R. Ippoliti

1. Pharmaceutical clinical research, an empirical work on the European marketof human experimentation R. Ippoliti

2. Goals • Market of human experimentation, theoretical approach • Empirical analysis to support the proposed model • Policy maker’s point of view, suggestions

3. Introduction Pharmaceutical company’s productive process 100 Tested Molecules 10 Candidate Drugs 10,000 Molecules 1 DRUG Clinical Research Administrative procedures Marketing and Drug Control Pre clinical Tests Basic Research 0 5 years 10 years 15 years 20 years Research & Development Patent Application Patent Expiration Collect data….. ….. saving time and money! Data source: L’industrie du médicament en France, réalités économiques, Edition 2008 - LEEM

4. The market idea Experimental Medical treatment Fee Clinical Evidence Alternative Medical treatment Pharmaceutical Company • Bring demand into contact • with supply; • - Facilitate the choice.. Physician ..delegation process Sick person …considering an open market… Behind assumptions that companies and patients can interact directly (demand-supply), as well as people are able to compare options and make choice (information-rationality)…. Changing assumptions, that is to say bounded rationality as well as no direct interaction... …the previous ideal market, in which innovation was exchanged for clinical evidences, change in an imperfectly one where data on the experimental treatment are exchanged for fee now. … an ideal market in which innovation is exchanged for clinical evidences, where the innovation could be thought as the difference (drug’s effectiveness) between the experimental treatment and the current one.

5. Empirical Analysis - wealth (1/6) In order to test the idea of market, the testing phase of pharmaceutical companies are considered as any productive process: Physicians as national workers (labor) Patients as national resource (raw material) • Assumptions: • labor as the dominant cost in productive processes; • raw materials’ cost equal to zero; • expected physicians’ fee is proportional to the national per capita • wealth; • - wealth growth is the consequence of wage competitiveness;

6. Empirical Analysis - wealth (2/6) W is the gross domestic product (GDP) based on purchasing-power-parity (PPP) per capita of the i-th country in the year t, considering n countries. Example:

7. Empirical Analysis - wealth (3/6) • Sample analyzed: • 33 European Countries: EU 27 countries plus the candidate states (Croatia, the Former Yugoslav Republic of Macedonia, Turkey), Norway, Switzerland and Iceland; • Panel data (2000-2007); • Dependent variables: • Clinical studies (National clinical trials funded exclusively by Industry, phase II - III)1; • Research Index (Clinical studies but weighted for national locations); 1 Source: The U.S. National Institutes of Health (NIH)

8. Empirical Analysis - wealth (4/6) • France (6) • Hôpital Albert Michallon, Grenoble; • Hôpital de la Timone, Marseille; • Centre Renè Gauducheau, Nantes; • Centre Renè Huguenin, Saint-Cloud; • Hôpital Rangueuil, Toulouse; • CHU de Nancy, Vandoeuvre les Nancy; • Germany (3) • Universitätsklinik Aachen, Aachen; • Universitätsklinikum des Saarlandes, Homburg/Saar; • University Hospital of Schleswig-HolsteinKiel; • Sweden (3) • University Hospital, Dept. of Oncology, Linköping, • Radiumhemmet, Karolinska University Hospital, Stockholm; • Länssjukhuset Sundsvall-Härnösand, Sundsvall; • United Kingdom (4) • Velindre Hospital, Cardiff; • Leicester Royal Infirmary, Leicester; • Newcastle General Hospital, Newcastle Upon Tyne; • Derriford Hospital, Plymouth; Dependent variables example1: Title: Study of Radium-223 for the Palliation of Painful Bone Metastases in Hormone Refractory Prostate Cancer (HRPC) Patients Sponsor: Algeta ASA ClinicalTrials.gov Identifier: NCT00667199 Phase: Phase II Study Start Date: May 2005 Locations: 16, France (6), Germany (3), Sweden (3), UK (4); Clinical Studies: 4 national clinical trials France (1), Germany (1), Sweden (1), UK (1); Research Index: 1 trial with all locations in Europe, spread among 4 countries, that is to say 4 national clinical trials with a weight equal to the national centers: France - Germany - Sweden – United Kingdom (0.375) (0.1875) (0.1875) (0.25) 1 Source: The U.S. National Institutes of Health (NIH)

9. Empirical Analysis - wealth (5/6) Table 1: Relation between pharmaceutical clinical research and national features, Europe (700,000<population<45,000,000) from 2000 to 2007 Cross-sectional time-series regression model with fixed-effects option (within regression estimator), Population (2000) as analytical weight

10. Empirical Analysis - wealth (6/6) Table 2: Relation between pharmaceutical clinical research and national features, Europe (33 countries) from 2000 to 2007 Cross-sectional time-series regression model with fixed-effects option (within regression estimator), Population (2000) as analytical weight

11. Empirical Analysis - IRB (1/3) Protection system of patients’ rights and policy maker • Healthy people, interested to pharmaceutical clinical research since • able to increase national health care system’s knowledge and to save • public money; • Sick people, interested to medical treatment and… the higher the • effectiveness is, the better is… but they are not rational; Institutional Review Boards (IRB) • - efficient, that is to say able to minimize the time required to authorize the trial; • pharmaceutical company’s freedom to choose the review board (central, regional and local system);

12. Empirical Analysis - IRB (2/3) • Considering the pharmaceutical companies’ freedom, represents IRB territorial competence of the i-th country (Central=1, Regional=2, Local=3); • considering a review of an international clinical trial with a single opinion, are efficiency factors: • x1= Is there an economic fee charged by Ethics committees for their review? • (positive effect) • x2= Considering the deadline of the European Union directive, does the • national law try to reduce Ethic committees’ time to review trials? • (positive effect) • x3= Is there a competitiveness mechanism able to downgrade Ethics committees? • (positive effect) • x4= Taking the regional and local system into account, regardless of the • Single opinion, is the approval of all Ethics committees involved necessary? • (negative effect)

13. Empirical Analysis - IRB (3/3) Table 3: Relation between pharmaceutical clinical research and national features, Europe (700,000<population<45,000,000) in 2007

14. Policy maker Minimize the bargain cost Remove the market’s inefficiency Moral incentives within the society Economic incentive linked to the physicians’ career From policy maker’s point of view, how could pharmaceutical clinical research be improved? - Efficient and competitive protection system of patients’ rights - Facilitate the exchange of innovation for clinical evidence - Alternative system of incentives …to be more attractive on the European market of human experimentation!

15. Thank you for the attention