- Email: [email protected]
Need for Multicriteria Evaluation of Generic Drug Policies
VALUE IN HEALTH 18 (2015) 346–351
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jval
POLICY PERSPECTIVES
Need for Multicriteria Evaluation of Generic Drug Policies Zoltán Kaló, MD, MSc, PhD1,2,*, Anke-Peggy Holtorf, PhD, MBA3,4, Rafael Alfonso-Cristancho, MD, MSc, PhD5, Jie Shen, MSc, MBA6, Tamás Ágh, MD, MSc, PhD2, András Inotai, PharmD, PhD2, Diana Brixner, RPh, PhD4 1
Faculty of Social Sciences, Department of Health Policy and Health Economics, Eötvös Loránd University (ELTE), Budapest, Hungary; Syreon Research Institute, Budapest, Hungary; 3Health Outcomes Strategies, Basel, Switzerland; 4Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA; 5Department of Surgery, School of Medicine, University of Washington, Seattle, USA; 6Abbott Products Operations AG, Allschwil, Switzerland 2
AB STR A CT
Policymakers tend to focus on improving patented drug policies because they are under pressure from patients, physicians, and manufacturers to increase access to novel therapies. The success of pharmaceutical innovation over the last few decades has led to the availability of many off-patent drugs to treat disease areas with the greatest public health need. Therefore, the success of public health programs in improving the health status of the total population is highly dependent on the efficiency of generic drug policies. The objective of this article was to explore factors influencing the true efficiency of generic prescription drug policies in supporting public health initiatives in the developed world. Health care decision makers often assess the efficiency of generic drug policies by the level of price erosion and market share of generics. Drug quality, bioequivalence, in
some cases drug formulations, supply reliability, medical adherence and persistence, health outcomes, and nondrug costs, however, are also attributes of success for generic drug policies. Further methodological research is needed to measure and improve the efficiency of generic drug policies. This also requires extension of the evidence base of the impact of generic drugs, partly based on real-world evidence. Multicriteria decision analysis may assist policymakers and researchers to evaluate the true value of generic drugs. Keywords: adherence, drug policies, generic drug, multicriteria decision analysis, price erosion, real-world evidence.
Introduction
conference in Seoul, the Latin American ISPOR meeting in Buenos Aires, the European ISPOR meeting in Dublin, the European Health Policy Forum in Gastein, and the Asian ISPOR meeting in Beijing as well as dedicated roundtable discussions of the subject in Latin America and Asia with a broad range of health care decision makers and payer representatives throughout 2012 to 2014. The objective of this article was to introduce the topic of variance in generic drug purchasing policies, and their potential impact on the efficiency of generic prescription drug policies to support public health initiatives in the developed world. This article will be followed by several articles that go into greater depth in specific areas.
In December 2011, an international group of health outcomes and policy researchers from 21 countries have participated in a series of workshops concerning the current practice around generic drug policies. The objective of these meetings was to understand how the success of generic drug policies is measured and interpreted, to expand the evidence base around generic drug policies, and to explore the health care and methodological challenges related to different drug policy initiatives. The steering committee formed as a consequence of the workshops has met several times over the last 2 years. Research teams of the international expert group conducted several literature reviews in related areas, for example, on definition and classification of off-patent drugs in emerging markets [1], on physicians’ and pharmacists’ perspectives on generic drugs and generic substitution [2], and on the impact of generic substitution on health and economic outcomes [3]. Several health policy workshops have been conducted at different scientific events, including the HTAi
& 2015 Published by Elsevier Inc. on behalf of International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Definition of Generic Drugs In any evaluation of generic drugs and policies, definition is a key issue. There is significant disparity around the definition of both a branded, innovator, original drug and its bioequivalent,
* Address correspondence to: Zoltán Kaló, Faculty of Social Sciences, Department of Health Policy and Health Economics, Eötvös Loránd University, H-Budapest, Pázmány P. 1a. – 1117, Hungary. E-mail: [email protected]. 1098-3015$36.00 – see front matter & 2015 Published by Elsevier Inc. on behalf of International Society for Pharmacoeconomics and Outcomes Research (ISPOR). http://dx.doi.org/10.1016/j.jval.2014.12.012
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VALUE IN HEALTH 18 (2015) 346–351
interchangeable generic version meeting the bioavailability threshold. For this article, we use the term generic drug in concordance with the definition from the World Health Organization: A generic drug is a pharmaceutical product 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 [4]. We will consistently refer to the innovator drug as the original drug and assume the generic drug to be considered interchangeable within currently described generic drug policies.
