CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE
For the purposes of the survey, research funded by charities (organisations for public benefit that rely on donations for financial support, eg Cancer Research UK) was combined with that of private and not-for-profit organisations (those whose securities are not offered to the public, eg Wellcome Trust). Funding by a government agency was defined as an administrative unit of government, sup- ported in whole or part by public funds, charged by another official body or agen- cy to make reports, investigations or recommendations (eg Medical Research Council or National Institutes of Health).
The survey found that, in total, absolute spending on cancer research in the fis- cal year 2002/2003 by public funding organisations across Europe was €1.43 bil- lion, with the EC contributing approximately €90 million over this period. EU Member States accounted for 93% of total funding for cancer research. The EU 15 countries (France, Germany, Italy, Spain, the UK, Sweden, Finland, Denmark, Austria, Belgium, the Netherlands, Luxembourg, Ireland, Portugal and Greece [not including those countries that joined the EU on May 1, 2004]) accounted for just over 50% of this spending.
The National Cancer Institute’s Common Scientific Outline is the only validated tool that categorises expenditure according to the research domain. According to those organisations that report their annual research spend according to these research domains, the EU spends proportionally more on basic research and less on clinical research than the USA.
The average spending per country was €44.3 million with a median of €3.9 mil- lion; however, this varied greatly across Europe (Figure 5.2):
• 3 countries (UK, Germany and France) spent more than €100 million per year on cancer research
• 9 countries (Italy, the Netherlands, Sweden, Belgium, Denmark, Norway, Spain, Finland and Ireland) spent more than €10 million
• 10 countries spent less than €1 million
• of all the countries involved in this survey, only Bulgaria failed to report any financial information and only Malta reported a zero spend.
Figure 5.1.
Figure 5.2. Direct cancer research spend by country, including the EC and Trans-European Organisations (2002/2003).1
Figure 5.2.
The highest per capita spending was found in Sweden and the UK with just over €7 per capita, followed by approximately €5 per capita in Norway and Germany (Figure 5.3). The average per capita spending on cancer research across the entire EU (including the EC and Trans-European Organisations) was €2.56. However, the spend of the EU 15 countries is €3.67 per capita compared with spend in the USA of €17.63 per capita.
Figure 5.3. . Direct cancer research spend per capita for all Member States in the 2002/2003 survey, as well as the EU and the USA for comparison.1
CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE
Figure 5.4. Direct cancer research spend by organisation type and country 2002/2003.1
Figure 5.4.
Table 5.1. Three estimates of the capitalised costs (in € million) of an NCE2.
5.1.1 Distribution of cancer research funding between government
and the charitable sector
The survey identified 139 different sources of European cancer research funding contributing to the total spend of €1.43 billion for the fiscal year 2002/2003. Of these sources, 25 accounted for 80% of the total spend on research. Approxi- mately half of public funding for cancer research in the EU (including the Euro- pean Free Trade Association and Associate States) was provided by the charitable sector.
• 65 major charities across 23 countries contributed around €667.3 million to can- cer research; average spending for charities was €21.5 million (median spend of €400,000; ranging between €0 and €232 million)
• 74 governmental sources of cancer research funding across 28 countries reported a spend of €662.3 million in 2002/2003; average spending for government agen- cies was €21.4 million (median spend of €1.9 million; ranging between €0 and €226 million)
• 8 countries had no charitable organisational spend (Bulgaria, Estonia, Greece, Latvia, Lithuania, Malta, Romania and Slovenia) and 3 countries had no govern- mental spend (Bulgaria, Cyprus and Malta)
• 11 countries (Cyprus, Denmark, Hungary, Iceland, Israel, Italy, the Nether- lands, Norway, Poland, Sweden and the UK) had a charitable spend on cancer research greater than the government spend and 18 countries (Austria, Bel- gium, Czech Republic, Estonia, Finland, France, Germany, Greece, Ireland, Latvia, Lithuania, Luxembourg, Portugal, Romania, Slovak Republic, Slovenia, Spain and Turkey) had a governmental spend on cancer research greater than the charitable spend (Figure 5.4).
5.2 Private/commercial funding for cancer research
The pharmaceutical industry accounts for the overwhelming majority of all pri- vate commercial research funding. However, due to the lack of available data, the exact contribution of commercial organisations other than the pharmaceutical industry to cancer research funding cannot be determined. From 1987 to 2004, 45 oncology drugs out of a total of 555 new chemical entities (NCEs) [8.1%] en- tered the European market. In this report, three different approaches have been used to assess the spending in Europe on cancer research by private commercial organisations.
• Considering the cost of developing a new drug (NCE) and the number of NCEs entered into the European market. This gives an estimate of the private/for-profit spending supporting the new drugs coming to the European market regardless of where this money is spent.
