Less is Sometimes More – How Generic Substitution Can Affect Patient Adherence
It is undisputed that the use of generic drugs saves the healthcare system significant costs. Although doctors should certainly care about the health of the system, they primarily care for the health of individual patients – and for them, generic substitution may not always be the best choice. For instance, it is now known that it is not ideal for drugs with a narrow therapeutic range, such as antiepileptics, antidepressants, or antiparkinsonian drugs. But does this mean that generic substitution is always a welcome choice for other drugs?
Greater or Lesser Difference
Generic drugs do not differ in active substance, strength, or dosage form from their reference drugs (most often the originals). However, they may differ in excipients, which can slightly modify the pharmacokinetics of the drug. The evaluation of bioequivalence primarily assesses bioavailability. The requirements of the European Medicines Agency (EMA) can be simplified to the condition that the absorption of the active substance from the generic and reference product must be similar from 80–125%.
Fig. Bioequivalence of medicinal products (CI = Confidence Interval; adapted from: Bakker, 2017)
Can these differences be clinically significant, or can they affect treatment effectiveness? They shouldn’t be. However, it is an area deserving further attention, not just with the above-mentioned neurotropic drugs and psychotropic drugs. Similarly, in substitution therapy with levothyroxine, relatively mild differences in the absorption of the active substance can have a clinical impact and this may also apply to other drugs from different therapeutic groups.
Spanish authors in their observational study published last year focused on patients who had just started treatment with metformin at a dose of 850 mg. They retrospectively gathered data on patients taking the original and generic products over a 2-year period. Using the propensity score, they matched 863 patients treated with the original 1:1 with patients taking the generic product. The studied population had a median age of 60.8 years, and 52.6% were women. After 24 months, more patients in the original product group continued treatment compared to the generic (63.2 vs. 58.2%; p = 0.034). This likely also reflected a percentage reduction in glycated hemoglobin (-6.8% for the original vs. -4.1% for the generic; p = 0.013).
What About the Patient?
Even more than permissible differences in pharmacokinetics, treatment outcomes are influenced by patient adherence to therapy. Health literacy, patient education, and various psychological aspects of treatment come into play. The phenomenon of the impact of switching products with the same active substance has been studied in various European countries over the past 10 years. Most authors agree that a single switch from the original to a generic product does not significantly affect adherence or clinical outcomes. However, it is different in the case of repeated switching between different products with the same active substance.
When Less is More
Italian specialists in health economics assessed data on the handling of generic products in the Lombardy region repeatedly. In an observational study published in 2016, they selected 5 drugs (metformin, amlodipine, simvastatin, sertraline, propafenone, and alendronate) and monitored whether generic substitution occurred during the 36 months of follow-up and what impact it had. It occurred in 61.5% of individuals. Adherence to treatment and continuity of treatment significantly decreased with more frequent product switching: patients who had a generic substitution frequency of 1–15% continued treatment for 800–1000 days, while those with a substitution frequency of more than 60% continued treatment for only 197–448 days (p < 0.001).
Conclusion
The results of observational studies should be taken with awareness of the limitations of retrospective data collection. They are usually not able to confirm a causal relationship, rather they show us that the use of originals or generics and their interchangeability can belong among the factors that can influence the success of treatment and the patient's willingness to follow the doctor's recommendations.
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Sources:
- European Medicines Agency. Guideline on the investigation of bioequivalence. First revision. EMA, 2010. Available at: www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf
- Bakker A. Is brand name best? Brand name versus generic pharmaceuticals in clinical practice. University of Ottawa Journal of Medicine 2017; 7 (1): 31–34, doi: 10.18192/uojm.v7i1.1438
- Sicras-Mainar A., Sicras-Navarro A. Persistencia al tratamiento con metformina de marca vs. genérica en monoterapia para la diabetes tipo 2: estudio retrospectivo de vida real mediante propensity score matching [Treatment persistence with brand-name vs. generic metformin in monotherapy for type 2 diabetes: real-life retrospective study using the propensity matching score]. Semergen 2021; 47 (5): 321–331, doi: 10.1016/j.semerg.2020.12.010.
- Colombo G. L., Agabiti-Rosei E., Margonato A. et al. Impact of substitution among generic drugs on persistence and adherence: a retrospective claims data study from 2 local healthcare units in the Lombardy region of Italy. Atherosclerosis Supplements 2016; 21: 1–8, doi: 10.1016/j.atherosclerosissup.2016.02.001.
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