Importance of Generic Drugs In health care systems of developed countries, pharmaceuticals play a central role in the practice of medicine and patients are increasingly treated with off-patent drugs [5,6]. Once the patent of a commercially successful, original pharmaceutical has expired and exclusivity rights are lost, several generic manufacturers proceed with the production and commercialization of the drug. The market authorization process is simplified because of substantial scientific evidence behind the original drugs from clinical trials and real-world evidence from many patient-years demonstrating the effectiveness and safety of the compound. The most important policy objective of health care systems is to improve the health status of the population [7]. The success of pharmaceutical innovation over the last few decades has improved the health status of patients for most major diseases, reducing the unmet medical need for new pharmaceutical therapies. In disease areas with the greatest public health burden (e.g., cardiovascular diseases, mental health, and diabetes mellitus [8]) first-line therapy is usually off-patent medicines [9–11]. Therefore, the success of public health programs in improving the health status of the total population—in addition to preventive
health care services and accessibility to primary health care services—is highly dependent on the availability and appropriate utilization of off-patent drugs. The price differential between original and generic pharmaceuticals is usually significant, but often extremely variable, and, to some degree, depends on the strength of price regulation [12]. Because of scarcity of health care resources, original patented drugs are increasingly used only for those patients who cannot benefit from existing low-priced generic drugs. The number of patients on original drug therapies is limited; thus, improvement in health status based on these small groups may not apply to the total population. Therefore, the major societal benefit of original drugs is the improved equity in access to effective therapies for those patients with relatively greater unmet medical need.
Components of Generic Drug Policies Market authorization criteria for generic drugs are simplified compared with those for original pharmaceuticals. After market entry, generic substitution, international nonproprietary name prescribing, price control for generics, generic reference pricing, and tenders are widely used measures to promote the uptake of generic drugs at the lowest drug acquisition cost [13,14]. Policymakers have several options to incentivize stakeholders to abide by generic drug policies [15–17]. These tools appear to influence each other; thus, generic drug policies commonly include mixed approaches applied by decision makers and health policy experts with the ultimate aim to accelerate price erosion and penetration of generics. In Table 1, a nonexclusive list of different policy options for generic prescription drugs is presented, with their expected societal benefits related to different stakeholders.
Table 1 – Common generic drug policy interventions and their expected societal benefits Policy interventions
Expected societal benefit related to different stakeholders Pharmaceutical manufacturers
Registration based on proof of bioequivalence to originals or reference Mandatory price reduction of new generics compared with reference product International reference pricing Central tendering in public reimbursement
International nonproprietary name prescribing and generic substitution by pharmacists NA, not applicable.