• Estimating the total research and development (R&D) expenditure by pharma- ceutical companies in Europe on cancer research as a proportion of the total re- search expenditure. This approach highlights research spending by the European pharmaceutical industry regardless of whether this spending results in products marketed beyond the EU.
• Utilising a worldwide survey of pharmaceutical expenditure according to the dis- ease area (assuming that the share spent on cancer research is the same in Europe as in the rest of the world).
5.2.1 Cost of an NCE
In 2002, the European Federation of Pharmaceutical Industries and Associations highlighted the increasing costs of developing an NCE over time (Table 5.1).
Year Reference Cost of NCE (€ million)
1993 Office of Technology Assessment 307
1997 Myers and Howe 378
2001 DiMasi J., Tufts University – Centre for the Study of Drug Development 895
In this approach to determining pharmaceutical industry funding for cancer re- search, the total spending for each year was obtained by multiplying the number of oncology NCEs by the cost of a single NCE that same year (Table 5.2).
Years Number of NCEs Cost per NCE (€) Total spending (€) Spending per year (€)
1990-1994 8 307,000,000 2,456,000,000 491,200,000
1995-1999 19 378,000,000 7,182,000,000 1,436,400,000
2000-2004 12 895,000,000 10,740,000,000 2,148,000,000
CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE
Table 5.3. R&D expenditure for cancer in Europe in €, 1990-2004.
This results in an estimate of approximately €24 billion as the total spending over 18 years (1987-2004) to develop new oncology drugs. This represents an aver- age of €1.3 billion per year. Over the past 5 years, the estimated average annual spending on cancer research by the pharmaceutical industry would be in the magnitude of €2.1 billion.
5.2.2 Total R&D expenditure in the European pharmaceutical
industry
R&D investment by pharmaceutical companies in Europe has risen more than sevenfold2,3 over the past 20 years and doubled over the past 10 years (to reach €18,800 million in 2001 from €7800 million in 1990). Between 1987 and 2004, 8.1% of all the NCEs that entered the market have been oncology drugs. The second method used to calculate pharmaceutical funding of cancer assumes that this proportion of oncology NCEs to total NCEs is equivalent to that for cancer research as a percentage of total R&D expenditure.
This calculation estimates total R&D expenditure for cancer in 2002 at €1.6 bil- lion (Table 5.3).
5.2.3 Pharmaceutical expenditure according to disease area
The 2004 Centre for Medicines Research International Ltd (CMR) Internation- al R&D Factbook provides a comprehensive, up-to-date overview of emerging trends in worldwide pharmaceutical R&D. Source data are derived exclusively from primary sources that include all major pharmaceutical companies and which account for some 80% of the industry’s global R&D spend.
In 2003, global pharmaceutical R&D expenditure reached US$50 billion world- wide4 and oncology accounted for 15% of total R&D expenditure, or US$7.5 bil- lion. Europe accounted for about 38% of total R&D expenditure in 2003. Thus, approximately US$3 billion was spent on oncology research in Europe in 2003, or €2.4 billion (an exchange rate of 1.2439 US$/€ has been used).4 This estimate
of private funding into cancer research in Europe - €2.4 billion - is higher than the two previous estimates.
5.2.4 Comparison of different methods of calculating private/
commercial funding for cancer research
Thus there are different estimates for private R&D spending:
• Based on cost of an NCE (2000-2004) €2.1 billion
• Based on total R&D expenditure in Europe
weighted by share of marketed oncology drugs (2003) €1.6 billion
• Total expenditure in cancer (2003) according to CMR €2.4 billion
Years Total R&D expenditure R&D expenditure in cancer (8.1%) Total expenditure in cancer per year
1990-1994 45,316,400,000 3,670,628,400 734,125,680
1995-1999 67,863,800,000 5,496,967,800 1,099,393,560
2000-2004 99,860,667,000 8,088,714,027 1,617,742,805
The estimates give a range of €1.6 to €2.4 billion being invested by the private/for- profit pharmaceutical sector in cancer research. The estimate is probably rather low since the share of research going into oncology has increased over time (it has been noted that the share of cancer publications out of all health economic publications has increased).
Estimating R&D expenditure based on the share for introduced oncology drugs is also inaccurate since this reflects spending in previous periods. It is also im- portant to realise the amount of time and cost needed to develop drugs in dif- ferent therapeutic areas is not the same. Cancer drugs are more expensive to develop and have higher attrition rates than other drugs, such as anti-infectives. A share of 10-12% for cancer research is more accurate based on this trend of increased investment in cancer research. This would then result in an estimate of €2.1 to €2.5 billion being spent by the European pharmaceutical industry (based on total R&D investment by the European pharmaceutical industry).
