The state of chemotherapy for cancer in 2010

Transcription

1 Measure 21 THE CARE AND LIVES OF THE ILL The state of chemotherapy for cancer in 2010 COLLECTION Reports & summaries ANALYSIS OF RECENT DEVELOPMENTS IN THE PRACTICE OF CHEMOTHERAPY IN FRANCE DEBATE AND PROPOSALS FOR IMPROVED CONTROL OF COSTS AND PRACTICES

2 2 THE STATE OF CHEMOTHERAPY The Institut National du Cancer is the national scientific health agency tasked with coordinating the fight against cancer in France. This document is available for download from the following site: THIS REPORT IS PART OF THE IMPLEMENTATION OF THE CANCER PLAN. Measure 21: Guarantee equal access to treatments and innovations Action 21.1: Facilitate access to treatment with innovative drugs This document must be referred to as follows: The state of chemotherapy for cancer in Collection Reports & summaries, collective work published by INCa, Boulogne-Billancourt, September This document may be reproduced or freely shared for private non-commercial use or for short citations For any other use, please request authorization from INCa by filling out a reproduction request form available on the internet at or through INCa s institutional communication department at the following address: diffusion@institutcancer.fr

3 THE STATE OF CHEMOTHERAPY 3 TABLE OF CONTENTS Preface 5 I. The number of patients treated for cancer in France has increased by 12% compared with 2005 and cancer mortality has diminished 7 II. The number of patients treated by chemotherapy has increased dramatically: More than 270,000 patients received chemotherapy in 2009 (+ 24% compared to 2005) 8 III. Chemotherapy is now part of standard care for an increasing number of cancers, and its use is increasing 9 IV. The use of anticancer drugs has seen quantitative growth and a marked change in quality 10 V. Chemotherapy has continued its growth in the hospital environment. The amount of (intravenous) chemotherapy performed has increased by + 4.7% in comparison with This practice is mostly concentrated in the 473 institutions authorized to perform this type of treatment by the French Regional Health Authorities (RHAs). 91% of treatments are performed on an outpatient basis 13 VI. Oral chemotherapy, taken at home, has also seen a marked growth 16 VII. The use of new substances in chemotherapy has continued to expand rapidly in the hospital sector, generating high and increasing treatment costs (> 1 billion euros in the public and private sectors in 2009, an increase of 6.5% compared to 2008) 18 >>>

4 4 THE STATE OF CHEMOTHERAPY VIII. The substances used have changed qualitatively: In 2009, "biotherapy" substances were the most widely-used category for the second year in a row and account for 57% of the cost of anticancer substances used (listed in the appendix) 20 IX. Debates aimed at improving the use, in terms of safety and cost control, of innovative and costly substances for anti-cancer chemotherapy 25 Methodological appendix 31 List of anticancer drugs on the "non-fixed-tariff" list in 2009 (INN) which was used as the basis to analyze the 2009 data in the report 32 Additional appendices 33 List of the 30 new oncology substances which were granted marketing authorization for the first time in Europe from 2004 to July List of the anticancer drugs on the "non-fixed-tariff" list in July 2010 according to their registration date 34

5 THE STATE OF CHEMOTHERAPY 5 PREFACE This document collates and analyzes recent changes in the practice of chemotherapy for cancer in France. The term chemotherapy is generally used to refer to the use of cytostatic substances which impede the growth of cells in the rapid multiplication phase. This document will also discuss "new substances", of biotechnological or other origin, whose mechanisms of action are "better" at targeting the biological alterations present in the sub-groups of cancers. Some of these new substances are often referred to as "biotherapy" (e.g.: monoclonal antibodies), targeted therapies etc. The goal of this report is to establish a consensus regarding the state of this healthcare practice in the context of changing needs, practices, cost and legitimate hopes borne by a surge of innovations now available to patients being treated for these diseases. This document refers not only to the practice of intravenous chemotherapy in healthcare establishments, but also highlights the rapid changes which have taken place in oral chemotherapy prescribed by specialists in these establishments which are taken at home. The economic and practice-derived data analyzed are focused on the use of certain substances, following innovative practices, which are widely available in France subject to the "proper use guidelines" produced by INCa and Afssaps 1. This report is part of the implementation of the cancer plan. Measure 21: Guarantee equal access to treatments and innovations. Action 21.1: Facilitate access to treatment with innovative drugs. Include a report on the status of cancer-fighting drugs in INCa s annual report. 1. The data is taken from an analysis of the ATIH/PMSI database, which includes the consumption of substances on the "non-fixed-tariff supplementary list" for public- and private-sector healthcare facilities, cancer centers, etc. Data taken from the Afssaps report (May 2010, 10th e edition): Entitled "Analysis of sales to dispensaries and hospitals in France: " was also used.

6 6 THE STATE OF CHEMOTHERAPY

7 THE STATE OF CHEMOTHERAPY 7 I. THE NUMBER OF PATIENTS TREATED FOR CANCER IN FRANCE HAS INCREASED BY 12% COMPARED TO 2005, AND THE MORTALITY RATE HAS DECREASED. The rapid increases in the incidence of cancer and population demographics has led to a growing number of new patients, estimated at 358,000 in 2010, a 12% increase in new cases requiring treatment compared with 2005 (320,000 cases) 2. The number of deaths from cancer was estimated at 147,000 in 2010, compared to 146,000 in 2005 (+ 0.5%). The reduction in mortality per 100,000 inhabitants has increased over the past ten years (- 16% in men and - 8% in women) 3. This is the result of several factors such as a reduction in the incidence of certain types of cancer and improved overall access to earlier diagnoses, but also to progress made in care given to patients, including chemotherapy. This increase in the number of patients "requiring treatment" leads inevitably to a "quantitative" growth in the consumption of care for all cancer pathologies, including chemotherapy. FIGURE 1. EVOLUTION OF THE NUMBER OF CANCER INCIDENTS AND MORTALITY FROM 1990 TO 2010 IN FRANCE 250,000 Cas Incidence among men TSM ,000 Cas Incidence among women TSM , , , , , , ,000 50, Year Years observed Projected Years Year Cas Mortality among men TSM 100, Cas Mortality among women TSM 100, , , ,000 60,000 40, , ,000 20, Source: InVS 2010 Year Year 2. Hospices civils de Lyon/Institut de veille sanitaire/institut National du Cancer/Francim/Institut national de la santé et de la recherche médicale. "Projections de l incidence et de la mortalité par cancer en France en 2010". Technical report April InVS. "Mortalité observée par cancer en France et dans 22 régions métropolitaines". "Situation pour la période et évolution entre et ".