Reduced development cost for generics; increased competition by more generic drugs Continuous generic price erosion with new generic entries
Domino effect of generic price erosion in other countries Maximized price erosion by delisting higherpriced off-patent competitors Reduced investment into continued medical education (CME) and marketing activities
Prescribers (physicians and health care providers)
Pharmacies
Patients
Increased therapeutic alternatives
Opportunity for drug substitution
Increased accessibility to lower-priced drugs
Increased therapeutic alternatives according to socioeconomic status of patients NA
Opportunity for drug substitution by considering the socioeconomic status of patients NA
Reduced financial burden on patients
Reduced variability in drug prescribing
Reduced variability in drug dispensing
Minimized co-payment for patients
Reduced impact of marketing and CME activities on prescribers
Incentives to dispense the cheapest generic alternative
Increased utilization of nonbranded generics
Reduced financial burden on patients
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Success Criteria of Generic Drug Policies Policy tools given in Table 1 are used to increase savings from the use of generic drugs to support cost-containment objectives. Price erosion and market share of generics are often considered a proxy for the success of drug policies by health care policymakers [6,18]. There is not much evidence, however, that either one of these benchmarks is an indicator of achievement of good health status, a main policy objective in health care systems worldwide. Generic drug policy interventions are intended to assure that health outcomes are maintained, or even improved, in parallel with the reduction in health care expenditure [3]. Therefore, the efficiency of generic drug policies can be defined as reduction in health care expenditure without compromising health outcomes. This definition is based on the disinvestment aspect of generic drug policies. The efficiency of generic drug policies can also be defined from an investment perspective, especially in those countries with volume limits for the use of original patented drugs: increase in population health gain by improved patient access with no increase in health expenditure. Several factors may attenuate the efficiency of generic drug policies related to both health outcomes and health expenditure objectives. Proof of bioequivalence to the originator or reference product is a mandatory requirement for the registration of generic drugs in most countries; however, evidence on therapeutic equivalence may be limited [19]. In addition, although two different generic drugs may be bioequivalent to the reference drug, they may not be bioequivalent to each other because the range of bioequivalence intervals may not overlap if one remains in the upper range of the confidence interval to the reference product and the other in the lower range. The efficacy or safety profile of nonbioequivalent generic products can be different, which may limit their interchangeability. This is especially true for drugs with a narrow therapeutic window (e.g., warfarin and cyclosporin) [20–22]. Differences in drug administration, such as inhaler devices, can also influence therapeutic equivalence and may result in negative health outcomes in the case of generic substitution [23,24]. Drug shortages have become an increasing concern in global health care. Consequences are limited access to effective therapies and increased cost for purchase of suitable compensatory medication or therapy. Drug shortages occur more frequently with less expensive drugs, and reasons are often connected to the lowest price–driven drug policies [25–27]. Lowest cost drugs are
purchased from several countries or manufactured locally and may not keep up with manufacturing to meet demand, resulting in shortages, or lower-quality output. Frequent generic drug substitution may result in increased adverse effects and decreased tolerability [28] and patient confusion [29]. Generic drug substitution in hospitals may result in medication errors by care personnel [30]. The real-world health gain for patients with chronic diseases depends on their persistence and adherence with maintenance drug therapies. Lower co-payments may improve the accessibility of medication for patients, and therefore improve their adherence to drug therapies [31,32]. However, changes in drug formulations, color of tablets, and pack size as a consequence of generic drug prescribing or regular revision of generic reference products may decrease medical adherence [33] and persistence [34], especially in vulnerable patient populations such as elderly patients with several comorbidities [35,36], less educated patients, immigrants [37], or patients with psychiatric illnesses [38]. Regular switching of drug therapies for chronic diseases may lead to poorer adherence [39], which may result in an increase in hospitalizations [40–42]. The impact of generic drug demand and supply policies on generic drug price erosion can be limited in certain countries [43]. As a consequence of all the abovementioned factors, current generic drug policies may not always decrease the overall health care expenditure or guarantee equal health outcomes [44–46]. A recent systematic literature review confirmed that a significant proportion of published articles opposed the use of generic drugs [3]. By considering these factors, we propose that multiple success criteria should be applied to assess the efficiency of generic drug policies, as depicted in Figure 1. Further research is needed to validate whether the list of criteria is exhaustive or should be extended, or even should be simplified to ensure its applicability in routine practice.
Importance of Consistent Drug Therapy for Patients with Chronic Diseases Implications of inconsistent drug therapy for patients with chronic diseases may be underestimated when assessing the success of generic drug policies [47]. Physicians often have a strong preference to continue prescribing the branded drug for patients with chronic diseases after patent expiry [48]. This is especially true in special disease areas, such as schizophrenia. If patients with schizophrenia are switched back and forth among different drug formulations, their confidence in drug therapy may deteriorate, and therapy discontinuation may increase [49]. Although non-
Fig. 1 – Success criteria for generic drug policies.