5.2.5 Comparison of pharmaceutical industry R&D expendi-
ture to sales
Global pharmaceutical sales reached US$466 billion in 2003.5 Based on data from the CMR, oncology accounts for 7% of total global sales; ie US$33 billion in 2003. The same report states that Europe accounts for about 33% of total global sales. This results in total European sales of oncology drugs of approximately US$11 billion, or €8.8 billion. This estimate is higher than our previous (Table 2.4) estimates of sales of cancer drugs (€5050 million). There are several possible reasons for this. It can occur when the definition of Europe is not the same. Our estimate is also based on drug sales at public prices, which may explain lower cancer drug sales as a proportion of all drug sales. Also, the definition of ‘an on- cology drug’ may differ from our definition, including drugs that have significant sales for other indications as well.
In 2003, companies indicated that they reinvest approximately 15% of their total global sales in R&D (using the R&D expenditure to sales ratio and calculated as a median of data supplied).5 This is almost double the percentage of new cancer
drugs vis-à-vis the total of NCEs introduced (8.1%) in the past 15 years, and is 2-4 times more than the proportion of cancer drug sales (5-8%) vis-à-vis total pharmaceutical sales. This assessment would result in approximately €1 billion being reinvested by the pharmaceutical industry into cancer drug research. It is therefore possible to conclude that approximately 25% of total cancer drug sales are being reinvested into cancer drug research. This is greater than indicated by traditional measures of sales to R&D investment. Present cancer drug sales rep- resent investment of years past while today’s investments will generate new drugs for the future. It can be expected that the share of cancer drugs of total pharma- ceutical sales will increase from 5-8% to 12-15%, thus reflecting the share of cancer research in total private/for-profit pharmaceutical company research.
5.3 The process of approval of new cancer drugs in Europe
The introduction of new cancer drugs is dependent on public and private invest- ment in R&D. The public arena is focused on basic research, while the major investment in clinical R&D is made in the private pharmaceutical industry. But investment in R&D is not enough to get new drugs to patients. There is a com- plicated and time-consuming regulatory process to establish safety, efficacy and quality before a new drug can get a market authorisation or licence. >>>
CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE
Table 5.4. Timelines for regulatory approval of cancer drugs. Adapted from6
Forty-five new cancer drugs were introduced between 1987 and 2004, and 39 of these were introduced between 1990 and 2004.
Currently, oncology drugs can be authorised in the EU via two different routes. The Mutual Recognition Procedure can be used for all oncology drugs except biotech products. The Centralised Procedure (CP) can be used for all innovative oncology drugs and has to be used for products manufactured by certain bio- technological processes. Beginning in November 2005, all new oncology drugs will have to be authorised via the CP and thus will be reviewed by the CHMP (Committee for Medicinal Products for Human Use), formerly known as the CPMP (Committee of Proprietary Medicinal Products).
5.3.1 Regulatory approval time lines
In the EU, 20 anticancer agents have been authorised via the CP since its imple- mentation in 1995. The time for regulatory approval of these 20 cancer drugs is shown in Table 5.4.
In this table:
• ‘Active time’ is the time needed for scientific evaluation by the CPMP and ‘clock- stop time’ is the time needed by the applicant to answer the objections raised by the authorities as given in the annual reports of the European Agency for the Evaluation of Medicinal Products (EMEA).
• ‘Scientific time’ is the time needed for scientific evaluation by the CPMP plus the time needed by the applicant for answering the authorities’ objections (calcu- lated as the interval between the start of the procedure and the CPMP opinion; theoretically, the sum of the active time and clock-stop time. Yet these times do not always add up exactly to the total review times due to apparently different ap- proximations used in the different sources. Where discrepancies across reports were noted, the time intervals were manually recalculated).
• ‘Administrative time’ is the time needed for translation, approval of the nation- al product information and publication of the EC decision. According to current EU legislation, the administrative time is foreseen to be 90 days. The administra- tive time was calculated as the interval between the CPMP opinion and the date of decision of the EC as given in the annual reports of the EMEA.
• ‘Total time’ is the time needed for the overall duration of the marketing au- thorisation procedure and was calculated as the interval between the start of the procedure and the date of decision of the EC as given in the annual reports of the EMEA, ie the sum of the scientific time and the administrative time.
