Prescription costs are key to non-adherence: Can generics help?
- Prescription costs are a potent driver for non-adherence to medication1-3.
- Generic substitution of prescriptions is key to lowering the out-of-pocket costs of medications4-6.
- Distrust in generic medications needs to be addressed to encourage their usage and reduce cost-related non-adherence7.
Cost-related non-adherence (CRNA):
Cost of medicines is an overriding issue for adherence to the treatment plan and is an easily modifiable factor to improve non-adherence. Multiple studies report medication costs as a concern for patients in both high-income and mid-to-low income countries1-3,8. A 2016 survey of the US medicare population revealed CRNA in 34.5% of <65 year olds and 14.4% of >65 year olds and an additional 19.4% and 4.7% of patients of the respective age groups compromised on other essentials expenditures to meet the costs9. Patients faced with concerns about medication cost tend to prioritize drug usage for ones that provide symptomatic treatment over the other medications that are preventive or treat asymptomatic chronic ailments10. This issue is exacerbated in the ones suffering from multiple comorbidities with almost 32% of patients being sub-optimally adherent as their out-of-pocket costs for prescription increase 11,12. Patients take substantial health risks to offset medication costs using various strategies like delaying prescription initiation, delaying refills, selective dispensing, or taking smaller doses13. The financial burden of medications hugely influences cost reductions in other essential items and the standard of living.
Are generics an answer to CRNA?
Partially yes. A large retrospective Japanese cohort study of statin-usage in cardiovascular patients reported higher adherence and persistence in the sub-group using generic medicines as compared to the brand-name counterpart. However, no significant difference in the clinical outcomes of both subgroups was observed4. Similar results were obtained in studies elsewhere indicating the effectiveness of generics in reducing CRNA5. Importantly, complete elimination of co-payments during dispensing further augmented the adherence over and above the enhancement reported for the generic prescription, highlighting the financial burden of healthcare on patients 6. However, the studies where patients initiated treatment with branded drug and then switched to generics conclude opposite results6. The suboptimal adherence and lower effectiveness of the drug in comparison with the brand-name drug in such studies were likely due to the prevailing prejudice against generics discussed later in the article6,14.
Clinical equivalence of generics and brand-name drugs
Generic medicines are defined by the Food and drug administration (USA) as a pharmaceutical product identical as their reference brand-name drugs in active ingredient, dosage, safety, quality, performance, intended use, and route of administration15. This essentially means that a generic substitute is both pharmaceutically equivalent and bioequivalent to the reference drug. A meta-analysis of clinical evidence on generic drugs and their brand-name drugs for seven different classes of cardiovascular disease reported similar clinical outcomes for both generics and the reference branded drugs in multiple clinical trials for each class of the drug like statins, β-blockers, antiplatelet agents, etc16. Even with slightly different preparations (tablet formulation and dissolution) of levothyroxine, the generics and the brand-name drugs were found to be bioequivalent by Food and Drug Administration, USA17.In many cases, generics available for a given pharmaceutical agent are the brand-name drug that has gone off-patent. Therefore, the apprehensions regarding the safety of such medicines are largely unfounded18.
Prejudice against generic drugs:
Even with overwhelming evidence of bioequivalence of generics to their reference-listed drug and guidelines encouraging the use of generics19, people are skeptical of using generics in general. Studies have mentioned the negative perception of generics among medical experts and patients alike. Even for generics reported to have similar clinical equivalence, almost 50% (23/ 43) of editorials (dispensing expert opinion) documented negative reviews for such substitutes16.The resulting reluctance impedes generic drug usage and is a key barrier to adherence7. Some of the concerns are completely unfounded in evidence-based science while a few are valid apprehensions as described below16.
Vitriol for generics:
The negative lay press and the expert opinion based either anecdotal evidence or motivated by financial gains berate generic substitutes16. Even with the lowering of medical bills, patients are apprehensive about generics. A study reporting the usage of analgesics in patients describes lower adherence and effectiveness of pills labeled generic as compared to brand-name labeled pills, even though in reality both the pills were an identical branded drug with simply different labels20. A few factors that drive such mistrust in generics are:
- The perception of expensive is better and cheaper is inferior in quality
- Brand-name products are more effective than generics20
- Branded products are more safe than generic substitutes
- Generic products causes higher side effects14
- Once initiated with branded drugs, patients find it difficult to switch to generic prescriptions6.
- Complex health insurance coverage of generics along with higher co-payments21.
- Different physical characteristics of generics like size, shape, or taste influence patient reservation especially in the elderly22.