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Table 2 – Potential outcomes of hypothetical generic drug policy scenarios in schizophrenia. Scenario
Persistence Health outcomes Health care costs Overall societal impact
Patients continue drug therapy on preferred offpatent therapy
Patients are frequently switched between off-patent drugs
Patients are switched to a patented drug
Maintained Same as before patent expiry
Relatively poor Increased rate of clinical events
Maintained Similar to health outcomes before patent expiry
Savings in drug budget
Savings in drug budget Increased costs in primary and specialty care Uncertain (savings in drug budget, increased nondrug costs, inferior health outcomes)
Increased pharmaceutical costs
Societal gain (savings with equal health outcomes)
persistence of patients reduces direct pharmaceutical costs, the health status of patients without drug therapy can decline. Acute schizophrenic events may increase the cost of inpatient care, and therefore the cost-savings potential on the total health expenditure after patent expiry can be difficult to predict. To minimize such switching induced by generic substitution policies, physicians may prescribe patented drug therapies to prevent stable patients with schizophrenia from switching back and forth among different generic drug formulations [50]. In such cases, patients can stay on effective drugs without the risk of substitution by pharmacists. This scenario results in potentially equal health gain with increased pharmaceutical expenditure. The example of schizophrenia shows how persistence with drug therapy after patent expiry influences the success of generic drug policies in some chronic diseases (Table 2).
Economic Value of Different Generic Drug Policies The value of innovative pharmaceuticals depends on multiple criteria that differentiate the innovator product from other
Societal loss (increased drug costs with no improvement in health outcomes)
available treatments [51]. A similar approach can be used to illustrate the value of generic drug policies, where the individual components that comprise value include cost, quality, and outcomes as demonstrated by a waterfall diagram (Fig. 2). Patent protection provides additional value for new original drug manufacturers compared with off-patent medicine manufacturers. Two policy scenarios can be differentiated for offpatent drugs. In the first scenario with multiple criteria policy objectives, there would be more regulatory control on the bioequivalence criterion, and regulators often check product quality. Payers would not force patients to switch to the least expensive generic drug. Therefore, patients can stay on the same off-patent drug formulations for longer periods, and their adherence and persistence may remain more stable. This may lead to health outcomes equal to those with original pharmaceuticals, without an increase in nonpharmaceutical cost of care. This policy scenario adds differential value to an alternative policy scenario in which the maximization of generic drug price erosion serves the only policy objective. The added value of the multiple criteria policy scenario compared with the lowest price policy scenario is that such methods can be country specific. Further local research is needed to quantify the potential magnitude of multicriteria
Fig. 2 – Example for multicriteria value assessment of chronic maintenance off-patent drugs. R&D, research and development.
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decision analysis methods applied to generic drug policies in major markets.
