- Email: [email protected]
Cost comparison and economic implications of commonly used originator and generic chemotherapy drugs in India
research article
Annals of Oncology 24 (Supplement 5): v13–v16, 2013 doi:10.1093/annonc/mdt323
Cost comparison and economic implications of commonly used originator and generic chemotherapy drugs in India G. de L. Lopes* The Johns Hopkins Singapore International Medical Centre, The Johns Hopkins University School of Medicine, Singapore, Singapore
Non-communicable diseases (NCDs) caused 63% of global deaths in 2008, 80% of which occurred in low- and middleincome countries. In September 2011, recognizing the burden of non-infectious maladies, the United Nations held a high level summit on the prevention and control of NCDs [1]. Aiming to raise awareness and lead the efforts in combating NCDs in member nations, the general assembly adopted resolution 66/2 [2]. Cancer, leading to >7.1 million deaths yearly and exceeding those caused by tuberculosis, human immunodeficiency virus/ acquired immunodeficiency syndrome and malaria combined [3], is the most important cause of lost years of life and productivity worldwide. Cancer had a total economic impact of USD 895 billion in 2008, not including direct costs of treatment, according to a study supported by the American Cancer Society and the LiveStrong foundation [4]. Cancer control strategies including tobacco control, vaccines to prevent viral infections that cause cancer, screening programs, early detection and innovative treatments have started to make strides against malignancies overall, especially against specific types of cancer. In particular, there have been marked improvements in the management of childhood cancer, for which 5-year survival rates now reach 80% when compared with <50% four decades ago [5]. Moreover, in the last couple of decades, adjusted cancer death rates have decreased by nearly *Correspondence to: Dr G. de L. Lopes Jr, Senior Consultant in Medical Oncology, Assistant Professor of Oncology, The Johns Hopkins Singapore International Medical Centre, The Johns Hopkins University School of Medicine, 11 Jalan Tan Tock Seng, Level 1, Singapore 308433, Singapore. E-mail: [email protected]
21% in men and 12% in women in the United States, due to better prevention, early diagnosis and treatment of specific malignancies, such as those of the breast, colon and lung among others [6]. Even patients with non-curable metastatic disease have seen a significant impact in their survival and quality of life with systemic treatment with chemotherapeutic, hormonal and other targeted agents. Patients with colon and lung cancers now have median survivals that are measured in a few years rather than just a few months. In the period 1999–2006, according to the SEER Cancer Statistics Review, 5-year survival rates in the United States improved 36% when compared with the period between 1975 and 1977, when one considers all tumor types [7]. Access to medications in general—and cancer treatments in particular—is one of the major challenges facing the oncology and public health communities today, especially in low- and middle-income countries. Drug development is a long and expensive process; it may take a decade or longer, the screening of thousands of compounds and capitalized costs of nearly USD 1.8 billion to bring a new medication to market [8]. As such, nations and the international community grant patents, which give manufacturers a period of exclusive rights to sell a new drug, as incentive for innovation. Once a patent expires, other companies are allowed to make and market a once-exclusive branded agent, as long as they can demonstrate bio-equivalence [9]. Once generic competition sets in, the price of medications can drop significantly, often by ≥80% [10], allowing access to a larger number of patients. In this paper, the author provides a cost comparison between the most frequently used generic and originator chemotherapy
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
research article
introduction
Downloaded from http://annonc.oxfordjournals.org/ at Gazi Universitesi on October 4, 2014
Cancer treatments have improved outcomes but access to medications is an issue around the world and especially so in low- and middle-income countries, such as India. Generic substitution may lead to significant cost savings. The author aimed to compare the cost and estimate potential cost savings per cycle, per patient, and for the country as a whole with generic substitution of frequently used chemotherapy drugs in the treatment of common cancers in India. Generic paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine, oxaliplatin and irinotecan cost from 8.9% to 36% of their equivalent branded originator drug, resulting in cost savings of ∼ Indian Rupees (INR) 11 000 to >INR 90 000 (USD 200–1600, Euro 160–1300) per cycle; and ∼INR 50 000 to >INR 240 000 (USD 900–4300, Euro 700–3400) per patient. Overall, potential yearly savings for health systems in India were nearly INR 47 billion (∼USD 843 million, Euro 670 million). In conclusion, generic substitution for frequently used chemotherapy drugs in the treatment of common cancers has an enormous potential to generate significant cost savings and increase access to cancer treatments in India and other low- and middle-income countries.
research article drugs in India, paclitaxel (Taxol), gemcitabine, docetaxel (Taxotere), oxaliplatin and irinotecan, highlighting and discussing the economic implications of generic substitution in common cancers in the country.
methods cost and currency Using cost data of chemotherapy agents provided by Fresenius Kabi, a pharmaceutical company, as list price in India, the author calculated the cost savings per patient per cycle for the generic drugs when compared with the originator-branded versions. Costs are depicted in 2012 Indian Rupees (INR) and represent drug costs only, assuming that the cost of administration, physician visits, complications and others would be similar between the generic and the originator drugs.
