{array}}\times 100$

The total percentage of switching back from generic to brand medications was calculated using the same concept in the equation above; the number of generic products that have been switched to brands divided by total number of generic products in our hospital drug formulary.

The second part of the study was conducted to assess patients’ understanding of their medications and the risk of potential medication misadventure; medication errors and adverse drug events. The sample size was calculated using an online sample calculator (Raosoft^®) with a selection of a 5% margin of error and a 95% confidence interval, which provided a sample size of 218 participants. Descriptive statistics were used to present descriptive data.

Results

A total of 1,554 items (medications) were systematically reviewed. At the beginning of the study time period, 553 out of 1,554 were generics (35.5%). After 5-years, 640 out of the 1,554 formulary items were generic medications (41.1%). The number of items that were not switched over the 5-year period was 1,110 (71.42%, 837 brand medications and 273 generic medications). The number of medications that had been switched at least 1 time over the 5-year study period (regardless of whether they were brand or generic) was 444 (28.57%, Figure 1A and B). The percentage of switching from brand to generic over the 5-year period was 15.9%. The percentage of switches back from generic to brand was 12.8%. The total number of generic medications that had been switched to other generic medications was 256 (16.5%). The highest frequency of generic-generic medication switching was 4 times (switching between 5 generic companies [1.1%]). This was reported for 3 items (omeprazole 20 mg capsule, nitrofurantoin 50 mg tablet, and aminophylline solution for injection [250 mg/10 mL] vial). Seventeen items had been switched 3 times (switching between 4 generic companies [6.6%]). Fifty-one items had been switched 2 times (switching between 3 generic companies [19.9%]). One hundred eighty-five items had been switched 1 time (switching between 2 generic companies [72.2%], Figure 2). The overall percentage of generic products increased from 35.5% in 2015 to 41.2% by the end of 2020.

Figure 1.

Medication switching over the 5-year study period [Panel A: Overall switching, Panel B: Detailed switching].

Figure 2.

The magnitude of generic to generic switching frequency and the overlap of the top 20 switched products.

Two hundred eighteen patients were included in the second part of the study. The median age was 59 years. Males accounted for 57.3% of the participants. All the study patients were following up in other hospitals or primary healthcare centers. Out of the 218 patients, 48.6%, 39.4%, 8.7%, and 1.4% were following up in 1, 2, 3, and 4 centers, respectively. Patients’ characteristics are summarized in Table 1. Only 43 patients (19.7%) were able to identify the indication by the name of generic medications. One hundred forty-six patients (67%) were able to know the indication of generic medications exclusively by their physical Trademark characteristics (visual elements such as size, shape, and color). Twenty-nine patients (13.3%) were unable to identify medications by either name or visual identification (Figure 3). One hundred ninety-three patients (88.5%) were able to identify duplications of generic medications (same active ingredient, strength, and dosage form), and 25 patients (11.5%) could not identify duplications. Sixteen patients had 1 discrepancy (7.3%), 5 patients had 2 discrepancies (2.3%), 3 patients had 3 discrepancies (1.4%), and 1 patient had 4 discrepancies (0.5%, Figure 4). Out of the 25 patients with duplications, 5 (20%) had a side effect due to taking a duplicate medication (different generics with same active ingredient). Two patients had bradycardia, 1 patient had myalgia, 1 patient had cough, and 1 patient had hypoglycemia due to beta-blockers, simvastatin, lisinopril, and glipizide, respectively. Patients’ understanding of the concept of brand-generic medication switching is presented in Table 2. The majority of patients did not know how to distinguish between their medications and they lacked a general comprehension of the concept of generic-medication switching (65.6%, Figure 5).

Table 1.

Baseline patients characteristics (n = 218).

Characteristics	Number of patients and percentage, n = 218
Age, years	Median: 59
	Mean ± SD: 57 years ± 12
Male: gender (n, %)	125, 57.3%
Education level (n, %)	University degree or higher: 61, 28.0%
	Diploma: 15, 6.9%
	High school or less: 93, 42.6%
	Not educated: 49, 22.5%
Counseling status by healthcare provider (n, %)	Counseled: 126, 57.8%	Pharmacist*: 79, 62.7%
		Physician*: 72, 57.14%
		Pharmacist assistant: 1, 0.7%
		Nurse: none
	Not counseled: 92, 42.2%
Number of hospitals or healthcare centers that patient visited in addition to our organization (n, %)	One: 106, 48.6%
	Two: 86, 39.4%
	Three: 19, 8.7%
	Four: 3, 1.4%
	Unknown: 4, 1.8%
Number of follow-up years in the hospital (n, %)	1 or less: 14, 6.4%
	2: 8, 3.7%
	3: 12, 5.5%
	4: 17, 7.8%
	5: 15, 6.9%
	6: 9, 4.1%
	7: 16, 7.3%
	8: 10, 4.6%
	9: 9, 4.1%
	10: 13, 6.0%
	>10 years: 95, 43.6%
Patient medication administration status (n, %)	Independently: 196, 89.9%
	By guardian: 22, 10.1%

^*Some patients were counseled by both pharmacist and physician.

Figure 3.

Patients’ understanding of their medications (n = 218).

Figure 4.

Medications discrepancy among the study sample (n = 218).

Table 2.

Patients understanding of the brand to generic medication switching concept.