8 8 THE STATE OF CHEMOTHERAPY II. THE NUMBER OF PATIENTS TREATED BY CHEMOTHERAPY HAS INCREASED DRAMATICALLY: MORE THAN 270,000 PATIENTS RECEIVED CHEMOTHERAPY IN 2009 (+ 24% COMPARED TO 2005) The number of patients treated using chemotherapy in healthcare institutions has undergone rapid and sustained growth in all private- and public hospital settings. More than 270,000 patients received this type of treatment in The increase in the number of patients treated was +9% between 2008 and % over the past five years. The rise in the number of patients undergoing chemotherapy is outstripping the number of new patients (by a factor of two): The indications for chemotherapy therefore involve an increasing number of cancer patients. FIGURE 2. PATIENTS TREATED WITH CHEMOTHERAPY IN HEALTHCARE INSTITUTIONS FROM 2002 TO 2009 Number of patients 300, , , , , , , , , , , , ,300 50, ESPIC and the others CLCC CHU- R CH Private All institutions Source: ATIH-PMSI MCO base updated /INCa treatment and base 2009 INCa treatment

9 THE STATE OF CHEMOTHERAPY 9 III. CHEMOTHERAPY IS NOW PART OF STANDARD CARE FOR AN INCREASING NUMBER OF TYPES OF CANCER Cancers can spread beyond the initial tumor, which is why this is such a serious condition. This characteristic justifies the use of systemic treatments as part of the initial treatment either in addition to localized treatments (known as "adjuvant") or as the dominant or sole means of treatment 4. The growth of chemotherapy indications, which stem from clinical research, have contributed to an improvement in the survival and "cure" rates of a number of the most common cancer pathologies 5. Chemotherapy is the standard treatment in the case of relapse and metastasis. In the context of this unfortunate prognosis, new chemotherapy practices have greatly extended patients life expectancy, sometimes for very extended periods of time (hence the description of the illness as "chronic"). These results were obtained thanks to prolonged, repeated and continuous treat ments for certain metastatic cancers such as colorectal, breast, lung etc. The contribution provided by "new substances" has been significant in this particular context. Treatment by chemotherapy for "advanced" forms of the disease have now been validated as the "standard" treatment by learned societies and national and international evaluation agencies with "levels of proof" of measured benefits and commonly documented cost/efficacy ratios. The practice of chemotherapy in the treatment of cancer is conducted in a validated and harmonized context via the regular publication of joint national recommendations by the HAS and INCa, produced in collaboration with learned societies. These recommendations provide structure and support for other major measures set out in the Cancer Plan, such as obligatory multidisciplinary meetings prior to initiating patient treatment 6 and the requirement to offer treatments based on good practice standards in healthcare institutions authorized to perform cancer treatments such as chemotherapy. 4. To quote significant examples of the practice of chemotherapy and the treatment of the most common forms of cancer such as: Breast cancers (51,000 new cases per year), colorectal cancers (39,000 new cases per year), lung cancers (32,000 new cases over year) and malignant lymphoma (13,000 new cases per year), etc. 5. "Survie attendue des patients atteints de cancer en France: État des lieux et perspectives" ,000 were performed in Ref: "Synthèse Nationale des tableaux de bord de réseaux régionaux de cancérologie". July 2010, (

10 10 THE STATE OF CHEMOTHERAPY IV. THE USE OF ANTICANCER DRUGS HAS SEEN QUANTITATIVE GROWTH AND A MARKED CHANGE IN QUALITY Other than the increased use of "old" substances in more patients, in new indications, and for extended periods of time, since the beginning of the decade there has been an acceleration in the appearance and use of numerous "new substances". These new substances now occupy a large section of the anticancer substance market. This evolution is illustrated in figure 3 which expresses the sales of these substances in Europe, based on the date they entered the market 7. There is an increasing growth in the share of overall anticancer expenditure devoted to the newest substances. FIGURE 3. EVOLUTION OF ANTICANCER DRUG SALES ( /100,000 INHABITANTS) IN EUROPE ACCORDING TO THEIR MARKET LAUNCH DATE 3,000,000 2,500,000 2,000,000 Date of placing on the market ,500, ,000,000 <= , Source: From N. Wilking et al. 7. "Comparator report on patient access to cancer drugs in Europe" Nils Wilking et al. Karolinska Institute ww.comparatorreports.se. ASCO 2010 abstract N 6525 Access to oncology drugs in France, Germany, Great Britain, Spain and Italy. A comparison based on sales years

11 THE STATE OF CHEMOTHERAPY 11 The oncology sector is particularly dynamic in terms of keeping up to date with the development and launch of new drugs. From 2004 to July 2010, 30 new oncology substances were granted marketing authorization for the first time and were quickly made available in France 8 The marketing authorization decisions taken by the regulatory agencies (FDA, EMA, Afssaps) with regard to oncology drugs are generally based on documented improvements in progressionfree and/or overall survival rates (depending on context). Several of these marketing authorization indications were considered to bring about a major or significant "improvement in actual benefit" (IAB). These new substances are less often cytostatic drugs, belonging instead to a new class of substances which target biological phenomena. They generally stem from an explosion of knowledge which has occurred over the past few years in the biology of cancer. Several of these new substances have come directly or indirectly from biotechnology. Among these new substances, monoclonal antibodies which attack biological targets in tumor cells currently hold a major place in the market. Almost half of the new substances on the market were "biotherapy" substances, many of which are monoclonal antibodies. In addition to the "quantitative evolution" in the practice of chemotherapy (more patients to be treated, in more indications), it is important to stress the "impact of the qualitative evolution" of the new substances that have recently become available. As these therapies target biological phenomena present in only sub-groups of patients, it is therefore necessary to analyze all the tumors of potential patients (often by using a molecular test) before choosing the appropriate substance. Access to these chemotherapy "companion" tests, or biomarkers, is crucial to avoiding treatments being given blindly to all patients when only a fraction of them will benefit. It is becoming increasingly possible to define which particular patients will benefit. >>> 8. In 2009, 6 new anticancer substances were put on the market: Firmagon degarelix, Javlor vinflunine, Removab catumaxomab, Mepact mifamurtide, Afinitor everolimus and Iressa gefitinib.