Annals of Oncology colon cancer in 2008, suggesting that 70% of patients developed metastases during the course of their disease. The author assumes that 20% of patients with colorectal cancer also require adjuvant treatment. There were 115 251 cases and 53 592 deaths from breast cancer—the author assumes that all deaths represent metastatic cases and that 40% of patients are eligible for adjuvant chemotherapy; finally, there were 8960 cases and 7766 deaths from pancreatic cancer, suggesting that 1194 patients were eligible for adjuvant therapy and the remainder for palliative chemotherapy.
sensitivity analyses The author also carried out sensitivity analyses by halving and doubling the parameters used to calculate cost savings in order to test the robustness of the findings as variables were changed.
results cost comparison
No discount is employed due to the short time horizon of 1 year.
The cost of generics ranged from 8.9% to 36% of the branded drug (irinotecan, 8.9%; paclitaxel, 23%, docetaxel, 24%; oxaliplatin 32%; gemcitabine, 36%). Table 1 depicts the potential cost savings with commonly used generic chemotherapy drugs compared with originator versions in India.
chemotherapy drug usage The following commonly used chemotherapy drugs were chosen as both generics and branded originator drugs are available: paclitaxel (Intaxel and Taxol), docetaxel (Taxotere) (Daxotel and Taxotere), oxaliplatin (Oxitan and Eloxatin), irinotecan (Irinotel and Camptosar) and gemcitabine (Gemita and Gemzar). Drug usage was calculated based on a body surface area of 1.7 and chemotherapy doses as follows: oxaliplatin 85 mg/m2 on days 1 and 15 of each 28-day cycle; irinotecan 180 mg/m2 on days 1 and 15 of each 28-day cycle; paclitaxel 80 mg/m2 on days 1, 8 and 15 of each 21-day cycle; docetaxel 75 mg/m2 every 21 days; gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle.
exchange rates At the time of writing, at current exchange rates, one INR equals USD 0.018 and Euro 0.0143.
cost-savings estimate Cost savings were estimated for each cycle based on the details above. For an estimate of cost savings for India as a whole, the author made the following assumptions: oxaliplatin and irinotecan were used to treat patients with colorectal cancer, the former in stage III for 6 months and in stage IV for 8 months (as in the non-bevacizumab containing arms in the NO16966 trial) [11] and the latter in stage IV only for a duration of 2.6 months (as in the control arm of the EPIC trial) [12]; paclitaxel and docetaxel were used to treat patients with breast cancer in the adjuvant and metastatic settings, assuming each was used for 50% of patients and a duration of 12 weeks in the adjuvant and 6 months for paclitaxel and 8 months for docetaxel in the metastatic setting [13, 14]; gemcitabine was used to treat patients with metastatic pancreatic cancer for a median duration of 3.3 months (as in the control arm in the recent comparison with FOLFIRINOX), patients with operable pancreatic cancer for 4 months and patients with metastatic breast cancer for a duration of 2.2 months as in the control arm of the EMBRACE trial [15, 16]. GLOBOCAN 2008 data for India were used to estimate the number of cancer cases in the country [17]. Stage distribution and eligibility for treatment were estimated based on the discussions with Indian oncologists and extrapolation from GLOBOCAN data as actual data on the exact stage distribution and percentage of patients who actually have access to treatment in the country is incomplete and/or unavailable. The author considered that ALL eligible patients would receive the respective agent. According to these data, there were 36 476 cases and 25 690 deaths from
v | Lopes
cost savings per cycle With a 68% cost difference between the branded originator and generic oxaliplatin, average cost savings per patient per cycle were INR 11 782.90. Cost savings were INR 70 697.40 for each patient who received adjuvant treatment for colorectal cancer and INR 94 263.20 for patients with metastatic disease. As for generic irinotecan, cost savings per patient per cycle were INR 93 052.00. Average savings per patient with metastatic colorectal cancer were calculated at INR 241 935.20. Average cost savings with the use of the generic paclitaxel were INR 27 654 per cycle, INR 110 616 for each patient with breast cancer in the adjuvant setting and INR 237 034.29 per patient with metastatic breast cancer. Generic docetaxel costs only 24% of the branded originator, so cost savings per cycle were INR 15 680 and cost savings per patient were INR 62 720 for those who received adjuvant treatment for breast cancer and 179 200 per patient who received treatment for metastatic disease. Cost savings per cycle with the use of generic gemcitabine were INR 23 352. Cost savings per patient who received adjuvant treatment for pancreatic cancer were INR 93 408; and INR 77 061.60 and INR 51 374.40 for those with metastatic pancreatic and breast cancers, respectively.
