Pediatric Trials in Latin America Clinical Research in Pediatric Oncology Prof. Dr. Antonio Sérgio Petrilli
Clinical Research Regulations Timeline Best Pharmaceuticals for Children Act estabilished programme and funding for study of off-lpatent drugs. Pediatric Research Equitity Act Pediatric Rule FDA requiring manufactures to assess the safety and effectiveness of new drugs and biological products for pediatric labeling. Marketing authorization applications must contain a pediatric plan or waiver. Page 2
Objectives 1. When to perform pediatric research? 2. Timing of initiation; 3. Types of studies; 4. Age categories; 5. Ethical considerations. Page 3
1. When to perform pediatric research? Take into account: The prevalence of the condition to be treated in the pediatric population; Seriousness of the condition; Availability of alternative treatments in the pediatric population, including efficacy and adverse event profile. Page 4
1. When to perform pediatric research? Take into account: Whether the medicinal product is novel or one of a class of compounds with known properties; Age ranges of pediatric patients likely to be treated; Unique pediatric safety concerns (developmental) Page 5
2. Timing of initiation Concomitantly After initial safety analysis Phase I Phase II Phase III Diseases predominantly or exclusively affecting pediatric patients. Serious or life-threatening diseases, occurring in both adults and pediatric patients. After efficacy and safety analysis Other diseases and conditions. Page 6 Risk x Benefit
3. Types of studies Pharmacokinetics Consider: Number of patients and samples x patient: sparse sampling, sufficient to generate a comparison with adult parameters. Routine collections, wherever possible, at the same time as samples for pharmacokinetic analysis. Trained staff and sensitive assays in order to decrease the volume of blood required per sample. Page 7
3. Types of studies Efficacy Consider: Measurement of subjective symtoms (ie: pain) Specific Assessment instruments. Ie: pain, quality of life. Page 8 Caran, E, et al. Pediatr Blood Cancer, 45:925 32, 2005
3. Types of studies Performance Score Karnofsky (pacientes> 16 anos) Lansky (pacientes< 16 anos) 100 Totalmente ativo; normal. Sem queixas; sem evidência de doença; 90 Restrições leves em atividades físicas vigorosas. Atividade normal; sinais ou sintomas da doença leves. 80 Ativo, mas cansa mais rápido. Atividade normal com esforço; alguns sinais ou sintomas da doença 70 Grandes restrições e tempo menor nas atividades físicas. 60 Em pé e caminhando, mas mínima atividade, ocupa-se com atividades mais calmas. 50 Veste-se, mas fica muito deitado durante o dia; capaz de participar em todas as atividades calmas 40 Maior parte na cama; participa de atividades calmas 30 Na cama; necessita de assistência mesmo para atividades calmas Page 9 Cuida-se; capaz de exercer atividades normais ou de fazer trabalho ativo Necessita de assistência ocasional, mas tem capacidade de cuidas de muitas necessidades pessoais. Necessita de assistência considerável e cuidados médicos frequentes; atividades calmas. Incapacitado; necessita de cuidado e assistência especiais Gravemente incapacitado; é indicada internação embora a morte não seja iminente. 20 Dorme com frequência; atividades passivas Muito doente; necessária internação, necessário tratamento de suporte ativo 10 Sem atividade, não deixa a cama Moribundo 0 Não responsivo Morto
3. Types of studies Efficacy Consider: - Dosing Weight x BSA FIG. 1. The percentage of full dose administered resulting from three methods of dose reduction in response to weight loss (A) and the drug exposure, or area under the curve (AUC), resulting from the administration of these doses (B). Page 10 Dose Reduction of Chemotherapeutic Agents after Weight Loss. O Marcaigh, Aengus; Gilchrist, Gerald, American Journal of Clinical Oncology. 20(2):193 195, 195, April 1997.
