1 Sonia Mansoldo Dainesi, MD, PhD, MBA Post-trial access to trial drugs: Legal, ethical and practical issues Brocher Founda-on, Geneva Dec th, 2011
2 Poten-al conflicts of interest São Paulo University / Medical School (HCFMUSP) Specialization: Endocrinology PhD: Public Health Pharma companies: Rhodia Farma Sandoz Aventis Boehringer Ingelheim (currently Medical Director) Former president of SBMF (Braz Soc of Pharmaceutical Medicine) University ( ): Clinical Research Support Center (HCFMUSP) Brazilian Network of Clinical Research (Ministry of Health)
3 Background Local legislation E- Survey on post- trial access in Brazil Final considerations
4 Background Continuous growing of Brazil participation in international clinical trials (as well as other developing countries) BR: Strong history in ethics, mainly in biomedical research National Ethics Commission on Research (CONEP) as second ethics approval of protocols, after the EC/IRB approval Thiers F et al. Trends in the globalization of clinical trials. Nature Reviews. Drug Discovery 2008; 7:13-4. CONEP:
5 Legisla-on Resolutions from National Council of Health (CNS, Conselho Nacional de Saude) Res. 196/1996 Res. 251/1997 Res. 404/2008 Current options Res. ANVISA 26/1999: Expanded Access (EAP) Study Extension Donation Program
6 Res. CNS 196/96 (general principleson biomedical research) III.3m: Assure that, whenever possible, the research in communities is translated into benefits whose effects continue to be present after the research is concluded III.3n: Research involving human beings shall comply with the following: guarantee the benefits of the research to the people and communities where research is carried out.
7 Res. CNS 196/96 III.3p: Research involving human subjects must ensure to research subjects the benefits resulting from the research project, be it in terms of social return, access to procedures, products or research agents.
8 Res. CNS 251/97 (new drugs) IV.1m: access to the medicine being tested must be assured by the sponsor or by the institution, researcher, or promoter in the event its superiority to the conventional treatment is proven.
9 Res. CNS 404/08 (DoH modificagons not accepted)...all research participants should be assured the access to the best methods identified by the study... DoH
10 OpGons currently available in Brazil 1) ResoluGon 26 (1999) - ANVISA: Expanded Access (EAP) hvp://www.anvisa.gov.br/legis/resol/26_99rdc.htm 2) Study extension (Follow- up study) hvp://www.anvisa.gov.br/medicamentos/pesquisa/extensao.htm hvp://conselho.saude.gov.br/biblioteca/livros/manual_ceps.pdf 3) DonaGon program hvp://www.anvisa.gov.br/medicamentos/pesquisa/doacao_medicamento.htm Or other clinical trial.
11 Law 6360 RDC 26/1999: Expanded Access Follow- up study Donation of study medication New product Not approved in the country Severe and life- threatening conditions Lack of therapeutic satisfactory options Protocol, CRF, Informed Consent Patients who benefit from treatment: optional continuity of treatment will be provided EC approval (and CONEP) together with the mother protocol Defined before the study initiation ANVISA recommends: Final report of the trial Medical report with the reasons for the donation Sponsor declaration: provide medication and continuous safety assessment
12 Since Multicenter International Clinical Trials If access to study medication after trial is not clearly stated in the protocols and informed consents, the trial is not approved by CONEP.
14 I. Identify the main issues on the continuity of study medication after trial end; II. Analyse the perspective of main players in clinical research on the topic.
15 Survey, with questionnaires sent through the internet ( ) Participants : 1. Clinical investigators (HIV/AIDS and DM) Identified through sponsors and 2. Members of ECs (Ethics Committees) As available at CONEP site (Feb 2009) 3. Sponsors Pharma companies and CROs established in Brazil 4. Research participants (patients) Questionnaires (paper & pen) through the clinical investigators
16 Mat & Met a) Non- probabilistic approach (convenience sample) b) Questionnaires Based in literature and adapted to current scenario (i) (ii) Three models: Clinical investigators Sponsors and EC members (iii) Research participants
17 Mat & Met c) Pilot assessment of questionnaires 2 lawyers with experience in clinical trials 2 members of ECs 2 clinical investigators 4 sponsors 1 assistant (lay people in research) Four domains: (i) Participants characteristics (ii) Informed consent (iii) Motivation (iv) Post-trial supply of study medication
18 Mat & Met Informed consent Questionnaire 3 weeks Mailing lists
19 Mat & Met EC (IRB) approval (Apr 2009; Aug 2009)
20 Sta-s-cal Analysis Data base Data base construction EpiData version 3.0 (2003) Validation Double entry, with validation Analysis Analysis: descriptive and non- inferential Absolute and relative frequency Significance level: 5% * Likert scale: Kruskal- Wallis test and, if necessary, non- parametric multiple comparisons * Non- Likert: Association (chi- square test or likelihood ratio test) * Verification inside each question: Friedman test, followed by non- parametric comparisons if necessary.