potential yearly cost savings for India as a whole The estimated cases per year were 25 533 for metastatic colorectal cancer, 7295 for adjuvant colorectal cancer, 69 150 for adjuvant breast cancer, 53 592 for metastatic breast cancer, 1194 for adjuvant pancreatic cancer and 7766 for metastatic pancreatic cancer. As such, potential yearly overall cost savings with these generic chemotherapy agents in the specific clinical situations described were INR 46 856 335 283.36 (USD 843 414 035.10,
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discounting
research article
Annals of Oncology
Table 1. Potential cost savings with commonly used generic chemotherapy drugs compared with originator versions Generic Drug
Irinotecan generic Oxaliplatin generic
Cost savings per dose
Cost savings per cycle
Cost savings per patient with
46 526.00
93 052.00
241 935.20
5891.45
11 782.90
70 697.40 94 263.20
Paclitaxel generic
9218.00
27 654.00
110 616.00 237 034.29
Docetaxel generic
15 680.00
15 680.00
62 720.00 179 200.00
7784.00
23 352.00
93 408.00
77 061.60
51 374.40 Potential overall savings
Euro 670 045 594.55). The details for each drug and clinical scenario are given in Table 1.
sensitivity analyses When the author decreased the cost savings seen with each generic drug by 50%, the overall cost savings were INR 33 604 319 746.48 (USD 604 877 755.44, Euro 480 541 772.37). Cost savings when the number of cases was halved were INR 22 826 457 357.12 (USD 410 876 232.43, Euro 326 418 340.21).
discussion This is the first study to estimate the potential yearly cost savings with the substitution of generic versions of frequently used chemotherapy drugs in the treatment of common cancers in India. As described in other diseases and settings, the average sales cost of generic drugs was 64%–91% lower than that of the respective originator-branded drug. Moreover, there were significant cost savings per cycle and per patient, ranging from ∼INR 11 000 to >INR 90 000 (USD 200–1600, Euro 160–1300) and from ∼INR 50 000 to >NR 240 000 (USD 900–4300, Euro 700–3400), respectively. Overall, potential yearly savings for health systems in India were nearly INR 47 billion (∼USD 843 million, Euro 670 million). These numbers are clearly significant in a country with a gross national income per capita of
Volume 24 | Supplement 5 | September 2013
Potential yearly cost savings in India In Indian rupees (INR)
In USD
In Euros
25 533
6 177 379 848.64
111 192 837.28
88 336 531.84
7295
515 751 672.48
9 283 530.10
7 375 248.92
25 533
2 406 841 138.24
43 323 140.49
34 417 828.28
69 150
7 649 162 769.60
137 684 929.85
109 383 027.61
53 592
12 703 141 440.00
228 656 545.92
181 654 922.59
69 150
4 337 125 632.00
78 068 261.38
62 020 896.54
53 592
9 603 686 400.00
172 866 355.20
137 332 715.52
1194
111 529 152.00
2 007 524.74
1 594 866.87
7766
598 460 385.60
10 772 286.94
8 557 983.51
53 592
2 753 256 844.80
49 558 623.21
39 371 572.88
46 856 335 283.36
843 414 035.10
670 045 594.55
Several caveats have to be brought up. Economic evaluations rely on several assumptions and changing these variables can modify the results significantly. As seen in the sensitivity analyses, potential yearly savings decrease to INR 33 604 319 746.48 (USD 604 877 755.44, Euro 480 541 772.37) and INR 22 826 457 357.12 (USD 410 876 232.43, Euro 326 418 340.21), respectively, if the cost savings per drug and the number of patients treated is reduced by half. These numbers still represent sizable cost savings, however. It should also be noted that this study had other shortcomings. First, it relies on one source of data for the list price of drugs. Discussions with colleagues in India and with IMS Health, a consultancy, however, suggest that the numbers obtained are reliable and representative ( personal communication). Second, incomplete data exist about the number of patients with each specific disease and clinical situation and the percentage of patients who actually have access to these specific drugs. Third, these numbers may actually under-represent the potential savings as the estimates only include a specific set of drugs and clinical conditions, suggesting that the benefits of generic substitution may be even bigger overall. Finally, as the country has a robust generic industry, cost savings seen in India may not mirror those achievable in other low- and middle-income countries, especially in those that rely on imports for most of their medications. Due to these caveats, it is unclear if these results can be extrapolated to other settings and they should be confirmed by further studies, preferably using real world cost data. Major challenges for the greater penetration of generics include public and health care worker perception and quality
doi:10.1093/annonc/mdt323 | v
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Gemcitabine generic
Metastatic colorectal cancer Adjuvant colorectal cancer Metastatic colorectal cancer Adjuvant breast cancer Metastatic breast cancer Adjuvant breast cancer Metastatic breast cancer Adjuvant pancreatic cancer Metastatic pancreatic cancer Metastatic breast cancer
Number of cases per Year
research article
disclosure The author has been a consultant for Fresenius Kabi.
