Lecture 2.pdf

Overview of Clinical Research in Oncology Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School  Overview of Clinical Research in Oncology A. principles, aims, mechanisms of introducing drugs into patient testin...

Overview of Clinical Research in Oncology Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School  Overview of Clinical Research in Oncology A. principles, aims, mechanisms of introducing drugs into patient testing, scientific consideration and principles, ethical consideration, financial consideration, regulatory considerations, FDA approval process, specific indications, secondary indications, impact on the practice of medicine B. Ethics of clinical research, expected benefit for individual vs. human race, benefit to investigator physician, bias of physician in patient selection, independent study office, data safety monitoring boards C. Financial costs of clinical trials, preparing a budget, institutional support for “loss leaders” eg. Cooperative groups, insurance coverage for standard of care  Why do clinical research in cancer?  Long term survival from all cancers is about 63%  Most solid tumors are not curable once they are not resectable  Many treatments are toxic and few result in long term responses  Preclinical laboratory and animal models are inadequate in predicting efficacy in patients  Cancer drugs can only be licensed if they show efficacy in clinical trials  Why do clinical research in cancer? Depends whom you ask:  patients and relatives want cure  politicians want cure and to be re-elected  physicians want cure and tenure and success  drug companies want cure and financial success  From the benchtop to the bedside  1/10,000 drugs screened make it to human patient development - big investment ~$2 billion  the process is long and rigorous  preclinical efficacy testing  cost benefit analysis for company - needs to make in excess of $2 billion first year out - only have 10 years to recoup investment  Preclinical testing  In vitro screen against hundreds of cell types - automated  Promising agents tested in mouse tumors for efficacy, dose, schedule and safety  Decision to proceed with one or a few agents in larger animal tests - rats, dogs  find lowest dose that gives grade 4 toxicity and lowest lethal dose in rats and dogs  Clinical trials  Experiments to determine the value of treatment  Two key components  Results rather than reasoning required to support conclusions  Experiments prospectively planned and conducted under controlled conditions to provide definitive answers to well-defined questions  Formulating a clinical trial  Require careful planning and thought  First step is a written protocol  Protocol defines:  Specific question to be answered  Number of patients needed to answer it  Treatment and evaluation of a well- defined set of patients Subject headings for protocols  Introduction - scientific background and references  Objectives  Selection of Patients  Design of study (include diagram)  Treatment plan  Drug information  Toxicities to be monitored and dosage modifications  Required clinical and laboratory data and calendar  Criteria for evaluating effect of Rx; defined endpoint  Statistical considerations; data forms  Informed consent, investigators, IRB Chair, phone #s  Subject headings for protocols Introduction - scientific background and references  Write a narrative describing the gap in knowledge regarding the treatment of the disease, setting up the rationale for asking a specific question  Describe the drug and how it was developed, existing preclinical including basic science and animal studies and other clinical trials for other indications  Describe clearly the need that exists that has led you to develop this clinical trial Subject headings for protocols (cont.) Objectives  Clearly state the objective for conducting this clinical trial  State the rationale for the design of the study, including what data or logic tree backs up your reason for selecting the patient population, the study design, the drug dose and schedule, the use of other drugs in combination  What you expect the study to demonstrate when you complete it  And, what importance will the result have in furthering treatment or development of new questions Subject headings for protocols  Introduction - scientific background and references  Objectives  Selection of Patients - inclusion and exclusion criteria  Design of study (include diagram)  Treatment plan  Drug information  Toxicities to be monitored and dosage modifications  Required clinical and laboratory data and calendar  Criteria for evaluating effect of Rx; defined endpoint  Statistical considerations; data forms  Informed consent, investigators, IRB Chair, phone #s Subject headings for protocols (cont.) Selection of patients Eligibility criteria - Inclusion and exclusion criteria  Age  confirmed disease status  measurable Dz  Performance status (Karnofsky, ECOG/Zubrod)  Hematopoietic functions (WBC, hgb, plt)  Renal Function  Hepatic function  Cardiac function  HIV status  Pregnant or lactating, gyn complications  Exclusion of other malignancies  Drug-specific exclusion criteria Eligibility criteria – Inclusion and exclusion criteria Age  Usually > 18 years for solid tumor protocols. Pediatric protocols have their specific age ranges depending on the drug tested  Usually < 75 years old  Co-morbid conditions add up in older populations  Disease characteristics frequently different on molecular or microenvironmental basis  Immune response may different in elderly Eligibility criteria – Inclusion and exclusion criteria (cont.) Confirmed disease status  Pathologic confirmation – usually requires same institution’s pathologists to read  Margins must be clearly stated in path report  Molecular markers are requisite for some diseases; eg. ER/PR and Her2/neu in breast cancer  Eligibility criteria – Inclusion and exclusion criteria (cont.) Response Evaluation Criteria in Solid Tumors (RECIST)  Measurable disease - the presence of at least one measurable lesion confirmed by cytology/histology.  Measurable lesions - lesions that can be accurately measured in at least one dimension with longest diameter (LD) 20 mm using conventional techniques or 10 mm with spiral CT scan.  Non-measurable lesions - all other lesions, including small lesions (longest diameter