Conclusions Pharmaceutical policymakers tend to focus on improving patented drug policies because they are under pressure from patients, physicians, and manufacturers to increase access to novel therapies. Most of the patients, however, are treated with off-patent medicines; therefore, the success of public health programs in improving the health status of the total population is highly dependent on the efficiency of generic drug policies. Researchers and policymakers often assess the efficiency of generic drug policies by measuring the level of price erosion and market share of generics. Drug quality, bioequivalence, in some cases drug formulations, supply reliability, medical adherence and persistence, health outcomes, and nondrug costs, however, are also attributes of success for generic drug policies. In conclusion, further methodological research is needed to understand and improve the efficiency of generic drug policies. This also requires expansion of the evidence base concerning the use of generic drugs and the impact of generic drug policies, based, in part, on real-world evidence. The development of applications of multicriteria decision analysis may assist policymakers and researchers to assess the true value of off-patent drugs and drug policies. Source of financial support: The writing of this article was supported in part by Abbott. However, the authors summarized their independent professional opinion and take full responsibility for potential errors in the article. R EF E R EN CE S
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Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jval
POLICY PERSPECTIVES
Need for Multicriteria Evaluation of Generic Drug Policies Zoltán Kaló, MD, MSc, PhD1,2,*, Anke-Peggy Holtorf, PhD, MBA3,4, Rafael Alfonso-Cristancho, MD, MSc, PhD5, Jie Shen, MSc, MBA6, Tamás Ágh, MD, MSc, PhD2, András Inotai, PharmD, PhD2, Diana Brixner, RPh, PhD4 1
Faculty of Social Sciences, Department of Health Policy and Health Economics, Eötvös Loránd University (ELTE), Budapest, Hungary; Syreon Research Institute, Budapest, Hungary; 3Health Outcomes Strategies, Basel, Switzerland; 4Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, UT, USA; 5Department of Surgery, School of Medicine, University of Washington, Seattle, USA; 6Abbott Products Operations AG, Allschwil, Switzerland 2
AB STR A CT
Policymakers tend to focus on improving patented drug policies because they are under pressure from patients, physicians, and manufacturers to increase access to novel therapies. The success of pharmaceutical innovation over the last few decades has led to the availability of many off-patent drugs to treat disease areas with the greatest public health need. Therefore, the success of public health programs in improving the health status of the total population is highly dependent on the efficiency of generic drug policies. The objective of this article was to explore factors influencing the true efficiency of generic prescription drug policies in supporting public health initiatives in the developed world. Health care decision makers often assess the efficiency of generic drug policies by the level of price erosion and market share of generics. Drug quality, bioequivalence, in
some cases drug formulations, supply reliability, medical adherence and persistence, health outcomes, and nondrug costs, however, are also attributes of success for generic drug policies. Further methodological research is needed to measure and improve the efficiency of generic drug policies. This also requires extension of the evidence base of the impact of generic drugs, partly based on real-world evidence. Multicriteria decision analysis may assist policymakers and researchers to evaluate the true value of generic drugs. Keywords: adherence, drug policies, generic drug, multicriteria decision analysis, price erosion, real-world evidence.
Introduction
conference in Seoul, the Latin American ISPOR meeting in Buenos Aires, the European ISPOR meeting in Dublin, the European Health Policy Forum in Gastein, and the Asian ISPOR meeting in Beijing as well as dedicated roundtable discussions of the subject in Latin America and Asia with a broad range of health care decision makers and payer representatives throughout 2012 to 2014. The objective of this article was to introduce the topic of variance in generic drug purchasing policies, and their potential impact on the efficiency of generic prescription drug policies to support public health initiatives in the developed world. This article will be followed by several articles that go into greater depth in specific areas.
In December 2011, an international group of health outcomes and policy researchers from 21 countries have participated in a series of workshops concerning the current practice around generic drug policies. The objective of these meetings was to understand how the success of generic drug policies is measured and interpreted, to expand the evidence base around generic drug policies, and to explore the health care and methodological challenges related to different drug policy initiatives. The steering committee formed as a consequence of the workshops has met several times over the last 2 years. Research teams of the international expert group conducted several literature reviews in related areas, for example, on definition and classification of off-patent drugs in emerging markets [1], on physicians’ and pharmacists’ perspectives on generic drugs and generic substitution [2], and on the impact of generic substitution on health and economic outcomes [3]. Several health policy workshops have been conducted at different scientific events, including the HTAi
& 2015 Published by Elsevier Inc. on behalf of International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Definition of Generic Drugs In any evaluation of generic drugs and policies, definition is a key issue. There is significant disparity around the definition of both a branded, innovator, original drug and its bioequivalent,
* Address correspondence to: Zoltán Kaló, Faculty of Social Sciences, Department of Health Policy and Health Economics, Eötvös Loránd University, H-Budapest, Pázmány P. 1a. – 1117, Hungary. E-mail: [email protected]. 1098-3015$36.00 – see front matter & 2015 Published by Elsevier Inc. on behalf of International Society for Pharmacoeconomics and Outcomes Research (ISPOR). http://dx.doi.org/10.1016/j.jval.2014.12.012
347
VALUE IN HEALTH 18 (2015) 346–351
interchangeable generic version meeting the bioavailability threshold. For this article, we use the term generic drug in concordance with the definition from the World Health Organization: A generic drug is a pharmaceutical product 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 [4]. We will consistently refer to the innovator drug as the original drug and assume the generic drug to be considered interchangeable within currently described generic drug policies.