1. Patients know the general concept of the difference between brand name and generic medication. Total count: 218 Yes (25, 11.5%), No (193, 88.5%)

1.a. Generic medications are the same as brand medication in the trade name and their physical “trade dress” characteristics (such as size, shape, and color). Total count: 25 Yes (14, 56.0%), No (11, 44.0%)

1.b. Generic of the brand medication contains the same active ingredient as brand. Total count: 25 Yes (17, 68.0%), No (8, 32.0%)

1.c. Generic medications are as effective as brand medications. Total count: 25 Yes (11, 44.0%), No (14, 56.0%)

1.d. Generic medications are as safe as brand medications. Total count: 25 Yes (14, 56.0%), No (11, 44.0%)

1.e. Generic medications are cheaper than brand medications. Total count: 25 Yes (20, 80.0%), No (5, 20.0%)

1.f. Number of generic medications. Total count: 25 Patient answered correctly (8, 32.0%) Patient did not answer correctly/did not know (17, 68.0%)

2. Do you think there are manufacturers that produce generic medications of the same active ingredient but with different names and physical characteristics? Total count: 218 Yes (16, 7.3%), No (202, 92.7%)

Figure 5.

General understanding of the medication switching concept and ability to distinguish between medications.

Discussion

Brand to generic medication switching is encouraged by health authorities worldwide with a main goal to reduce medical expenses. ⁶ However, to our knowledge, the frequency of switching from brand to generic or from generic to generic medications, its impact on patient comprehension, and the risk of medication errors has never been assessed.

The healthcare system in Saudi Arabia is fully supported by the government for its citizens. Therefore medications are provided for free for all patients. To assure the best price at the time of procurement all governmental hospitals procure their medications through National Unified Procurement Company (NUPCO). This is done through an annual biding system. The product that win the bid will be procured for all hospitals. Our study showed that more than one-fourth of our formulary medications were switched between generics and brand medications over 5 years. This includes switching the same medication multiple times between brand and generics. This is a result of multiple factors such as the availability of alternatives at a lower price, discontinuation of the drug from the market, or the annual unified purchasing system of pharmaceutical products. Saudi Arabia purchases medications through a national procurement process, awarding procurement contracts for a set time frame. Lengthening the time for a procurement contract may decrease the total number of generic to generic switches, which may reduce the potential errors. This particular concern deserves review by the National Unified Procurement Company (NUPCO), the Local Contents and Government Procurement authority, and the Center of Spending Efficiency.

One of the objectives of our study was to assess the impact of this product switching on patient comprehension. The frequency of switching contributes to serious issues in patients who cannot differentiate between medications, especially without Arabic translation, which is the native language in our country. Moreover, companies that produce generic medications may spell out medications’ names differently in Arabic. The Saudi FDA may need to unify and standardize the way of writing medication names in Arabic to make it easy for patients to know their medications both verbally and in writing. The presence of 1 Arabic medication dictionary is consequently becoming more important than ever. For instance, switching a medication between 3 generics has been reported in almost 20% of the cases. Pharmacists play a major role in medication counseling, but this rate of switching can be confusing, especially for patients on polypharmacy. In addition, mail order prescriptions are an important cornerstone of dispensing medication refills for patients around the country. As medication switches take place for mail order prescriptions, verbal communication with patients is even more important to ensure patient safety. More interestingly, approximately 50% of the patients follow-up on other hospitals, which aggravates the problem of duplication and miscommunication. This highlights the urgent need for the unified patients’ medical file among governmental hospitals.

The Gulf Cooperation Council (GCC) standardizes the directory of pharmaceuticals, devices, and medical supplies and controls medication purchasing across GCC Member States, including the Kingdom of Saudi Arabia, through a bidding system. Medications with lower prices will generally earn approval. In turn, NUPCO is responsible for purchasing medicines and medical supplies through standardized procurement for the Saudi government health subscribers. Brand medications are more expensive than their generic counterparts. ⁶ Branded medication pricing is reduced by 20% when the first generic drug is registered in Saudi Arabia. The price of the second generic drug competitor will be reduced by 10% from the cost of the first generic. As additional generic products come to market, the prices continue to fall by 10% from the previous generic drugs up to the fourth generic iteration, at which point the price will be constant. The decision of annual bidding to improve spending efficiency may lead to frequent switches among products and should not be done in isolation from the anticipated clinical patient outcome, quality, availability of alternatives, and safety impact.

During our study, it was also noticed that we had a period in which drug therapies were out of stock, and our institution had to find a therapeutic alternative to cover this medication shortage. The alternative might be another product of the same active ingredient or another medication from the same therapeutic class. This switch may have contributed to worsening our patients’ comprehension and understanding of their drug therapies. Drug authorities should be more vigilant when it comes to the management of medication supplies and the selection of appropriate alternatives. It takes a team effort, with the involvement of all stakeholders including medical staff, to manage medication supplies. Training programs for medication supply chain management to ensure the appropriateness and safety of medication procurement, utilization, and distribution are highly encouraged.

Despite how simple the principle of generic switching appears, it can become a serious safety issue. Our real-life data flagged a safety concern for our patients. A national evaluation of the drug use ecosystem to minimize switching, assess patient understanding and comprehension, and assess the pharmacoeconomic value of switching with regard to patient outcomes is needed. This would be a great future direction to assess the direct impact of medications switching on patients’ clinical and safety outcomes.

Conclusion

There is a clear trend to switch branded medications to generics and to switch between generic products. However, the percentage of switching back to branded medications is alarming. Frequent switching negatively impacts patient comprehension and cause duplicate medication administration. There is a crucial need for appropriate medication counseling, especially for patients who have multiple generic medications and who are on complex therapeutic regimens.