12 12 THE STATE OF CHEMOTHERAPY This evolution towards personalized treatments has already had a major effect on the practice and organization of cancer care, and the trend is set to continue: Access to molecular typing of the patient s tumor before treatment is crucial in order to offer patients every possible chance of benefiting from personalized treatment. These tests are performed on a very large scale in 28 hospital molecular genetics platforms. In 2009, a battery of 44 tests was available to these platforms and 102,000 patients had one or more of these tests 9 with financing coming from INCa and health insurance. Eleven of the 44 tests were performed as a part of access to targeted therapy and were conducted on 42,000 patients in 2009 (9 of these tests are direct indicators of whether the patient would benefit from a substance that is currently on the market) Improving the prognosis of survival for patients being treated also has a major impact on public health: Often, patients are (and will be) treated and followed for a longer period, though increasingly healthcare institutions are treating patients on an outpatient basis for shorter periods, which has an impact on "community care", because treatments are very often taken at home with the active and increasing involvement of GPs, pharmacists and nurses. Evidence for this can be seen in the increased use of "oral chemotherapy", a suitable administration route for many therapeutic classes of innovative drugs (such as kinase inhibitors, the use of which is increasing rapidly) These changes have also had a major impact on the rapid evolution of treatment costs, the optimization and control of which presents a major challenge to all healthcare systems. In general, and thanks in particular to the policies of the Cancer Plans, the speed and equity of access to the benefits of innovation in cancer treatments has been particularly notable in France (compared to other European countries, see reference 7). 9. "Summary of the activity of hospital molecular genetics of cancer platforms in 2009". INCa:

13 THE STATE OF CHEMOTHERAPY 13 V. CHEMOTHERAPY HAS CONTINUED ITS GROWTH IN THE HOSPITAL ENVIRONMENT. THE AMOUNT OF (INTRAVENOUS) CHEMOTHERAPY PERFORMED HAS INCREASED BY + 4.7% IN COMPARISON WITH THIS PRACTICE IS MOSTLY CONCENTRATED IN THE 473 INSTITUTIONS AUTHORIZED TO PERFORM THIS TYPE OF TREATMENT BY THE RHAS. 91% OF TREATMENTS ARE PERFORMED ON AN OUTPATIENT BASIS Since 2009, this practice has been concentrated in 473 health institutions (out of 881) which were authorized by the RHAs on the basis of designation criteria. Other "associated" institutions are involved in patient care on geographical grounds and because of close ties to the authorized institutions which were responsible for the primary prescription. The geographical distribution of these institutions is presented at the following website: MAPPING OF THE SUPPLY OF HOSPITAL CARE IN CANCEROLOGIN In 2009, over 2,000,000 stays and sessions for chemotherapy were conducted in healthcare institutions (+ 4,7% compared to 2008). 91% of the treatments were performed repeatedly as day sessions, and only 9% of patients were treated on an in-patient basis. The average number of sessions per patient in 2009 was 7.1 (median 5, Q1 : 2, Q3 : 10). the overall gender ratio (M:F) of patients treated was 0.98 (with more women treated as out-patients, where the gender ratio is 0.86). >>>

14 14 THE STATE OF CHEMOTHERAPY The average age of the patients treated was 61.4 (median 62) with a bimodal distribution (see the diagram below). 9,000 8,000 7,000 6,000 5,000 4,000 3,000 2,000 1, Five major cancer pathologies accounted for 77.8% of the chemotherapy performed in 2009: Digestive cancers 28%; Breast cancers 19.5%; Hematological neoplasias 13.2%; Lung cancers 11.8%; Gynecological cancers 5.3%.

15 THE STATE OF CHEMOTHERAPY 15 FIGURE 4. DISTRIBUTION OF PATIENTS UNDERGOING CHEMOTHERAPY IN HEALTHCARE INSTITUTIONS AS A FUNCTION OF THE MAJOR TYPES OF CANCER OTHER DEVICES 479,015 DIGESTIVE 613,471 GYNECOLOGY 116,277 RESPIRATORY DEVICES 263,816 BREAST 425,580 HEMATOLOGY 289,122 Source: ATIH-PMSI MCO Base 2009 INCa Treatment This area of activity has a strong economic impact on the hospitalization sector in particular: The global hospitalization costs for chemotherapy were estimated in 2009 at 1.04 billion euros (fixed-tariff scale, not including expensive substances financed outside the fixed-tariff system). In 2008, anticancer drugs were the single largest expenditure for hospitals 10, accounting for 30% of hospital drug sales. 10. Afssaps, report "Analyse des ventes de médicaments aux hôpitaux et officines en France ". May 2010.

16 16 THE STATE OF CHEMOTHERAPY VI. ORAL CHEMOTHERAPY, TAKEN AT HOME, HAS ALSO SEEN MARKED GROWTH Oral chemotherapy prescribed by specialists in healthcare institutions is becoming more commonplace. These drugs, which are not restricted to hospital use only, are delivered in dispensaries and taken at home. These substances may, depending on the situation, be given in addition to intravenous substances administered in a hospital environment, as a substitute for them, or may represent the sole form of treatment. Several of these substances belong to new therapeutic classes (often inhibitors of kinases which are activated by particular signals in tumor cells). This mechanism, in addition to other properties, restricts their use to specific molecular abnormalities in the patient s tumor which have to be identified. These substances therefore belong to the category of "targeted therapies". This class of drugs is often administered over a period of months or years: They have as a consequence made a significant contribution to making several types of cancer "chronic", improving both the lifespan and the quality of life for patients. Though their use has little impact on the financial burden of hospitals, where consultants make decisions as to indication, prescription and follow-up, they are increasingly used in a primary care setting. In 2008, antineoplastics and immunomodulators (ATC class L) were at the 5 th rank for the most sold, in terms of price in dispensaries (9.5% of the market, in value, for dispensary drugs) 11. Within this class (ATC L), the sales figures for antineoplastics (class ATC L01) reached 382 billion in Spending on antineoplastics has practically tripled since This growth followed the decision to allow imatinib (Glivec ) to be prescribed in a non-hospital setting in The granting of new marketing authorizations for gefitinib (Iressa ) and erlotinib (Tarceva ) in lung cancers on the primary care market has boosted this growth. 11. Their average unit cost is globally higher than that of the other specialties sold in dispensaries: In fact, the drugs in this class only represent 0.4% of sales for units sold at dispensaries (see. Reference 10).