references 1. World health organization. United Nations High Level Meeting on Noncommunicable Disease Prevention and Control. http://www.who.int/nmh/ events/un_ncd_summit2011/en/ (20 August 2012, date last accessed).
v | Lopes
2. General Assembly. Political Declaration of the High-level Meeting of the General Assembly on the Prevention and Control of Non-communicable Diseases. Resolution 66/2. United Nations, 2011. http://www.who.int/nmh/events/ un_ncd_summit2011/political_declaration_en.pdf (20 August 2012, date last accessed). 3. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11): e442. 4. LiveStrong foundation and American Cancer Society. The Global Economic Cost of Cancer. http://www.cancer.org/acs/groups/content/@internationalaffairs/ documents/document/acspc-026203.pdf (20 August 2012, date last accessed). 5. National Cancer Institute. A Snapshot of Pediatric Cancers. Incidence and Mortality Rate Trends. http://www.cancer.gov/researchandfunding/snapshots/pdf/PediatricSnapshot.pdf. (20 August 2012, date last accessed). 6. Jemal A, Ward E, Thun M. Declining death rates reflect progress against cancer. PLoS One 2010; 5(3): e9584. 7. Altekruse SF, Kosary CL, Krapcho M et al. SEER Cancer Statistics Review, 1975– 2007. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/ 1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010. (20 August 2012, date last accessed). 8. Paul SM, Mytelka DS, Dunwiddie CT et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 2012; 9(3): 1474–1776. 9. United States Food and Drug Administration. Understanding Generic Drugs. http ://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/ UnderstandingGenericDrugs/default.htm (10 October 2012, date last accessed). 10. Generic pharmaceutical association. About Generics. http://www.gphaonline.org/ about-gpha/about-generics (10 October 2012, date last accessed). 11. Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666–2676. 12. Miles DW, Chan A, Dirix LY et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010; 28: 3239–3247. 13. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Eng J Med 2011; 364(19): 1817–1825. 14. Cortes J, O’Shaughnessy J, Loesch D et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011; 377(9769): 914–923. 15. International Agency for Research on Cancer. GLOBOCAN, India 2008. http ://globocan.iarc.fr/factsheet.asp (12 December 2012, date last accessed). 16. The world bank. Health Expenditures Per Capita (current USD). http://data. worldbank.org/indicator/SH.XPD.PCAP (31 August 2012, date last accessed). 17. The world bank. Data: India. http://data.worldbank.org/country/india (31 August 2012, date last accessed). 18. Shrank WH, Liberman JN, Fischer MA et al. Physician perceptions about generic drugs. Ann Pharmacother 2011; 45: 31–38. 19. Alwan F, Alshami A, Hatim A et al. Impact of switching therapy from imatinib mesylate to generic copy of Imatinib on hematologic response in patients with chronic phase chronic myeloid leukemia: single center study. Hematologica 2011; 96(2): Abstract 1219. 20. Kesselheim AS, Misono AS, Lee JL et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and metaanalysis. JAMA 2008; 300(21): 2514–2526.
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issues. In a survey of 839 physicians, for instance, nearly a quarter had a negative perception of the efficacy and 50% of the quality of generic medications [18]. Furthermore, there have been reports of low quality substitutes in oncology in low and middle income countries. For example, a study in Iraq showed that a significant proportion of patients with chronic myelogenous leukemia lost hematological, cytogenetic and molecular control after switching from branded to generic imatinib [19]. Quality assurance with the use of good manufacturing practices and adequate supervision by regulatory authorities is of paramount importance to ensure bioequivalence, and therefore the safety and efficacy of generic medications. A systematic review and meta-analysis of 38 randomized, controlled trials comparing generic and branded cardiovascular drugs confirmed their clinical equivalence [20]. Little has been published about the safety, efficacy and economic implications of the use of generic oncology medications, however, especially in low and middle income countries, and this gap clearly needs to be filled by further studies. Investigators from India, with grant support from Fresenius-Kabi, have retrospectively collected clinical data on 393 patients who received generic versions of docetaxel, oxaliplatin, irinotecan and gemcitabine (Personal communication to Dr G. de L. Lopes Jr). The median survival ranged from 12.8 months for patients with lung cancer (66% had metastatic disease) to 30 months for patients with colon cancer (67% of patients had metastatic disease) and 47 months for patients with breast cancer (45% had metastatic disease) and between 20% and 45% of patients reported serious adverse events. These data seem to conform to expectations of survival and toxicity but it is clear that the creation of formal registries would help the oncology community have a more precise estimate of the clinical equivalence of generic drugs beyond the bioequivalence required for their marketing approvals. In conclusion, generic substitution for frequently used chemotherapy drugs in the treatment of common cancers has an enormous potential to generate significant cost savings and increase access to treatment in India.