Importance of Generic Drugs In health care systems of developed countries, pharmaceuticals play a central role in the practice of medicine and patients are increasingly treated with off-patent drugs [5,6]. Once the patent of a commercially successful, original pharmaceutical has expired and exclusivity rights are lost, several generic manufacturers proceed with the production and commercialization of the drug. The market authorization process is simplified because of substantial scientific evidence behind the original drugs from clinical trials and real-world evidence from many patient-years demonstrating the effectiveness and safety of the compound. The most important policy objective of health care systems is to improve the health status of the population [7]. The success of pharmaceutical innovation over the last few decades has improved the health status of patients for most major diseases, reducing the unmet medical need for new pharmaceutical therapies. In disease areas with the greatest public health burden (e.g., cardiovascular diseases, mental health, and diabetes mellitus [8]) first-line therapy is usually off-patent medicines [9–11]. Therefore, the success of public health programs in improving the health status of the total population—in addition to preventive
health care services and accessibility to primary health care services—is highly dependent on the availability and appropriate utilization of off-patent drugs. The price differential between original and generic pharmaceuticals is usually significant, but often extremely variable, and, to some degree, depends on the strength of price regulation [12]. Because of scarcity of health care resources, original patented drugs are increasingly used only for those patients who cannot benefit from existing low-priced generic drugs. The number of patients on original drug therapies is limited; thus, improvement in health status based on these small groups may not apply to the total population. Therefore, the major societal benefit of original drugs is the improved equity in access to effective therapies for those patients with relatively greater unmet medical need.
Components of Generic Drug Policies Market authorization criteria for generic drugs are simplified compared with those for original pharmaceuticals. After market entry, generic substitution, international nonproprietary name prescribing, price control for generics, generic reference pricing, and tenders are widely used measures to promote the uptake of generic drugs at the lowest drug acquisition cost [13,14]. Policymakers have several options to incentivize stakeholders to abide by generic drug policies [15–17]. These tools appear to influence each other; thus, generic drug policies commonly include mixed approaches applied by decision makers and health policy experts with the ultimate aim to accelerate price erosion and penetration of generics. In Table 1, a nonexclusive list of different policy options for generic prescription drugs is presented, with their expected societal benefits related to different stakeholders.
Table 1 – Common generic drug policy interventions and their expected societal benefits Policy interventions
Expected societal benefit related to different stakeholders Pharmaceutical manufacturers
Registration based on proof of bioequivalence to originals or reference Mandatory price reduction of new generics compared with reference product International reference pricing Central tendering in public reimbursement
International nonproprietary name prescribing and generic substitution by pharmacists NA, not applicable.