Generics generate “Nocebo-effect”
This negative perception towards generics is called the “Nocebo effect” and makes patients to report generic medications to be less effective. Nocebo can be categorized into two types: primary nocebo effect due to which people perceive the medication to be overall ineffective for the ailment and secondary nocebo effect which enhances the perception of adverse effects of the medicines23. As the common phrase goes – What’s in a name? – It turns out that medicine labels are the game changers in the way their purported effects are perceived. Labeling the drug with a well-known company or a brand name enhances the perceived authenticity of the medications as converse to labeling only with its generic name. The name change is significantly associated with the attributed – both subjective and objective – effects of the drug24. In a study on young college students, the brand-name labeled tablets of both the active compound and the placebo were rated equally effective in the reduction of pain as compared to the generic-labeled active compound. Additionally, the brand-name labeled placebo was also reported to cause fewer side effects in comparison to the generic-labeled placebo25. This evidence demonstrates the generic-associated bias in reporting the effectiveness of treatment and can potentially reduce adherence.
Few generic medicines are not really “generic”?
Certain studies report that not all generic substitutes for a given agent are equivalent. The presence of certain impurities and slight changes in the chemical composition could result in slightly different pharmacokinetics and pharmacodynamics influencing the overall effectiveness of the drug. This is a concern for drugs with narrow therapeutic index (NTI) that could potentially become harmful due to slight changes in their bioavailability26,16. However, studies have shown that even with NTI drugs, generics demonstrate similar bioequivalence16. Similarly, reproductions of biologicals used as pharmaceutical agents are referred as biosimilar products and not generics because even minor differences during manufacturing could result in major differences between them18. Another concern is the design of clinical trials that demonstrate the bioequivalence of generic medicines to the reference brand-name drug. These equivalence trials are modest in size as compared to the clinical trials undertaken for the initial approval of the brand-name drug. It could mask the smaller differences making them statistically insignificant primarily due to the smaller study population16. Additionally, the bioequivalence data in patients with comorbidities are limited as several of these studies utilize younger, healthy subjects for evaluating drug equivalence. There is a risk of modest clinical differences getting pronounced in patients with comorbidities16.
Busting “generic” myths:
Several myths are associated with generic medicines such as:
- Generics are not as safe as branded drugs
- Generics take longer to produce purported effects
- Generics are cheaper because of inferior quality
- Generics cause enhanced adverse-effects14
- Switching from a brand-name drug to a generic is unsafe6,14
Clinical research has unequivocally demonstrated the safety and efficiency of generic drugs (also discussed in this article). Generics undergo a strict regulatory process before their approval. What is generally lacking is awareness about generic products and appropriate encouragement from policy-makers and healthcare practitioners to increase their usage and lower the financial burden.
Generic medicines have the potential to bring affordable healthcare and can be a cornerstone in reducing CRNA globally. The negative opinion of practitioners-patients towards generics needs to be placated through awareness campaigns. The state agencies need to ensure generic manufacturers attest to good manufacturing practices and uphold the drug quality. In addition, the trade, legal, and regulatory hurdles in the marketing and supply of generic medicines should be addressed27
- Atella V, Schafheutle E, Noyce P, Hassell K. Affordability of medicines and patients’ cost-reducing behaviour: empirical evidence based on SUR estimates from Italy and the UK. Appl Health Econ Health Policy. 2005;4(1):23-35. doi:10.2165/00148365-200504010-00005
- Chow CK, Nguyen TN, Marschner S, et al. Availability and affordability of medicines and cardiovascular outcomes in 21 high-income, middle-income and low-income countries. BMJ Glob Health. Nov 2020;5(11)doi:10.1136/bmjgh-2020-002640
- Holbrook AM, Wang M, Lee M, et al. Cost-related medication nonadherence in Canada: a systematic review of prevalence, predictors, and clinical impact. Syst Rev. Jan 6 2021;10(1):11. doi:10.1186/s13643-020-01558-5
- Gao J, Seki T, Kawakami K. Comparison of adherence, persistence, and clinical outcome of generic and brand-name statin users: A retrospective cohort study using the Japanese claims database. J Cardiol. May 2021;77(5):545-551. doi:10.1016/j.jjcc.2020.12.003
- Gagne JJ, Choudhry NK, Kesselheim AS, et al. Comparative effectiveness of generic and brand-name statins on patient outcomes: a cohort study. Ann Intern Med. Sep 16 2014;161(6):400-7. doi:10.7326/M13-2942
- Briesacher BA, Andrade SE, Fouayzi H, Chan KA. Medication adherence and use of generic drug therapies. Am J Manag Care. Jul 2009;15(7):450-6.