Annals of Oncology
Annals of Oncology 24 (Supplement 5): v13–v16, 2013 doi:10.1093/annonc/mdt323
Cost comparison and economic implications of commonly used originator and generic chemotherapy drugs in India G. de L. Lopes* The Johns Hopkins Singapore International Medical Centre, The Johns Hopkins University School of Medicine, Singapore, Singapore
Non-communicable diseases (NCDs) caused 63% of global deaths in 2008, 80% of which occurred in low- and middleincome countries. In September 2011, recognizing the burden of non-infectious maladies, the United Nations held a high level summit on the prevention and control of NCDs [1]. Aiming to raise awareness and lead the efforts in combating NCDs in member nations, the general assembly adopted resolution 66/2 [2]. Cancer, leading to >7.1 million deaths yearly and exceeding those caused by tuberculosis, human immunodeficiency virus/ acquired immunodeficiency syndrome and malaria combined [3], is the most important cause of lost years of life and productivity worldwide. Cancer had a total economic impact of USD 895 billion in 2008, not including direct costs of treatment, according to a study supported by the American Cancer Society and the LiveStrong foundation [4]. Cancer control strategies including tobacco control, vaccines to prevent viral infections that cause cancer, screening programs, early detection and innovative treatments have started to make strides against malignancies overall, especially against specific types of cancer. In particular, there have been marked improvements in the management of childhood cancer, for which 5-year survival rates now reach 80% when compared with <50% four decades ago [5]. Moreover, in the last couple of decades, adjusted cancer death rates have decreased by nearly *Correspondence to: Dr G. de L. Lopes Jr, Senior Consultant in Medical Oncology, Assistant Professor of Oncology, The Johns Hopkins Singapore International Medical Centre, The Johns Hopkins University School of Medicine, 11 Jalan Tan Tock Seng, Level 1, Singapore 308433, Singapore. E-mail: [email protected]
21% in men and 12% in women in the United States, due to better prevention, early diagnosis and treatment of specific malignancies, such as those of the breast, colon and lung among others [6]. Even patients with non-curable metastatic disease have seen a significant impact in their survival and quality of life with systemic treatment with chemotherapeutic, hormonal and other targeted agents. Patients with colon and lung cancers now have median survivals that are measured in a few years rather than just a few months. In the period 1999–2006, according to the SEER Cancer Statistics Review, 5-year survival rates in the United States improved 36% when compared with the period between 1975 and 1977, when one considers all tumor types [7]. Access to medications in general—and cancer treatments in particular—is one of the major challenges facing the oncology and public health communities today, especially in low- and middle-income countries. Drug development is a long and expensive process; it may take a decade or longer, the screening of thousands of compounds and capitalized costs of nearly USD 1.8 billion to bring a new medication to market [8]. As such, nations and the international community grant patents, which give manufacturers a period of exclusive rights to sell a new drug, as incentive for innovation. Once a patent expires, other companies are allowed to make and market a once-exclusive branded agent, as long as they can demonstrate bio-equivalence [9]. Once generic competition sets in, the price of medications can drop significantly, often by ≥80% [10], allowing access to a larger number of patients. In this paper, the author provides a cost comparison between the most frequently used generic and originator chemotherapy
© The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
research article
introduction
Downloaded from http://annonc.oxfordjournals.org/ at Gazi Universitesi on October 4, 2014
Cancer treatments have improved outcomes but access to medications is an issue around the world and especially so in low- and middle-income countries, such as India. Generic substitution may lead to significant cost savings. The author aimed to compare the cost and estimate potential cost savings per cycle, per patient, and for the country as a whole with generic substitution of frequently used chemotherapy drugs in the treatment of common cancers in India. Generic paclitaxel (Taxol), docetaxel (Taxotere), gemcitabine, oxaliplatin and irinotecan cost from 8.9% to 36% of their equivalent branded originator drug, resulting in cost savings of ∼ Indian Rupees (INR) 11 000 to >INR 90 000 (USD 200–1600, Euro 160–1300) per cycle; and ∼INR 50 000 to >INR 240 000 (USD 900–4300, Euro 700–3400) per patient. Overall, potential yearly savings for health systems in India were nearly INR 47 billion (∼USD 843 million, Euro 670 million). In conclusion, generic substitution for frequently used chemotherapy drugs in the treatment of common cancers has an enormous potential to generate significant cost savings and increase access to cancer treatments in India and other low- and middle-income countries.
research article drugs in India, paclitaxel (Taxol), gemcitabine, docetaxel (Taxotere), oxaliplatin and irinotecan, highlighting and discussing the economic implications of generic substitution in common cancers in the country.
methods cost and currency Using cost data of chemotherapy agents provided by Fresenius Kabi, a pharmaceutical company, as list price in India, the author calculated the cost savings per patient per cycle for the generic drugs when compared with the originator-branded versions. Costs are depicted in 2012 Indian Rupees (INR) and represent drug costs only, assuming that the cost of administration, physician visits, complications and others would be similar between the generic and the originator drugs.