3. Types of studies Safety Consider: Normal lab values age appropriate; Different metabolism (Ex: renal and liver clearance) Long-term safety studies (Ex: chemotherapy cardiotoxicity) Page 11 Pediatr Blood Cancer 2005;902 908 908
4. Age categories. Preterm Newborn Infants; Term Newborn Infants (0 to 27 days); Infants and toddlers (28 days to 23 months); Children (2 to 11 years); Adolescents (12 to 18 years). Page 12
5. Ethical Considerations Vulnerable population Consent and Assent: appropriate age? Economic aspects (patents extension) Page 13
Necessary actions from involved parts Sponsors Stimulate the development of pediatric studies Protocols designed to minimize risks. IRBs Knowledge of ethical, clinical and psico-social pediatric aspects Consider risks from the children s point of view Familiarity with study designs that minimize risks Faster approval processes without ethical prejudice. Investigators Training and experience in pediatric studies. Page 14
Pediatric Oncology Studies Our experience Protocols Phases I, II, III and IV Page 15
Phases I and II Protocols Our experience Objectives Risks Benefits Observations Phase I - Pharmacokinets/ dynamics, - Initial safety analysis Unknown toxicities Direct feeling to have tried all possible options Oncology nonresponders to other therapies. Phase II Efficacy and short-term safety Unproven efficacy Direct possibility of survival/quality of life benefits Still non-responders, but drugs already registered for adult use. Page 16
Phase I Protocols Page 17 J Clin Oncol 18:1900 1905. 1905. 2000 by American Society of Clinical Oncology
Difficulties Page 18 J Clin Oncol 18:1900 1905. 1905. 2000 by American Society of Clinical Oncology
Phases III and IV Protocols Our experience Objectives Risks Benefits Observations Phase III Short and long term risk/benefit analysis Known treatment toxicities Direct patients have access to drugs not otherwise available Phase IV Marketing and postmarketing surveillance Known treatment toxicities Direct medications without costs. Page 19
Pediatric Oncology Studies Our experience Protocols Phases I, II, III and IV Epidemiologic studies Page 20
Epidemiological Studies Our experience Objectives Risks Benefits Observations Increase knowledge about population and disease characteristics Disclosure of personal data Indirect Publication, health services Page 21
Pediatric Oncology Studies Our experience Protocols Phases I, II, III and IV Epidemiologic studies Collaborative treatment studies Page 22
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Collaborative treatment studies COG Since the 50s, increase from 10% to more than 77% on the cure rates. Participating centers Patients Children s Oncology Group: Chemotherapy benefits for children with cancer were first proven; Discovery of the first tumor suppressor gene; Multi-drug chemotherapy. Page 24 http://www.curesearch.org/our_research/index_sub.aspx?id=1527
Collaborative treatment studies COG 3% Relative mortality rate reduction - USA 1990-1998 2.8% 2.6% Média Anual em % 2% 1% Why? 1.8% 1.5% 0.9% 1.1% 1.5% 0.4% 0% 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 Idade (Anos) Page 25 Bleyer, W.A. The impact of childhood cancer on the United States and the world Ca,40:355-367,1990; Bleyer, W.A. Conferência ministrada durante a 30ª ASCO 2000
Collaborative treatment studies COG Inclusions on Treatment Protocols NCI 1990-1998 12000 11689 Clinical Trials Inclusions 8000 4000 7875 4786 3837 3532 6733 1071 1491 0 Idade (Anos) 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 Page 26 Bleyer, W.A. The impact of childhood cancer on the United States and the world Ca,40:355-367,1990; Bleyer, W.A. Conferência ministrada durante a 30ª ASCO 2000