21 First Domain: Participants characteristiscs
22 Response Rate Questionnaires sent Questionnaires received Response Rate ECs ,7% Clinical investigators ,o% Sponsors ,3% Research participants NA (60-67% of responses arrived after first message)
23 Age and sex distribu-on Number of respondents Age (mean; range) ECs Sponsors Clinical Investigators Research participants (28-74) 40 (29-65) 53 (24-72) 49 (30-81) Sex Male (%) 54 (44,6%) 9 (37,5%) 37 (63,8%) 28 (51,9%) Female (%) 67 (55,4%) 15 (62,5%) 21 (36,2%) 26 (48,1%)
24 DistribuiGon by sex Research participants Clinical investigators Sponsors EC members Male Female
25 Distribu-on according to the schooling Fundamental (4 years) High school (8 years) EC Sponsors Clinical Investigators Research Participants (47,2%) 2 (1,7%) (28,3%) University 5 (3,4%) 5 (20,8%) 1 (1,7%) 12 (22,6%) Especialization 15 (12,7%) 6 (25%) 6 (10,3%) 0 Master 39 (33,1%) 5 (20,8%) 13 (22,4%) 1 (1,9%) PhD 54 (45,8%) 6 (25%) 30 (51,7%) 0 Other 3 (2,5%) 2 (8,3 %) 8 (13,8%) 0 Total 118 (100%) 24 (100%) 58 (100%) 53 (100%)
26 Distribu-on of par-cipants according to the region in Brazil EC Sponsors Others: 57% Southeast: 43% Others: 21% Sponsors and Research Participants: 80% Southeast EC and Clinical Investigators: 43% Southeast Clinical investigators Southeast: 43% Others: 19% Southeast: 79% Research participants Others: 57% Southeast: 81%
27 Second Domain: Attitudes regarding to Informed Consent process
28 How well informed are the research pargcipants? Less informed item (all groups together)
29 Which is the importance of each informa-on in the Informed Consent? Importance of Research Participants group gives to each aspect in the IC EC Clin Invest Sponsors Res Partic Importance of each group interviewed gives to the potential risks in the IC Research objective Potential benefits Potential risks Study design was the less important info for all groups
30 Third Domain: Decision factors and motivation for patients and investigators
31 Patients motivation Main mo-va-on for par-cipa-ng in a clinical trial (all groups together) Altruism- related motivation is the last one in the all groups together analysis but it is one of the most important reasons for patients decision. (90.4% % % % % % respectively)
32 Investigators motivation Which is the main mo-va-on for inves-gators decide to par-cipate in clinical trials? Provide the most innovative option for the patients, through the clinical trial Be updated with new medicines and medical procedures Social motivation Receive training and capacitation in clinical research Have an additional income Obligation in the institution where he/ she works Very important Moderately important Neutral Somewhat important Not important (all groups together)
33 Would you par-cipate again in a clinical trial? Would you recommend to others? 98% of research participants would accept participate in another clinical trial 98% of research participants would recommend to others the participation 98% Participariam Yes e recomendariam Não No
34 Fourth Domain: Opinions and impressions on the continuity of provision of study medication after trial
35 To whom? Who should receive the medica-on aser trial, if a benefit is proven? If proven more effec3ve than available op3ons, who should receive the study medica3on a?er trial end? EC MEMBERS (N=119) CLINICAL INVESTIGATORS (N=58) SPONSORS (N=24) RESEARCH PARTICIPANTS (N=53) Research pargcipants 26% 43% 33% 7% ParGcipants who benefit from the study medicagon and don t have other treatment opgon 23% 40% 50% 19% All people with the same disease in the country 35% 9% 0% 60% No one 7% 9% 8% 7% Some other group 8% 0% 8% 6%
36 To whom? Who should receive the medica-on aser trial, if a benefit is proven? 43 and 40% Clinical investigators 35% EC members 60% Research participants 50% Sponsors None All study participants Participants who benefit All with the disease Other group