Annals of Oncology colon cancer in 2008, suggesting that 70% of patients developed metastases during the course of their disease. The author assumes that 20% of patients with colorectal cancer also require adjuvant treatment. There were 115 251 cases and 53 592 deaths from breast cancer—the author assumes that all deaths represent metastatic cases and that 40% of patients are eligible for adjuvant chemotherapy; finally, there were 8960 cases and 7766 deaths from pancreatic cancer, suggesting that 1194 patients were eligible for adjuvant therapy and the remainder for palliative chemotherapy.
sensitivity analyses The author also carried out sensitivity analyses by halving and doubling the parameters used to calculate cost savings in order to test the robustness of the findings as variables were changed.
results cost comparison
No discount is employed due to the short time horizon of 1 year.
The cost of generics ranged from 8.9% to 36% of the branded drug (irinotecan, 8.9%; paclitaxel, 23%, docetaxel, 24%; oxaliplatin 32%; gemcitabine, 36%). Table 1 depicts the potential cost savings with commonly used generic chemotherapy drugs compared with originator versions in India.
chemotherapy drug usage The following commonly used chemotherapy drugs were chosen as both generics and branded originator drugs are available: paclitaxel (Intaxel and Taxol), docetaxel (Taxotere) (Daxotel and Taxotere), oxaliplatin (Oxitan and Eloxatin), irinotecan (Irinotel and Camptosar) and gemcitabine (Gemita and Gemzar). Drug usage was calculated based on a body surface area of 1.7 and chemotherapy doses as follows: oxaliplatin 85 mg/m2 on days 1 and 15 of each 28-day cycle; irinotecan 180 mg/m2 on days 1 and 15 of each 28-day cycle; paclitaxel 80 mg/m2 on days 1, 8 and 15 of each 21-day cycle; docetaxel 75 mg/m2 every 21 days; gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle.
exchange rates At the time of writing, at current exchange rates, one INR equals USD 0.018 and Euro 0.0143.
cost-savings estimate Cost savings were estimated for each cycle based on the details above. For an estimate of cost savings for India as a whole, the author made the following assumptions: oxaliplatin and irinotecan were used to treat patients with colorectal cancer, the former in stage III for 6 months and in stage IV for 8 months (as in the non-bevacizumab containing arms in the NO16966 trial) [11] and the latter in stage IV only for a duration of 2.6 months (as in the control arm of the EPIC trial) [12]; paclitaxel and docetaxel were used to treat patients with breast cancer in the adjuvant and metastatic settings, assuming each was used for 50% of patients and a duration of 12 weeks in the adjuvant and 6 months for paclitaxel and 8 months for docetaxel in the metastatic setting [13, 14]; gemcitabine was used to treat patients with metastatic pancreatic cancer for a median duration of 3.3 months (as in the control arm in the recent comparison with FOLFIRINOX), patients with operable pancreatic cancer for 4 months and patients with metastatic breast cancer for a duration of 2.2 months as in the control arm of the EMBRACE trial [15, 16]. GLOBOCAN 2008 data for India were used to estimate the number of cancer cases in the country [17]. Stage distribution and eligibility for treatment were estimated based on the discussions with Indian oncologists and extrapolation from GLOBOCAN data as actual data on the exact stage distribution and percentage of patients who actually have access to treatment in the country is incomplete and/or unavailable. The author considered that ALL eligible patients would receive the respective agent. According to these data, there were 36 476 cases and 25 690 deaths from
v | Lopes
cost savings per cycle With a 68% cost difference between the branded originator and generic oxaliplatin, average cost savings per patient per cycle were INR 11 782.90. Cost savings were INR 70 697.40 for each patient who received adjuvant treatment for colorectal cancer and INR 94 263.20 for patients with metastatic disease. As for generic irinotecan, cost savings per patient per cycle were INR 93 052.00. Average savings per patient with metastatic colorectal cancer were calculated at INR 241 935.20. Average cost savings with the use of the generic paclitaxel were INR 27 654 per cycle, INR 110 616 for each patient with breast cancer in the adjuvant setting and INR 237 034.29 per patient with metastatic breast cancer. Generic docetaxel costs only 24% of the branded originator, so cost savings per cycle were INR 15 680 and cost savings per patient were INR 62 720 for those who received adjuvant treatment for breast cancer and 179 200 per patient who received treatment for metastatic disease. Cost savings per cycle with the use of generic gemcitabine were INR 23 352. Cost savings per patient who received adjuvant treatment for pancreatic cancer were INR 93 408; and INR 77 061.60 and INR 51 374.40 for those with metastatic pancreatic and breast cancers, respectively.