- Garattini L, van de Vooren K. Safety and Quality of Generic Drugs: A Never Ending Debate Fostered by Economic Interests? Appl Health Econ Health Policy. Aug 2015;13 Suppl 1:S3-4. doi:10.1007/s40258-015-0156-7
- Ocran Mattila P, Ahmad R, Hasan SS, Babar ZU. Availability, Affordability, Access, and Pricing of Anti-cancer Medicines in Low- and Middle-Income Countries: A Systematic Review of Literature. Front Public Health. 2021;9:628744. doi:10.3389/fpubh.2021.628744
- Nekui F, Galbraith AA, Briesacher BA, et al. Cost-related Medication Nonadherence and Its Risk Factors Among Medicare Beneficiaries. Med Care. Jan 2021;59(1):13-21. doi:10.1097/MLR.0000000000001458
- Lieberman DA, Polinski JM, Choudhry NK, Avorn J, Fischer MA. Medicaid prescription limits: policy trends and comparative impact on utilization. BMC Health Serv Res. Jan 15 2016;16:15. doi:10.1186/s12913-016-1258-0
- Briesacher BA, Gurwitz JH, Soumerai SB. Patients at-risk for cost-related medication nonadherence: a review of the literature. J Gen Intern Med. Jun 2007;22(6):864-71. doi:10.1007/s11606-007-0180-x
- Soumerai SB, Pierre-Jacques M, Zhang F, et al. Cost-related medication nonadherence among elderly and disabled medicare beneficiaries: a national survey 1 year before the medicare drug benefit. Arch Intern Med. Sep 25 2006;166(17):1829-35. doi:10.1001/archinte.166.17.1829
- Schafheutle EI, Hassell K, Noyce PR, Weiss MC. Access to medicines: cost as an influence on the views and behaviour of patients. Health Soc Care Community. May 2002;10(3):187-95. doi:10.1046/j.1365-2524.2002.00356.x
- Colgan S, Faasse K, Martin LR, Stephens MH, Grey A, Petrie KJ. Perceptions of generic medication in the general population, doctors and pharmacists: a systematic review. BMJ Open. Dec 15 2015;5(12):e008915. doi:10.1136/bmjopen-2015-008915
- Alfonso-Cristancho R, Andia T, Barbosa T, Watanabe JH. Definition and Classification of Generic Drugs Across the World. Appl Health Econ Health Policy. Aug 2015;13 Suppl 1:S5-11. doi:10.1007/s40258-014-0146-1
- Kesselheim AS, Misono AS, Lee JL, et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis. JAMA. Dec 3 2008;300(21):2514-26. doi:10.1001/jama.2008.758
- Dong BJ, Hauck WW, Gambertoglio JG, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA. Apr 16 1997;277(15):1205-13.
- Roy V, Rana P. Prescribing generics: All in a name. Indian J Med Res. May 2018;147(5):442-444. doi:10.4103/ijmr.IJMR_1940_17
- Choudhry NK, Denberg TD, Qaseem A, Clinical Guidelines Committee of American College of P. Improving Adherence to Therapy and Clinical Outcomes While Containing Costs: Opportunities From the Greater Use of Generic Medications: Best Practice Advice From the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. Jan 5 2016;164(1):41-9. doi:10.7326/M14-2427
- Goldszmidt RB, Buttendorf AR, Schuldt Filho G, Souza JM, Jr., Bianchini MA. The impact of generic labels on the consumption of and adherence to medication: a randomized controlled trial. Eur J Public Health. Feb 1 2019;29(1):12-17. doi:10.1093/eurpub/cky183
- Mager DE, Cox ER. Relationship between generic and preferred-brand prescription copayment differentials and generic fill rate. Am J Manag Care. Jun 2007;13(6 Pt 2):347-52.
- Lumbreras B, Lopez-Pintor E. Impact of changes in pill appearance in the adherence to angiotensin receptor blockers and in the blood pressure levels: a retrospective cohort study. BMJ Open. Mar 30 2017;7(3):e012586. doi:10.1136/bmjopen-2016-012586
- Faasse K, Martin LR. The Power of Labeling in Nocebo Effects. Int Rev Neurobiol. 2018;139:379-406. doi:10.1016/bs.irn.2018.07.016
- Faasse K, Cundy T, Gamble G, Petrie KJ. The effect of an apparent change to a branded or generic medication on drug effectiveness and side effects. Psychosom Med. Jan 2013;75(1):90-6. doi:10.1097/PSY.0b013e3182738826
- Faasse K, Martin LR, Grey A, Gamble G, Petrie KJ. Impact of brand or generic labeling on medication effectiveness and side effects. Health Psychol. Feb 2016;35(2):187-90. doi:10.1037/hea0000282
- Gauzit R, Lakdhari M. Generic antibiotic drugs: is effectiveness guaranteed? Med Mal Infect. Apr 2012;42(4):141-8. doi:10.1016/j.medmal.2011.10.013
- Rana P, Roy V. Generic medicines: issues and relevance for global health. Fundam Clin Pharmacol. Dec 2015;29(6):529-42. doi:10.1111/fcp.12155