Trade name Generic name approvalEU CP Active time (days)
Clock-stop
time (days) Administrative time (days)
Scientific time (days) Total time (days) Administrative time of total time (%) Fareston Toremifene Oct
1995 240 50 138 192 330 42
Taxotere Docetaxel Nov 1995 100 93 120 289 409 29
Caelyx Doxorubicin 1996Feb 222 150 129 408 537 24
Hycamtin Topotecan Nov 1996 154 28 116 185 301 39
Mabthera Rituximab 1998Jun 179 132 125 313 438 29
Temodal Temozolomide 1999Jan 203 60 96 265 361 27
Beromun Tasonermin 1999Apr 188 204 145 391 536 27
Paxene Paclitaxel 1999Jul 179 251 173 432 605 29
Myocet Doxorubicin 2000Jul 167 91 92 257 349 26
Herceptin Trastuzumab Aug 2000 147 305 95 454 549 17
Xeloda Capecitabine 2001Feb 201 159 106 364 470 23
Targretin Bexarotene Mar 2001 197 159 133 335 468 28
MabCampath Alemtuzumab 2001Jul 203 142 99 349 448 22
Foscan Temoporfin 2001Oct 215 238 119 6152 734 16
Glivec3 Imatinib
Mesilate Nov 2001 119 0 104 121 225 46
Trisenox Arsenic trioxide Mar 2002 180 51 138 233 371 37
Zevalin Ibritumomab tiuxetan 2004Jan 153 28 113 185 298 38
Faslodex4 Fulvestrant Mar 2004 212 57 111 269 380 29
Velcade4 Bortezomib Jan
2004 175 155 96 331 427 22
Erbitux4 Cetuximab Jun
2004 214 33 97 247 344 28
Mean 182 119 117 312 429 29
Median 184 113 115 301 418 28
The median time for regulatory approval of cancer drugs is 418 days. The mean time is 429 days, with a variation from 225 to 734 days. Regulatory time approval has been reduced during the past decade. However, there seem to be opportunities to further reduce the administrative time, which according to the EU legislation is foreseen to be 90 days but is, on average, 117 days (range 92-173).
CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE CANCER RESEARCH AND DRUG DEVELOPMENT AND APPROVAL IN EUROPE
5.3.1.1 Exceptional circumstances
The current EU drug law (Commission Directive 2003/63/EC) enables marketing authorisation to be granted based on a reduced development programme (eg only based on Phase II studies) under so-called ‘exceptional circumstances’. These exceptional circumstances include development for use in a rare condition (eg orphan drug status) or where comprehensive information cannot be provided in the knowledge base currently available or when it would be unethical to collect further data.
In 2000, the EU implemented Orphan Drug legislation, the purpose of which is to facilitate development of drugs for treatment of less frequent cancers such as gliomas, renal-cell cancer or certain haematological tumours. Two out of the 20 investigated oncology drugs have been granted orphan drug status before the initiation of their marketing authorisation procedure (imatinib and arsenic tri- oxide).
The CPMP Note for Guidance on Anticancer Medicinal Products further ex- plains how to use these provisions in order to facilitate the development of oncol- ogy drugs. According to this guideline, a marketing authorisation application can be based on data from uncontrolled clinical trials when there is no approved treatment available and an investigational drug shows outstanding anticancer activity. Additionally, this guideline endorses the use of tumour response as a surrogate end point, if it is justified to predict clinical benefit. Although this anticancer guideline provides no information for development of non-cytotoxic agents, it has been used for the assessment of a number of these agents.
Of the 10 oncology drugs authorised since the beginning of 2001, 6 (60%) were authorised under exceptional circumstances (only 1 had been authorised in this manner by the CP since its inception in 1995 prior to this date). Based on addi- tional clinical data submitted by the applicant, docetaxel has meanwhile received full approval. As the other drugs have only been authorised during the past 3 years they are still regarded to be authorised under exceptional circumstances and have to fulfil post-marketing obligations in order to achieve full approval status. These include alemtuzumab, temoporfin, imatinib, arsenic trioxide, ibri- tumomab and bortezomib.
5.3.1.2 Accelerated evaluation
Overall, it turns out that the exceptional circumstances provision has been fre- quently used over the past 3 years to facilitate the marketing authorisation of innovative oncology drugs in the EU. However, only one of the investigated oncology drugs has been authorised using an accelerated evaluation procedure - imatinib.
In 1996, the EMEA provided the first guidance on an accelerated evaluation of products. This guidance gives a scientific review time of 120 days instead of the standard 210 days for drugs that meet the following three cumulative criteria:
• indicated for treatment of a heavily disabling or life-threatening disease • absence of an appropriate alternative therapeutic approach
• anticipation of exceptionally high therapeutic benefit.
As a consequence of the accelerated evaluation, imatinib has the shortest total time for the EU marketing authorisation procedure (225 days) among all inves- tigated oncology drugs.
5.4 Conclusions
Significant investment is being made in cancer research. From a public-funding