17 THE STATE OF CHEMOTHERAPY 17 FIGURE 5. THE EVOLUTION OF SALES OF ANTINEOPLASTICS IN DISPENSARIES IN MILLIONS OF EUROS Anticancer sales, pharmacies Source: Afssaps, report 2010 In 2008, an antineoplastic drug imatinib (Glivec ) moved to 8 th place for the most widely sold pharmaceutical products at dispensaries (in value). Though it indication is limited to rare "orphan" diseases (annual incidence of around 1,500 new patients per year), this targeted treatment is highly effective and can be administered for very prolonged periods to patients who have a long and "normal" life without hospitalization. It is worth mentioning the interest and the growth in new oral substances used at home in 2009 such as lapatinib (Tyverb ) for breast cancer, antiangiogenic drugs for kidney and liver cancers (Sorafenib (Nexavar ), sunitinib (Sutent ) and others. New and numerous major oral drugs are in development and may be the subject of new marketing authorizations in the months and years ahead for lung cancers, melanomas, etc. The practice of oral chemotherapy is therefore coming to occupy a major place in anticancer treatment, not only a possible substitute for intravenous forms, but also in terms of access to drugs which are innovative (and costly) which are increasingly being used in patients homes.

18 18 THE STATE OF CHEMOTHERAPY VII. THE USE OF NEW CHEMOTHERAPY SUBSTANCES HAVE DEVELOPED RAPIDLY IN THE HOSPITAL SECTOR AND HAVE GENERATED HIGH TREATMENT COSTS WHICH ARE ONLY INCREASING (> 1 BILLION EUROS IN THE PUBLIC SECTOR AND ESPIC IN 2009, AN INCREASE OF 6,5% COMPARED TO 2008) Since 2004, the cost of some expensive substances on the fixed-tariff supplementary list has been reimbursed to healthcare institutions in order to allow more equitable access by patients in all hospital sectors to these types of treatment 12, subject to compliance with good practice guidelines. These good practice guidelines 13 are defined nationally and are jointly published by the Institut National du Cancer and Afssaps after consulting the HAS. They define the conditions under which substances not on the fixed-tariff list can be properly used for particular conditions according to two single parameters: Marketing authorization (MA) and temporary therapeutic protocol (TTP) 14. Failure to comply with the guidelines for the use of these substances by the healthcare institutions leads to financial penalties (reimbursement is reduced by up to 30%). The good practice guidelines for "non-fixed-tariff" drugs are available at and they are updated at least once a year for the major cancer pathologies: Digestive cancers Bronchial cancers and malignant pleural mesotheliomas Breast cancers Adult hematological cancers Gynecological cancers Male urological and genital cancers Epidermoid carcinomas of the head and neck Adult malignant cerebral tumors (in development) Pediatric cancers (in development) 12. Several of these substances cost in the order of 1,000 euros per dose, which is more than the eventual GHS cost for chemotherapy. The cost of these substances is reimbursed in addition to the GHS fees for chemotherapy billed by health institutions. 13. The best practice guidelines do not constitute recommendations for the practice but rather a classification of the situational guidelines permitted on the basis of an analysis of scientific literature which allows for an evaluation of the risk versus benefit in order to justify the financial control taken by medical insurance. 14. The PTT is the framework used and the reimbursement outside of the AMM for the substance. The PTT is temporary (annual revision for a duration of a maximum of 4 years).

19 THE STATE OF CHEMOTHERAPY 19 The use of the substances on the supplementary list is growing in all healthcare institutions concerned. FIGURE 6. DISTRIBUTION OF EXPENDITURES FOR ANTICANCER SUBSTANCES ON THE SUPPLEMENTARY LIST (EXCLUDING THE PRIVATE SECTOR) PER TYPE OF ESTABLISHMENT 1,200,000,000 Amount in Euros 1,000,000, ,000, ,000, ,000, ,974, ,088, ,756, ,382, ,651,585 1,038,421, ,000,000 0 Year Year Year Year Year Year ESPIC and HL CLCC CHU-R Total anticancer expenses CH Sources: Updated ATIH-PMSI database for /2009 INCa treatment and database/inca treatment The use of expensive "non-fixed-tariff" substances reimbursed does not relate only to anticancer substances, although these represent a significant proportion: In 2009, anticancer drugs accounted for 57% of the total cost of expensive substances reimbursed that were not on the fixed-tariff list.

20 20 THE STATE OF CHEMOTHERAPY VIII. THE SUBSTANCES USED HAVE EVOLVED QUALITATIVELY: IN 2009 "BIOTHERAPY" SUBSTANCES WERE USED MOST OFTEN FOR THE SECOND YEAR IN A ROW AND REPRESENTED 57% OF THE COST FOR ANTICANCER SUBSTANCES USED (ON THE LIST ATTACHED AS AN APPENDIX) The typology of the class of substances used over the course of time illustrates the major changes which have occurred in chemotherapy drugs, which stemmed from a global wave of research and development innovations in the sector 15. Over time, the importance of cytostatic substances has diminished, and they have largely been replaced by biotherapy substances which act, often via an antibody, on a biological target in the cancer cell and "spare" more normal cells. VIII.1. IN 2009, 57% OF THE COSTS AND PRACTICES WERE CONCENTRATED ON BIOTHERAPY SUBSTANCES FIGURE 7. DISTRIBUTION OF EXPENDITURE FROM 2004 TO 2009 FOR ANTICANCER CATEGORIES NOT ON THE FIXED-TARIFF LIST (EXCLUDING THE PRIVATE SECTOR) 1,600,000,000 1,400,000,000 Amount of expenses in Euros 1,200,000,000 1,000,000, ,000, ,000, ,974, ,088, ,756, ,382,095 1,038,421, ,651, ,000, ,000,000 0 Year Year Year Year Year Year Other anticancer Biotherapy Cytostatic Total anticancer expenses Source: ATIH-PMSI MCO base updated /INCa treatment and base 2009 INCa treatment 15. On a global scale, in 2007, the sales numbers for antibodies was $11 billion or 34% of the total market for anticancer drugs. The estimated sales figures for anticancer drugs may reach $43 billion by 2013 (The Cancer Market Outlook to 2013: Competitive Landscape, Pipeline Analysis and Growth Opportunities. Rachel Thompson).