Reduced development cost for generics; increased competition by more generic drugs Continuous generic price erosion with new generic entries
Domino effect of generic price erosion in other countries Maximized price erosion by delisting higherpriced off-patent competitors Reduced investment into continued medical education (CME) and marketing activities
Prescribers (physicians and health care providers)
Pharmacies
Patients
Increased therapeutic alternatives
Opportunity for drug substitution
Increased accessibility to lower-priced drugs
Increased therapeutic alternatives according to socioeconomic status of patients NA
Opportunity for drug substitution by considering the socioeconomic status of patients NA
Reduced financial burden on patients
Reduced variability in drug prescribing
Reduced variability in drug dispensing
Minimized co-payment for patients
Reduced impact of marketing and CME activities on prescribers
Incentives to dispense the cheapest generic alternative
Increased utilization of nonbranded generics
Reduced financial burden on patients
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Success Criteria of Generic Drug Policies Policy tools given in Table 1 are used to increase savings from the use of generic drugs to support cost-containment objectives. Price erosion and market share of generics are often considered a proxy for the success of drug policies by health care policymakers [6,18]. There is not much evidence, however, that either one of these benchmarks is an indicator of achievement of good health status, a main policy objective in health care systems worldwide. Generic drug policy interventions are intended to assure that health outcomes are maintained, or even improved, in parallel with the reduction in health care expenditure [3]. Therefore, the efficiency of generic drug policies can be defined as reduction in health care expenditure without compromising health outcomes. This definition is based on the disinvestment aspect of generic drug policies. The efficiency of generic drug policies can also be defined from an investment perspective, especially in those countries with volume limits for the use of original patented drugs: increase in population health gain by improved patient access with no increase in health expenditure. Several factors may attenuate the efficiency of generic drug policies related to both health outcomes and health expenditure objectives. Proof of bioequivalence to the originator or reference product is a mandatory requirement for the registration of generic drugs in most countries; however, evidence on therapeutic equivalence may be limited [19]. In addition, although two different generic drugs may be bioequivalent to the reference drug, they may not be bioequivalent to each other because the range of bioequivalence intervals may not overlap if one remains in the upper range of the confidence interval to the reference product and the other in the lower range. The efficacy or safety profile of nonbioequivalent generic products can be different, which may limit their interchangeability. This is especially true for drugs with a narrow therapeutic window (e.g., warfarin and cyclosporin) [20–22]. Differences in drug administration, such as inhaler devices, can also influence therapeutic equivalence and may result in negative health outcomes in the case of generic substitution [23,24]. Drug shortages have become an increasing concern in global health care. Consequences are limited access to effective therapies and increased cost for purchase of suitable compensatory medication or therapy. Drug shortages occur more frequently with less expensive drugs, and reasons are often connected to the lowest price–driven drug policies [25–27]. Lowest cost drugs are
purchased from several countries or manufactured locally and may not keep up with manufacturing to meet demand, resulting in shortages, or lower-quality output. Frequent generic drug substitution may result in increased adverse effects and decreased tolerability [28] and patient confusion [29]. Generic drug substitution in hospitals may result in medication errors by care personnel [30]. The real-world health gain for patients with chronic diseases depends on their persistence and adherence with maintenance drug therapies. Lower co-payments may improve the accessibility of medication for patients, and therefore improve their adherence to drug therapies [31,32]. However, changes in drug formulations, color of tablets, and pack size as a consequence of generic drug prescribing or regular revision of generic reference products may decrease medical adherence [33] and persistence [34], especially in vulnerable patient populations such as elderly patients with several comorbidities [35,36], less educated patients, immigrants [37], or patients with psychiatric illnesses [38]. Regular switching of drug therapies for chronic diseases may lead to poorer adherence [39], which may result in an increase in hospitalizations [40–42]. The impact of generic drug demand and supply policies on generic drug price erosion can be limited in certain countries [43]. As a consequence of all the abovementioned factors, current generic drug policies may not always decrease the overall health care expenditure or guarantee equal health outcomes [44–46]. A recent systematic literature review confirmed that a significant proportion of published articles opposed the use of generic drugs [3]. By considering these factors, we propose that multiple success criteria should be applied to assess the efficiency of generic drug policies, as depicted in Figure 1. Further research is needed to validate whether the list of criteria is exhaustive or should be extended, or even should be simplified to ensure its applicability in routine practice.
Importance of Consistent Drug Therapy for Patients with Chronic Diseases Implications of inconsistent drug therapy for patients with chronic diseases may be underestimated when assessing the success of generic drug policies [47]. Physicians often have a strong preference to continue prescribing the branded drug for patients with chronic diseases after patent expiry [48]. This is especially true in special disease areas, such as schizophrenia. If patients with schizophrenia are switched back and forth among different drug formulations, their confidence in drug therapy may deteriorate, and therapy discontinuation may increase [49]. Although non-
Fig. 1 – Success criteria for generic drug policies.