potential yearly cost savings for India as a whole The estimated cases per year were 25 533 for metastatic colorectal cancer, 7295 for adjuvant colorectal cancer, 69 150 for adjuvant breast cancer, 53 592 for metastatic breast cancer, 1194 for adjuvant pancreatic cancer and 7766 for metastatic pancreatic cancer. As such, potential yearly overall cost savings with these generic chemotherapy agents in the specific clinical situations described were INR 46 856 335 283.36 (USD 843 414 035.10,
Volume 24 | Supplement 5 | September 2013
Downloaded from http://annonc.oxfordjournals.org/ at Gazi Universitesi on October 4, 2014
discounting
research article
Annals of Oncology
Table 1. Potential cost savings with commonly used generic chemotherapy drugs compared with originator versions Generic Drug
Irinotecan generic Oxaliplatin generic
Cost savings per dose
Cost savings per cycle
Cost savings per patient with
46 526.00
93 052.00
241 935.20
5891.45
11 782.90
70 697.40 94 263.20
Paclitaxel generic
9218.00
27 654.00
110 616.00 237 034.29
Docetaxel generic
15 680.00
15 680.00
62 720.00 179 200.00
7784.00
23 352.00
93 408.00
77 061.60
51 374.40 Potential overall savings
Euro 670 045 594.55). The details for each drug and clinical scenario are given in Table 1.
sensitivity analyses When the author decreased the cost savings seen with each generic drug by 50%, the overall cost savings were INR 33 604 319 746.48 (USD 604 877 755.44, Euro 480 541 772.37). Cost savings when the number of cases was halved were INR 22 826 457 357.12 (USD 410 876 232.43, Euro 326 418 340.21).
discussion This is the first study to estimate the potential yearly cost savings with the substitution of generic versions of frequently used chemotherapy drugs in the treatment of common cancers in India. As described in other diseases and settings, the average sales cost of generic drugs was 64%–91% lower than that of the respective originator-branded drug. Moreover, there were significant cost savings per cycle and per patient, ranging from ∼INR 11 000 to >INR 90 000 (USD 200–1600, Euro 160–1300) and from ∼INR 50 000 to >NR 240 000 (USD 900–4300, Euro 700–3400), respectively. Overall, potential yearly savings for health systems in India were nearly INR 47 billion (∼USD 843 million, Euro 670 million). These numbers are clearly significant in a country with a gross national income per capita of
Volume 24 | Supplement 5 | September 2013
Potential yearly cost savings in India In Indian rupees (INR)
In USD
In Euros
25 533
6 177 379 848.64
111 192 837.28
88 336 531.84
7295
515 751 672.48
9 283 530.10
7 375 248.92
25 533
2 406 841 138.24
43 323 140.49
34 417 828.28
69 150
7 649 162 769.60
137 684 929.85
109 383 027.61
53 592
12 703 141 440.00
228 656 545.92
181 654 922.59
69 150
4 337 125 632.00
78 068 261.38
62 020 896.54
53 592
9 603 686 400.00
172 866 355.20
137 332 715.52
1194
111 529 152.00
2 007 524.74
1 594 866.87
7766
598 460 385.60
10 772 286.94
8 557 983.51
53 592
2 753 256 844.80
49 558 623.21
39 371 572.88
46 856 335 283.36
843 414 035.10
670 045 594.55
Several caveats have to be brought up. Economic evaluations rely on several assumptions and changing these variables can modify the results significantly. As seen in the sensitivity analyses, potential yearly savings decrease to INR 33 604 319 746.48 (USD 604 877 755.44, Euro 480 541 772.37) and INR 22 826 457 357.12 (USD 410 876 232.43, Euro 326 418 340.21), respectively, if the cost savings per drug and the number of patients treated is reduced by half. These numbers still represent sizable cost savings, however. It should also be noted that this study had other shortcomings. First, it relies on one source of data for the list price of drugs. Discussions with colleagues in India and with IMS Health, a consultancy, however, suggest that the numbers obtained are reliable and representative ( personal communication). Second, incomplete data exist about the number of patients with each specific disease and clinical situation and the percentage of patients who actually have access to these specific drugs. Third, these numbers may actually under-represent the potential savings as the estimates only include a specific set of drugs and clinical conditions, suggesting that the benefits of generic substitution may be even bigger overall. Finally, as the country has a robust generic industry, cost savings seen in India may not mirror those achievable in other low- and middle-income countries, especially in those that rely on imports for most of their medications. Due to these caveats, it is unclear if these results can be extrapolated to other settings and they should be confirmed by further studies, preferably using real world cost data. Major challenges for the greater penetration of generics include public and health care worker perception and quality
doi:10.1093/annonc/mdt323 | v
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Gemcitabine generic
Metastatic colorectal cancer Adjuvant colorectal cancer Metastatic colorectal cancer Adjuvant breast cancer Metastatic breast cancer Adjuvant breast cancer Metastatic breast cancer Adjuvant pancreatic cancer Metastatic pancreatic cancer Metastatic breast cancer
Number of cases per Year
research article
disclosure The author has been a consultant for Fresenius Kabi.