21 THE STATE OF CHEMOTHERAPY 21 VIII.2. THE COST OF ANTICANCER SUBSTANCES NOT ON THE FIXED-TARIFF LIST REMAIN FOCUSED ON A VERY SMALL NUMBER OF SUBSTANCES 91% of the costs are focused on 10 substances, the remaining 9% of the costs are distributed among all the other substances. FIGURE 8. DISTRIBUTION (IN %) OF EXPENDITURE ON THE 10 MOST PRESCRIBED ANTICANCER SUBSTANCES N 2009 THAT ARE NOT ON THE FIXED-TARIFF LIST (EXCLUDING THE PRIVATE SECTOR) 9.1 % Gemcitabine 3.4% Liposomal doxorubicin hydrochloride 2% Bevacizumab 19.3% Irinotecan 4.8% Bortezomib 5.5% Cetuximab 6.7% Cytostatic Biotherapy Other anticancer All other anti-cancer molecules Rituximab 16.8% Pemetrexed 8.1% Docetaxel 11.5% Trastuzumab 12.8% Source: ATIH-PMSI MCO Base 2009 INCa Treatment >>>

22 22 THE STATE OF CHEMOTHERAPY VIII.3. FIVE SUBSTANCES WHICH ARE PARTICULARLY REPRESENTATIVE OF PRACTICES ACCOUNT FOR 69% OF EXPENDITURE IN 2009 AND ILLUSTRATE THE RAPID PACE OF QUALITATIVE CHANGE IN PRACTICE Bevacizumab Avastin : 19.3% Rituximab Mabthera : 16.8% Trastuzumab Herceptin : 12.8% Docetaxel Taxotere : 11.5% Pemetrexed Alimta : 8.1% The dynamics of the trend in the use of these substances is illustrated in the following diagram. FIGURE 9. TREND IN EXPENDITURE FROM 2006 TO 2009 FOR ANTICANCER SUBSTANCES THAT ARE NOT ON THE FIXED-TARIFF LIST (EXCLUDING THE PRIVATE SECTOR) 250,000, ,000,000 Cytostatic Biotherapy 150,000, ,000,000 50,000, Bevacizumab Rituximab Trastuzumab Docetaxel Pemetrexed Source: ATIH-PMSI MCO base updated /INCa treatment and base 2009 INCa treatment

23 THE STATE OF CHEMOTHERAPY 23 A number of comments can be made on the trend in expenditure on these five representative substances, which is quite a good illustration of the rapid pace of change in terms of quality and practice standards that have already been mentioned. Pemetrexed Alimta saw a rapid growth in its sales figures in 2009: It was shown that this cytostatic substance used for lung cancers improved the survival of patients with extended use. This situation illustrates the economic impact of increasing lengths of treatment. Docetaxel Taxotere has seen elevated and stable sales figures: This cytostatic is part of routine chemotherapy for breast cancer in adjuvant and metastatic situations (clinical research has demonstrated 16 the benefits to survival and cost efficiency). Other than this very common form of cancer, docetaxel is indicated in several other cancers such as lung cancer. This situation illustrates the volume effect and the (stabilized) application of new practice standards to the population. Trastuzumab Herceptin is a targeted monoclonal antibody treatment which is active only in the 15-25% of breast cancers with an overexpression of the HER2-neu gene. This substance has seen elevated and stable sales figures. This treatment is widely used, but is limited to its target because of rapid access to this substance, and collaborative financing for tests which limit its practice. The use of this substance has been shown to be cost-effective in this context 17. Rituximab Mabthera is a targeted monoclonal antibody treatment which acts only on B lymphocytes, the major component of non-hodgkin s lymphoma, a common form of lymphoid neoplasia (10,000 new cases estimated in 2010). Its indications have been widely extended over recent years. In addition, the extension of treatment improves survival in sub-groups of common follicular lymphomas. The observed growth is connected to the economic impact of widened indications and is associated with extended lengths of treatment. It is worth noting that fast and widespread access to this substance in France has contributed to a marked decline in mortality related to these illnesses in the population, as indicated in figure 10. >>> 16. J Clin Oncol Dec 20;24(36): Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial; Ann Oncol Jul;21(7): Epub 2009 Dec 27.Cost-effectiveness of adjuvant docetaxel for node-positive breast cancer patients: results of the PACS 01 economic study. 17. Elkin EB, et al. HER-2 testing and trastuzumab therapy for metastatic breast cancer: A cost-effectiveness analysis. JCO, 2004:22 (5):

24 24 THE STATE OF CHEMOTHERAPY FIGURE 10 EVOLUTION OF MORTALITY RATES RELATED TO NON HODGKIN S LYMPHOMAS IN FRANCE PER 100,000 INHABITANTS (THE SHADED PARTS AFTER 2007 ARE PROJECTIONS FROM THE ESTIMATE) TSM for 100, Male Female (Source: InVS, Cedepic, INCa, 2010) Bevacizumab Avastin is a monoclonal antibody which acts by inhibiting angiogenesis (production of neovessels) to block tumor growth. The indications for this substance, the only monoclonal antibody to be registered in this new drug class, are very broad in metastatic breast, lung and colorectal cancers (the three most common cancers in France). There are not (yet) any tests that can ascertain which patients would benefit most from this substance. Therefore, it is currently administered to all patients. This substance is the largest source of anticancer expenditure worldwide (and in France): This fact is related to the breadth of its indication in frequent situations with a poor prognosis, for which new marketing authorizations are obtained very quickly.