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Table 2 – Potential outcomes of hypothetical generic drug policy scenarios in schizophrenia. Scenario
Persistence Health outcomes Health care costs Overall societal impact
Patients continue drug therapy on preferred offpatent therapy
Patients are frequently switched between off-patent drugs
Patients are switched to a patented drug
Maintained Same as before patent expiry
Relatively poor Increased rate of clinical events
Maintained Similar to health outcomes before patent expiry
Savings in drug budget
Savings in drug budget Increased costs in primary and specialty care Uncertain (savings in drug budget, increased nondrug costs, inferior health outcomes)
Increased pharmaceutical costs
Societal gain (savings with equal health outcomes)
persistence of patients reduces direct pharmaceutical costs, the health status of patients without drug therapy can decline. Acute schizophrenic events may increase the cost of inpatient care, and therefore the cost-savings potential on the total health expenditure after patent expiry can be difficult to predict. To minimize such switching induced by generic substitution policies, physicians may prescribe patented drug therapies to prevent stable patients with schizophrenia from switching back and forth among different generic drug formulations [50]. In such cases, patients can stay on effective drugs without the risk of substitution by pharmacists. This scenario results in potentially equal health gain with increased pharmaceutical expenditure. The example of schizophrenia shows how persistence with drug therapy after patent expiry influences the success of generic drug policies in some chronic diseases (Table 2).
Economic Value of Different Generic Drug Policies The value of innovative pharmaceuticals depends on multiple criteria that differentiate the innovator product from other
Societal loss (increased drug costs with no improvement in health outcomes)
available treatments [51]. A similar approach can be used to illustrate the value of generic drug policies, where the individual components that comprise value include cost, quality, and outcomes as demonstrated by a waterfall diagram (Fig. 2). Patent protection provides additional value for new original drug manufacturers compared with off-patent medicine manufacturers. Two policy scenarios can be differentiated for offpatent drugs. In the first scenario with multiple criteria policy objectives, there would be more regulatory control on the bioequivalence criterion, and regulators often check product quality. Payers would not force patients to switch to the least expensive generic drug. Therefore, patients can stay on the same off-patent drug formulations for longer periods, and their adherence and persistence may remain more stable. This may lead to health outcomes equal to those with original pharmaceuticals, without an increase in nonpharmaceutical cost of care. This policy scenario adds differential value to an alternative policy scenario in which the maximization of generic drug price erosion serves the only policy objective. The added value of the multiple criteria policy scenario compared with the lowest price policy scenario is that such methods can be country specific. Further local research is needed to quantify the potential magnitude of multicriteria
Fig. 2 – Example for multicriteria value assessment of chronic maintenance off-patent drugs. R&D, research and development.
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decision analysis methods applied to generic drug policies in major markets.
Conclusions Pharmaceutical policymakers tend to focus on improving patented drug policies because they are under pressure from patients, physicians, and manufacturers to increase access to novel therapies. Most of the patients, however, are treated with off-patent medicines; therefore, the success of public health programs in improving the health status of the total population is highly dependent on the efficiency of generic drug policies. Researchers and policymakers often assess the efficiency of generic drug policies by measuring the level of price erosion and market share of generics. Drug quality, bioequivalence, in some cases drug formulations, supply reliability, medical adherence and persistence, health outcomes, and nondrug costs, however, are also attributes of success for generic drug policies. In conclusion, further methodological research is needed to understand and improve the efficiency of generic drug policies. This also requires expansion of the evidence base concerning the use of generic drugs and the impact of generic drug policies, based, in part, on real-world evidence. The development of applications of multicriteria decision analysis may assist policymakers and researchers to assess the true value of off-patent drugs and drug policies. Source of financial support: The writing of this article was supported in part by Abbott. However, the authors summarized their independent professional opinion and take full responsibility for potential errors in the article. R EF E R EN CE S
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