37 How? How should the drug be furnished? How should be furnished the study medica3on a?er trial to the group iden3fied in the previous ques3on? EC MEMBERS (N=107) CLINICAL INVESTIGATORS (N=52) SPONSORS (N=22) RESEARCH PARTICIPANTS (N=44) Free of charge 55% 77% 64% 93% At a price established by government 20% 8% 0% 4% At the fabricagon cost 12% 4% 9% 0% At a price defined by the drug company 0% 2% 4% 2% Other 13% 10% 23% 0%
38 By whom? Who should be in charge of furnishing the drug aser trial? Who should be in charge of furnishing the drug a?er trial, before the regulatory approval in the country? EC MEMBERS (N=109) CLINICAL INVESTIGATORS (N=53) SPONSORS (N=22) RESEARCH PARTICIPANTS (NA) Sponsor (drug company) 64% 94% 68% NA Research insgtugon 8% 2% 4% NA Government 17% 4% 14% NA Other 10% 0% 14% NA (NA: not applicable, as this question was not applied to research participants)
39 How long? For how long.. For how long should the medica3on be furnished to the subjects? EC MEMBERS (N=124) CLINICAL INVESTIGATORS (N=58) SPONSORS (N=24) RESEARCH PARTICIPANTS (N=54) For the period defined in protocol and informed consent 17% 28% 4% 7% While the subjects benefit from the treatment 49% 38% 18% 29% While the researcher/physician believes appropriate 24% 24% 59% 31% Up to having the medicine available in the country or in the public system 41% 51% 73% 31% For all life 8% 2% 0% 51% Other 7% 7% 4% 2% (In this question, more than one alternative could be chosen.)
40 For how long? For a period defined in the protocol and/or in the IC While the participant keeps the benefit While the investigator judges as adequate Up to be available in the country and/or public sector For all life Other Clinical Investigators Ethics Committees Research Participants Sponsors
41 Benefit x Risks Thinking in the benefit but also in the safety of pa-ents (risks of an inves-ga-onal drug are not irrelevant), which would be the best op-on for the con-nuity of the treatment? Clin Invest (n=52) EC (n=116) Sponsors (n=22) All together Study medication 57.7% 28.3% % Treatment already available 28.8% 55.7% 81.8% 51.1% Other 13.5% 16% 18.2% 15.6%
42 Access? What do you understand by access? Clin Invest EC Sponsors (n=55) (n=115) (n=24) All together Furnished by the sponsor Made available after regulatory approval 67.3% 78.3% 25% 68.6% 25.5% 16.5% 54.2% 23.7% Other 7.3% 5.2% 20.8% 7.7% Furnished by the sponsor Made available after regulatory approval Clin Invest EC Sponsor Other
43 Beneficial? Is clinical trial conduc-on in Brazil beneficial or not?
44 Differences Differences between DM and HIV clinical inves-gators 38 investigators DM and 20 HIV/AIDS. (Only questions where significant difference was observed) The info regarding to how to obtain the study medication after trial The medicine should be kept while benefit exists Is better furnished by the HIV investigators than DM investigators. Is more mentioned by HIV investigators than DM investigators. Understanding access HIV investigators: furnished by the sponsor DM investigators: be available in the country after regulatory approval
45 Differences Differences between DM and HIV research par-cipants 14 patients DM and 40 HIV/AIDS. (Only questions where significant difference was observed) Free supply after trial? HIV patients: 100% free; DM patients: 78% free Study medication should be given while considered adequate by the investigator Is beneficial to have clinical trials in Brazil? More important for DM patients than HIV patients HIV patients: more beneficial (100% very beneficial) than DM patients (78% very beneficial)
46 - Selection method of patients - Only two diseases included Pioneer study: Conclusion - a chronic disease, besides HIV/AIDS, Limitations: - sponsors included, - developing country. - Population restrict to web users - Population restrict to Brazil - Small sample of patients - Assessment of what they think but not what they do. The solution is not simple nor unique Each research should have its evaluation as Each disease has its peculiarities and Each population, its needs. Thank you!