25 THE STATE OF CHEMOTHERAPY 25 IX. DEBATES AIMED AT IMPROVING THE USE, IN TERMS OF SAFETY AND COST CONTROL, OF INNOVATIVE AND COSTLY SUBSTANCES FOR ANTI-CANCER CHEMOTHERAPY Without claiming to be exhaustive, and while attempting to remain specific, several paths and measures may be explored and/or implemented. Though the combined effects of the number of patients being treated and benefiting from these treatments and the arrival of new substances lead to a constant growth in this area of activity, new measures might help improve control over these major changes. IX.1. IMPLEMENTATION AND CONTROL OF RESPECT FOR THE GOOD PRACTICE GUIDELINES (GPG) SHOULD PLAY A MAJOR AND GROWING ROLE, AND BE EXTENDED TO MORE SUBSTANCES, IN PARTICULAR FOR ORAL CHEMOTHERAPY This measure is, in our opinion, essential in the short term for several reasons: The safety of practice first and foremost: These innovative substances are not without risk, especially outside the very broad access offered to healthcare institutions, prescribers and patients in France. The dynamics of change in practices brought about by compliance with the guidelines, which govern more generous reimbursement. The control process, already underway, therefore needs to be continued and to become an established part of the system. a. Monitoring compliance with the guidelines for substances appearing on the supplementary list should now be a regular activity: > The guidelines are clear, known by prescribers, frequently updated, and leave no room for interpretation: The GPGs define the MAs, the TTPs, the unacceptable situations (ASs), while still leaving prescribers the option to prescribe particular substances in exceptional circumstances which they have to justify. > Control can now be targeted solely at institutions authorized to practice chemotherapy by the RHAs in > Verification of compliance with GPGs should be prioritized for the representative substances (previously mentioned). The use of these substances can often be compared against the representative pathologies for which they are indicated 18. >>> 18. For example, the use of Rituximab in an institutions which treat hematological pathologies and the use of Trastuzumab in institutions which treat breast cancer.

26 26 THE STATE OF CHEMOTHERAPY b. The field of substances covered by GPGs could be extended to new oral chemotherapy substances which are being used more often: Although this new practice provides considerable benefits in terms of patient s quality of life, the substances used carry the same (or greater) potential risk as intravenous chemotherapy if the guidelines are not followed. Prescribers, who are hospital consultants, should be able to benefit from the same types of guidelines governing primary care prescriptions when deciding on which substances to prescribe. Additionally, the increasing prescription of these "targeted" oral therapies depends on the relevant target having been identified in the patient s tumor by a (hospital) molecular biology platform. It is important for good practice guidelines to be updated regularly in these highly innovative fields where an understanding of use indications needs regular refreshment. Finally, the rapid rise in costs of these "dispensary" drugs would be improved by such an arrangement and would avoid possible displacement of practices not in accordance with the guidelines, shifting the financial burden to the primary care sector. c. Controlling compliance with the new GPGs on targeted oral chemotherapy could be accomplished by prioritizing the "targeted substances used in representative pathologies". The methods could be similar and synchronous with those used for intravenous substances. This evolution and practice will be facilitated by the deregulation underway in the health system, in particular via the RHAs which will have access to the national guidelines to monitor these new therapies. IX.2. SPECIFIC MEASURES ARE NECESSARY TO RESTRAIN THE USE OF "TARGETED CHEMOTHERAPY" TO PATIENTS WHOSE TUMORS CONTAIN BIOMARKERS WHICH HAVE BEEN IDENTIFIED PRIOR TO THE PRESCRIPTION OF THESE SUBSTANCES An increasing number of substances, used in 2009, fall under this definition: They are substances which "target" a molecular event that determines their anti-tumoral activity. They are therefore ONLY effective if a molecular test (for biomarkers) has been performed on a particular patient s particular tumor, confirming that the substance will be beneficial. The savings relating to the cessation of prescriptions that are useless to patients, and also to the overall cost, is potentially huge: As a broad outline, only 10 to 40% of candidate patients should receive the substance rather than a "blind" prescription given to 100% of the patients (and at a huge cost). The Institut National du Cancer regularly updates its "biomarker catalog" which is indispensable for the prescription of these substances. In 2009, 9 different biomarkers influenced the use of 8 substances currently on the market in 7 sub-groups of cancers. This list is growing, as is the number of substances involved (see details in the document cited in reference 9).

27 THE STATE OF CHEMOTHERAPY 27 Funding for these tests is initially ensured by grants from INCa and subsequently the PLFSS: The 28 hospital molecular genetics of cancer platforms conduct tests for all patients in the region, regardless of where they are being treated, and without any financial burden on the establishments and prescribing laboratories. It is worth noting that in 2009, two common forms of cancer benefited from this typing throughout the country: Colorectal cancers and pulmonary adenocarcinomas. A significant number of tests were performed in accordance with epidemiological predictions. The feasibility of this approach in France is now ensured. FIGURE 11A. EVOLUTION OF THE NUMBER OF KRAS TESTS GIVEN FOR COLORECTAL CANCER 20,000 18,000 17,246 Number of patients 16,000 14,000 12,000 10,000 8,000 6,000 4,000 10,012 2, , FIGURE 11B. EVOLUTION OF THE AMOUNT OF RESEARCH ON EGFR MUTATIONS IN LUNG CANCER 8,000 7,000 7,554 Number of patients 6,000 5,000 4,000 3,000 2,000 1,269 2,667 1, First Semester 2010 >>>