references 1. World health organization. United Nations High Level Meeting on Noncommunicable Disease Prevention and Control. http://www.who.int/nmh/ events/un_ncd_summit2011/en/ (20 August 2012, date last accessed).
v | Lopes
2. General Assembly. Political Declaration of the High-level Meeting of the General Assembly on the Prevention and Control of Non-communicable Diseases. Resolution 66/2. United Nations, 2011. http://www.who.int/nmh/events/ un_ncd_summit2011/political_declaration_en.pdf (20 August 2012, date last accessed). 3. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11): e442. 4. LiveStrong foundation and American Cancer Society. The Global Economic Cost of Cancer. http://www.cancer.org/acs/groups/content/@internationalaffairs/ documents/document/acspc-026203.pdf (20 August 2012, date last accessed). 5. National Cancer Institute. A Snapshot of Pediatric Cancers. Incidence and Mortality Rate Trends. http://www.cancer.gov/researchandfunding/snapshots/pdf/PediatricSnapshot.pdf. (20 August 2012, date last accessed). 6. Jemal A, Ward E, Thun M. Declining death rates reflect progress against cancer. PLoS One 2010; 5(3): e9584. 7. Altekruse SF, Kosary CL, Krapcho M et al. SEER Cancer Statistics Review, 1975– 2007. Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/ 1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010. (20 August 2012, date last accessed). 8. Paul SM, Mytelka DS, Dunwiddie CT et al. How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 2012; 9(3): 1474–1776. 9. United States Food and Drug Administration. Understanding Generic Drugs. http ://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/ UnderstandingGenericDrugs/default.htm (10 October 2012, date last accessed). 10. Generic pharmaceutical association. About Generics. http://www.gphaonline.org/ about-gpha/about-generics (10 October 2012, date last accessed). 11. Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666–2676. 12. Miles DW, Chan A, Dirix LY et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol 2010; 28: 3239–3247. 13. Conroy T, Desseigne F, Ychou M et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Eng J Med 2011; 364(19): 1817–1825. 14. Cortes J, O’Shaughnessy J, Loesch D et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 2011; 377(9769): 914–923. 15. International Agency for Research on Cancer. GLOBOCAN, India 2008. http ://globocan.iarc.fr/factsheet.asp (12 December 2012, date last accessed). 16. The world bank. Health Expenditures Per Capita (current USD). http://data. worldbank.org/indicator/SH.XPD.PCAP (31 August 2012, date last accessed). 17. The world bank. Data: India. http://data.worldbank.org/country/india (31 August 2012, date last accessed). 18. Shrank WH, Liberman JN, Fischer MA et al. Physician perceptions about generic drugs. Ann Pharmacother 2011; 45: 31–38. 19. Alwan F, Alshami A, Hatim A et al. Impact of switching therapy from imatinib mesylate to generic copy of Imatinib on hematologic response in patients with chronic phase chronic myeloid leukemia: single center study. Hematologica 2011; 96(2): Abstract 1219. 20. Kesselheim AS, Misono AS, Lee JL et al. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and metaanalysis. JAMA 2008; 300(21): 2514–2526.
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issues. In a survey of 839 physicians, for instance, nearly a quarter had a negative perception of the efficacy and 50% of the quality of generic medications [18]. Furthermore, there have been reports of low quality substitutes in oncology in low and middle income countries. For example, a study in Iraq showed that a significant proportion of patients with chronic myelogenous leukemia lost hematological, cytogenetic and molecular control after switching from branded to generic imatinib [19]. Quality assurance with the use of good manufacturing practices and adequate supervision by regulatory authorities is of paramount importance to ensure bioequivalence, and therefore the safety and efficacy of generic medications. A systematic review and meta-analysis of 38 randomized, controlled trials comparing generic and branded cardiovascular drugs confirmed their clinical equivalence [20]. Little has been published about the safety, efficacy and economic implications of the use of generic oncology medications, however, especially in low and middle income countries, and this gap clearly needs to be filled by further studies. Investigators from India, with grant support from Fresenius-Kabi, have retrospectively collected clinical data on 393 patients who received generic versions of docetaxel, oxaliplatin, irinotecan and gemcitabine (Personal communication to Dr G. de L. Lopes Jr). The median survival ranged from 12.8 months for patients with lung cancer (66% had metastatic disease) to 30 months for patients with colon cancer (67% of patients had metastatic disease) and 47 months for patients with breast cancer (45% had metastatic disease) and between 20% and 45% of patients reported serious adverse events. These data seem to conform to expectations of survival and toxicity but it is clear that the creation of formal registries would help the oncology community have a more precise estimate of the clinical equivalence of generic drugs beyond the bioequivalence required for their marketing approvals. In conclusion, generic substitution for frequently used chemotherapy drugs in the treatment of common cancers has an enormous potential to generate significant cost savings and increase access to treatment in India.
Annals of Oncology