Collaborative Treatment Protocols COG Correlation between Mortality rates reduction and Clinical Trials Admissions 1990-1998 Annual Mediam % Reduction of Mortality 3% 2% 1% 0% % Reduction on Mortality AGE Page 27 Bleyer, W.A. The impact of childhood cancer on the United States and the world Ca,40:355-367,1990; Bleyer, W.A. Conferência ministrada durante a 30ª ASCO 2000 25% 20% 15% 10% 5% 0% r =.91, p =.001 1,000 10,000 Admissions (log) 0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 0 12000 8000 4000 Admissions on Clinical Trials
Study III GCBTO Study N Sites Study III 117 5 *39 (9.3%)/421 Enrolled patients/brazil expected cases/year (1991 1994) Page 28 IBGE Censos 1991, 1996 e 2000 / SEER - Malignant Bone Tumors Chapter
Study IV GCBTO Study N Sites (1994 1999) Study III 117 5 *39 (9.3%)/421 Enrolled patients/brazil expected cases/year Study N Sites Study IV 119 5 *29 (6.8%)/427 Enrolled patients/brazil expected cases/year Page 29 IBGE Censos 1991, 1996 e 2000 / SEER - Malignant Bone Tumors Chapter
Study V GCBTO Study N Sites (2000 2005) Study III 117 5 *39 (9.3%)/421 Enrolled patients/brazil expected cases/year Study N Sites Study IV 119 5 *29 (6.8%)/427 Enrolled patients/brazil expected cases/year Study N Sites Study V 368 26 *74 (16.5%)/447 Enrolled patients/brazil expected cases/year Page 30 IBGE Censos 1991, 1996 e 2000 / SEER - Malignant Bone Tumors Chapter
Overall Survival x Protocol N=553 Kaplan-Meier survival estimates (2 yo)p=0.012 (5 yo)p<0.001 Study Page 31 Meta (%) 0.00 0.25 0.50 0.75 1.00 NMeta (%) III 23 77 IV 20 80 V 36 64 66% 58% 50% 48% 57% 46% 0 1 2 3 4 5 analysis time Study= III Study = IV Study= V
Overall Survival x Presence of Metastases N=553 Kaplan-Meier survival estimates P<0.001 0.00 0.25 0.50 0.75 1.00 73% 37% 0 1 2 3 4 5 analysis time Nmeta Meta 59% 22% Page 32
Collaborative Treatment Protocols GALOP Protocol GLATO 2006 28 sites Brasil 2 sites Argentina 1 site Uruguai Page 33
Inclusion Rates X # of Sites Study N Sites Study 2006 405 31 Page 34
Studies III, IV, V and 2006 Study Sites N Study III 5 117 Study IV 5 119 Study V 26 368 Study 2006 31 405 Total 1009 Page 35
Important Publications Page 36
Important Recent Citations Page 37
Pediatric Oncology Studies Our experience Protocols Phases I, II, III and IV Epidemiologic studies Collaborative treatment studies Studies of Supportive care medications Page 38
Support meds. Studies Our experience Objectives Risks Benefits Observations Supportive care (infectious diseases, emesis, nutrition, palliative care) Treatment toxicities and disclosure of personal data Direct improvements on life quality Increase knowledge about medications on patients with concomitant conditions (cancer, neutropenia, etc) Page 39
Pediatric Oncology Studies Our experience Protocols Phases I, II, III and IV Epidemiologic studies Collaborative treatment studies Studies of Supportive care medications Molecular biology studies Page 40
Molecular Biology Studies Our experience Objectives Risks Benefits Observations Determine molecular causes of pathologies, staging and prognosis. Disclosure of personal data Direct staging and prognosis Indirectscientific Biological Targets Obs: tumor banking Page 41
Tumor Bank Osteosarcoma 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 BX 0 0 0 5 18 16 16 16 15 17 12 7 Srg 1 0 0 2 15 15 19 14 14 11 10 13 Meta 7 6 23 19 24 13 46 23 12 12 6 10 Page 42 Specimen N % Biopsy (BX) 124 27 Surgeries (Srg) 130 28 Metastatic Disease (Meta) Total 465 211 45
Clinical Research Center IOP GRAACC GRAACC UNIFESP Page 43
IOP GRAACC Unifesp 115 Studies since 2004 being: - 81 Internal protocols - 22 Sponsored - 12 Cooperative International and National Groups 54 ongoing studies: Page 44
Of all the forms of inequity, injustice in health care is the most shocking and inhumane. Dr. Martin Luther King Jr. Email: pesquisaclinica@graacc.org.br Tel: (11) 5080 8494 Fax: (11) 5080 8440 Page 45