28 28 THE STATE OF CHEMOTHERAPY a. The major impact of the new field of targeted therapies underlines the importance of implementing a good practice framework to structure the performance of these biomarker tests, which are being prepared by Afssaps and INCa, of continuing to fund them through suitable measures (MIGACs and "fees" whose costs bear no relation to the use of these substances in a way that is not in line with good practice), and to adapt any regulatory changes to their "status" (in collaboration with other European countries). b. The publication of good practice guidelines for indications (possibly MAs and TTPs) for these targeted substances, as of 2011, is in our view highly desirable in order to secure their use, and to support hospital prescribers and make them aware of their responsibilities. IX.3. SYSTEMATIC REVISION OF THE SUBSTANCES ON THE "SUPPLEMENTARY LIST" SHOULD HELP AVOID AN INFLATIONARY EFFECT TO THE ADVANTAGE OF SUBSTANCES WHICH ARE NOT INNOVATIVE AND ALLOW ACCESS TO THIS STATUS FOR NEW DRUGS The supplementary list system is still a major step forward in our healthcare system. The list has allowed equal access to innovations for all patients being treated in healthcare institutions, a move which is being followed up under Measure 21 of the Cancer Plan. While the economic criterion is the founding element of the list, further debate can still take place on the evolutivity of the list "non-fixed-tariff list" by applying two basic criteria: Medical innovation brought about by drugs and the concept of potential risks related to their use. In this context, the approval criteria for a new substance generally take account of: > The principle of innovation: The substance is judged to be innovative (recently put on the market and costly). It offers benefits in terms of patient management compared to existing therapeutic alternatives. > In terms of the risk context: Use of the substance is potentially dangerous outside a strict framework of use. Therefore, medical supervision of its use must be possible. With this in mind, a listing on the supplementary list of anticancer substances with an orphan drug status would allow a systematic framework for prescriptions via good practice guidelines to be created The administration of anticancers with orphan status may be difficult because it is used in selected institutions and because the patients in question are treated close to their homes throughout France. Recent arrangements to help fight rare forms of tumors ( are guaranteed depending on the type of tumor and the performance of inter-regional or national multidisciplinary collaboration before a therapeutic decision is made. This should guarantee the indications (as a part of the new GPG framework) and allow patients to be treated close to their own homes in institutions which may obtain reimbursement for substances which are not on the fixed-tariff list for this condition.

29 THE STATE OF CHEMOTHERAPY 29 Similarly, radiation criteria could take into account an evolution in the "innovative" character of the substance: > Having the substance listed as a generic drug is a defining marker for the lifespan of the innovation and may act as an invitation to reconsider the presence of the substance on the supplementary list 20. > The same may be said of a major reduction in the use of the product, a situation which may bring about a re-evaluation of its medical interest and possibly lead it to be removed from the list. Keeping the product on the list could actually offer a competitive advantage and/or encourage its prescription, in contrast with the principle of equal treatment of products. In all cases mentioned, risk impact analysis for shifting prescription as a result of the addition or removal of a substance remains an important element which should where possible be anticipated. IX.4. ACCESS TO CLINICAL TRIALS IN THE FIELD MUST BE REINFORCED FURTHER IN ORDER TO ACCELERATE KNOWLEDGE AND FACILITATE MORE RATIONAL USE OF THESE NEW SUBSTANCES (MEASURES SET OUT IN THE CANCER PLAN) Inclusion in clinical trials remains the safest and most fairest way to allow patients in metastatic, and sometimes refractory, conditions to benefit from a drug which is not yet on the market and which could modify the natural course of their illness. Numerous types of public financing are used (notably via the PHRC cancer 20 million euros/year, and labelization which is currently underway in approximately a dozen early trial centers) which should help the pharmaceutical industry in the early development of their anticancer substances in France in a high-quality context while making financial savings, expanding access for patients and allowing speedier development. The current collaboration between INCa and the American NCI has opened the field by giving France access, via the NCI, to the same substances currently under investigation in the United States. The use of these drugs for cancer is established after the initial phase of their introduction to the market via their use in multidisciplinary strategic therapies applied in various cancer situations: The conduct of large-scale clinical trials on the diseases treated by all hospital sectors is indispensable for a rapid evaluation of the role of these substances in the therapeutic arsenal against various forms of cancer. In addition, it optimizes their use, measures their impact on patients quality of life and supplies the data needed to evaluate their cost/efficiency/utility with greater speed. Facilitating access to clinical trials is an important criterion for establishments authorized to practice chemotherapy, which should continue to stimulate the abilities of promoters to extend their inclusions in these establishments, closer to patients own homes. >>> 20. A time lage between being added to the list of generic drugs and the release of a product should however be defined in order to take into account the time required for the product to be made available (on the market and the sale of the new generic product).

30 30 THE STATE OF CHEMOTHERAPY

31 THE STATE OF CHEMOTHERAPY 31 METHODOLOGICAL APPENDIX CLASSIFICATION OF ANTICANCER SUBSTANCES Anticancer substances on the drugs "non-fixed-tariff" list of drugs are classed according to their pharmacological mechanisms into 3 categories. 1. Conventional chemotherapy: Drugs whose main mode of action is to target the mechanisms involved in either normal or neoplastic cellular multiplication: This action is known as "cytotoxic" or "cytostatic". This category is referred to in the document under the term "CYTOSTATIC". The pharmacotherapeutic classes included in this group are: antimetabolics, alkylating agents, topoisomerase inhibitors, alkaloids and taxanes. 2. Targeted chemotherapy, unlike conventional chemotherapy: Drugs whose main mode of action is to target the actual mechanisms of onocogenesis, focusing specifically on cancerous cells. This category is referred to in the document under the term "BIOTHERAPY". The pharmacotherapeutic class which represents this group is: monoclonal antibodies. 3. This category is made up of anticancer substances whose method of action is not defined by the two groups referred to above.: It is referred to in the document under the term "OTHER ANTICANCERS". It comprises drugs with different modes of action (example: proteasome inhibitor). The list of these drugs and their classifications are listed below. DATA FIELDS STUDIED The data for consumption given in this document uses the updated ATIH/PMSI-MCO database for and the 2009 database. The data was processed by INCa. This data covers the anticancer drugs on the "non-fixed-tariff" list and analyze expenditure made by public- and private-sector institutions.

32 32 THE STATE OF CHEMOTHERAPY LIST OF ANTICANCER DRUGS ON THE "NON-FIXED-TARIFF" LIST IN 2009 (INN) WHICH WAS USED AS THE BASIS FOR ANALYZING THE 2009 DATA IN THE REPORT CATEGORY INN 21 Azacitidine Busulfan Carmustine Cladribine Clofarabine Cytarabine Daunorubicin Docetaxel Epirubicin Fludarabine Fotemustine Gemcitabine CYTOSTATICS Idarubicin Irinotecan Liposomal doxorubicin Nelarabine Oxaliplatin Paclitaxel Pegylated liposomol doxorubicin hydrochloride Pemetrexed Pentostatin Pirarubicin Raltitrexed Topotecan Vinorelbine Alemtuzumab Bevacizumab Cetuximab TARGETED THERAPY Panitumumab Rituximab Trastuzumab Aldesleukin Arsenic trioxide Bortezomib Fulvestrant Iodinated fatty acid esters OTHER ANTICANCERS Ibritumomab tiutexan Lenalidomide Porfimer sodium Tasonermin Temsirolimus 21. The INNs may relate to multiple pharmaceutical products, generics and various presentations.

33 THE STATE OF CHEMOTHERAPY 33 ADDITIONAL APPENDICES LIST OF THE 30 NEW SUBSTANCES WHICH RECEIVED EUROPEAN MARKETING AUTHORIZATION FOR ONCOLOGY FROM 2004 TO JULY Pharmaceutical products INN Date of marketing authorization 1. Zevalin Ibritumomab tiutexan January Faslodex Fulvestrant March Photobarr Porfimer sodium March Velcade Bortezomib April Lysodren Mitotane April Erbitux Cetuximab June Alimta Pemetrexed September Avastin Bevacizumab January Tarceva Erlotinib September Evoltra Clofarabine May Nexavar Sorafenib July Sutent Sunitinib July Sprycel Dasatinib November Revlimid Lenalidomide June Atriance Nelarabine August Yondelis Trabectedin September Torisel Temsirolimus September Tasigna Nilotinib September Vectibix Panitumumab December Abraxane Albumin-bound paclitaxel January Thalidomide Thalidomide April Tyverb Lapatinib June Vidaza Azacitidine December Firmagon Degarelix February Mepact Mifamurtide March Removab Catumaxomab April Iressa Gefitinib June Afinitor Everolimus August Javlor Vinflunine September Arzerra Ofatumumab April Votrient Pazopanib June 2010

34 34 THE STATE OF CHEMOTHERAPY LIST OF ANTICANCER DRUGS ON THE "NON-FIXED TARIFF" LIST IN JULY 2010 ACCORDING TO THEIR APPROVAL DATE Approval date Pharmaceutical products INN 19/04/2010 JAVLOR Vinflunine 03/09/2009 VIDAZA Azacitidine 21/08/2009 HYCAMTIN (per os) Topotecan 17/06/2008 VECTIBIX Panitumumab 04/04/2008 TORISEL Temsirolimus 28/03/2008 ATRIANCE Nelarabine 20/02/2008 REVLIMID Lenalidomide 27/03/2007 EVOLTRA Clofarabine 03/02/2006 LITAK Cladribine 04/11/2005 DEPOCYTE Cytarabine 04/11/2005 FASLODEX Fulvestrant 26/07/2005 AVASTIN Bevacizumab 10/05/2005 ALIMTA Pemetrexed 10/05/2005 BEROMUN Tasonermin 10/05/2005 BICNU Carmustine 10/05/2005 BUSILVEX Busulfan 10/05/2005 CAELYX Pegylated liposomol doxorubicin hydrochloride 10/05/2005 CAMPTO Irinotecan 10/05/2005 DAUNOXOME Daunorubicin 10/05/2005 ERBITUX Cetuximab 10/05/2005 GEMZAR Gemcitabin 10/05/2005 GLIADEL Carmustine (implant) 10/05/2005 HERCEPTIN Trastuzumab 10/05/2005 HYCAMTIN Topotecan 10/05/2005 LEUSTATINE Cladribine >>>

35 THE STATE OF CHEMOTHERAPY 35 >>> LIST OF ANTICANCER DRUGS ON THE "NON-FIXED TARIFF" LIST IN JULY 2010 ACCORDING TO THEIR APPROVAL DATE Approval date Pharmaceutical products INN 10/05/2005 LIPIOCIS Iodinated fatty acid esters 10/05/2005 MABCAMPATH Alemtuzumab 10/05/2005 MABTHERA Rituximab 10/05/2005 MUPHORAN Fotemustine 10/05/2005 MYOCET Liposomal doxorubicin 10/05/2005 NIPENT Pentostatin 10/05/2005 PHOTOBARR Porfimer sodium 10/05/2005 PHOTOFRIN Porfimer sodium 10/05/2005 PROLEUKIN Aldesleukin 10/05/2005 TAXOTERE Docetaxel 10/05/2005 THEPRUBICINE Pirarubicin 10/05/2005 TOMUDEX Raltitrexed 10/05/2005 TRISENOX Arsenic trioxide 10/05/2005 VELCADE Bortezomib 10/05/2005 ZAVEDOS Idarubicin 10/05/2005 ZEVALIN Ibritumomab tiutexan

36 36 THE STATE OF CHEMOTHERAPY PERSONS WHO PARTICIPATED IN THE PRODUCTION OF THIS REPORT: Benoît MOURLAT, Department for Medication, Department of Patients Care and Life, French National Cancer Institute Dr Stéphanie GATHION, Department for Patient Care and Life Management, Department of Patients Care and Life, French National Cancer Institute Frédérique NOWAK, Taskforce for Anatomical Pathology and Genetics, Department of Patients Care and Life, French National Cancer Institute Dr Natalie HOOG LABOURET, Department for Medication, Department of Patients Care and Life, French National Cancer Institute As well as the teams from the Technical Agency for Hospital Information (ATIH) whom we would like to thank for submitting PMSI data.

37 THE STATE OF CHEMOTHERAPY 37 Notes

38 38 THE STATE OF CHEMOTHERAPY Notes

39 Published by the Institut National du Cancer Design/Production: Institut National du Cancer All rights reserved Siren : ISSN LEGAL DEPOSIT SEPTEMBER 2010

40 For more information please consult: REF: ETUSITCHIM10 Institut National du Cancer 52, avenue André Morizet Boulogne-Billancourt Cedex Tel.: Fax: