1、TeacherTECH Summer Science July 1, 2005Dr. Joseph M. Cleary Project Manager, San Diego Supercomputer Center, UCSD Adj. Assoc. Professor, Biology Department, SDSU,Uncovering the Mystery of Clinical Drug Trials,Objectives for Todays Presentation,Cover the basics on drugs Describe clinical trials (type
2、s, history process , cost, players , timelines, etc.) Examine types of web accessible information Explore resources for information on specific clinical trials and drugs,The Big Picture for New Drugs,Identify the Disease Target for Treatment Conduct Preclinical Research - pharmacology File for using
3、 a Investigational New Drug (IND) Conduct Clinical Trials Develop Manufacturing Capability concurrently File a New Drug Application (NDA) Get Regulatory Approval Market and Make Money Conduct Post Approval Studies safety & new uses,Drugs vs. Biologics,Small molecules low molecular weight (typically
4、10kD) organic and inorganic compounds Regulated by FDA Center for Drug Evaluation and Research (CDER),Therapeutic Proteins and peptides (large molecules) high Mol. Wt. ( typically 10 kD) Monoclonal antibodies (MAb) in vivo use Cytokines (e.g. interferons), Enzymes (e.g. thrombolytics), Immunomodulat
5、ors (products intended to treat disease by inhibiting/modifying a pre-existing immune response) Growth factors, cytokines, and monoclonal antibodies that alter the production of hematopoietic cells All novel proteins, except those specifically assigned to CBER from plants, animals, or microorganisms
6、, and recombinant versions Regulated by FDA Center for Drug Evaluation and Research (CDER)Other Biologics Vaccines Antitoxins Antivenins blood components cellular products Regulated by FDA Center for Drug Evaluation and Research (CBER),Traditional Drugs are small,FLUDARA (fludarabine phosphate) Chro
7、nic lymphocytic leukemia Molecular weight 365.2 daltons Chemical formula C10H13FN5O7P,Biological Drugs are BIG!,RITUXAN (rituximab) B-cell non-Hodgkins lymphoma Molecular weight 145,000 daltons Chemical formula (non-glycosylated IgG1k) C3264H5002N840O998S20,The Place of Drugs in Healthcare (US Sourc
8、es and Spending (2003),Where it came from,Where it went,“Other Spending“ includes dental services, other professional services, home health care, durable medical products, over-the-counter medicines and sundries, public health activities, research and construction,SOURCE: Centers for Medicare & Medi
9、caid Services, Office of the Actuary, National Health Statistics Group,Making Money from Drugs,Drug Development Timeline,Date of patent application,“Launch” date (drug is marketed publicly),Expiration of patent,Cost Recovery,Patent Life (17 years + up to 5 years for drug approval time losses),R&D Ti
10、meline (5 20 years, AVG = 9 years),Drug development cost1998 - $500 million2001 - $650 million2005 - $900 million +,US Drug MarketTotal Revenue - $220 Billion (2003)Growth 12-15%/yr (2000-2003),Clinical Trials: Testing New Medicines,Large Scale Experiments application of the scientific method to the
11、 health sciences Human volunteers (healthy and patients) What is evaluated: Drugs, Biologics, Medical Devices, Medical Procedures Types of clinical trials: treatment, prevention, quality of life, early detection Oversight by government (Federal) regulations Equation for Successful Trials Good result
12、s = Good clinical science + good statistical design + sound ethical conduct + thorough data analysis,Brief History of Clinical Trials,Earliest recorded clinical trial:600 BCE (documented in the Old Testament) Daniel, following a diet of pulses and water instead meat and wine, recommended by King Neb
13、uchadnezzar II, stayed healthy. First clinical trial of a novel therapy: 1537 - Ambroise Par used a concoction of turpentine, rose oil & egg yolk to prevent infection of battlefield wounds, noting the new treatment much more effective that the traditional formula. First use of control groups: 1747 -
14、 James Lind, considered the father of clinical trials, documented that citrus prevented scurvy, by comparing diet supplements of cider, elixir vitriol, vinegar, seawater, nutmeg and (crucially) oranges and lemons. First use of a placebo: 1863 First regulations against false therapeutic claims: 1912
15、US product labeling laws enacted First use of randomization: 1923 First body to manage clinical trials: 1930 Therapeutic Trials Committee (UK) First US regulation to require drug safety: 1938 US Food, Drug, and Cosmetic Act First multicenter studies employing the same protocol: 1938 enabled pooling
16、of data to increase statistical power First properly randomized clinical trial with control groups and blind assessment: 1948 The British Medical Research Council (MRC) evaluated the use of streptomycin to treat pulmonary tuberculosis. First strict, ethical regulations for medical experimentation: 1
17、945 and onward - the Nuremburg Codex (1947) and the Declaration of Helsinki (1964, amended in 1975, 1983, 1989,2001) First regulation for proof of efficacy: 1962 Kefauver-Harris Drug Amendment (US) required proof of efficacy required for new drug approval, in addition to safety,Drug Development Time
18、line,2-4 yrs,3-6 yrs,Source: FDA,Preclinical Research,Basic biology, molecular biology and biochemistry Drug target selection, assay design, screening (chemical libraries), identify hits, lead optimization, lead selection Testing in vitro (cell or bacterial culture) Biochemistry Effectiveness Safety
19、 toxicity, mutagenicity, teratogenicity Surrogate markers in animals (two “relevant” species - mice, rats, dogs, armadillos, etc.) Toxicity Testing Genotoxicity (DNA damage), Carcinogenicity, Immunogenicity, Teratogenicity (developmental thalidimide) Acute vs Chronic Use (2 weeks vs. 6 months) Route
20、s of Administration and Dosing Regimen Studies Injectable (subcutaneous, IM), oral, nasal, transdermal Concentration and frequency Pharmacokinetics Studies ADME (absorption, distribution, metabolism, excretion) studies (useful) Toxic Dose and NOAEL (No-Observed-Adverse-Effect Levels) need multiples
21、of human dose for safety margin Good Laboratory Practices (GLP) Compliance Documentation, instrument validation, records, records, records,Clinical Trial Process: Four Stages,Phase I - Tests SAFETY for humans 30 to 100 healthy volunteers establish initial dosage range Phase II - Tests EFFICACY in hu
22、mans 50 to 300 patients with disease or condition optimal dosages, side effects & dosing schedules Phase III Tests SAFETY & EFFICACY 3,000 patients, on average (up to 10,000) Large and diverse population compares new vs. standard treatment Size exceptions orphan drugs, low incidence diseases Phase I
23、V Post Marketing Studies Risks, benefits, optimal use,Clinical Trial Requirements,Protocol strict preset research plan (experimental design) to: Select appropriate patient study groups Provide consistent testing procedures Specified doses, frequency & duration of treatment Assessment Measurements (l
24、ab tests, scans, etc.) Comparison with control (placebo or std treatment) Participant selection criteria Randomization (double blind) Follow medical, ethical and legal guidelines Extensive, independent peer review process Institutional Review Board (IRB) Regulatory Oversight Preclinical test data, r
25、esearch plan, authorization,The Players,Sponsors Pharmaceutical & Biotech companies Government Agencies, e.g., NIH Non-profit Organizations, e.g., AHA Health care institutions, e.g, Humana Investigators and Collaborators Academic (medical schools, govt labs) Industry (medical organizations, testing
26、labs, protocol labs),Clinical Trial Terms,Arm treatment group Randomization distribution based on chance Blinding aka masking (single, double, triple blind study) Endpoint outcome being evaluated (toxicity, disease progression, or death. Efficacy positive result compared to outcome (determined prior
27、 to trial) Exclusion (Inclusion) Criteria standards of appropriateness for participation, e.g. sex, medical condition Cohort group of individuals with common characteristics (epidemiology) Statistically significant - the result is very unlikely due to chance alone, and, therefore, that the treatment
28、 or test had an effect,Randomization: Essential for Statistical Validity,Most trials are divided into two arms (but occasionally three or more,Clinical Data,Data Quality is Paramount Good Clinical (Research) Practices (GCP) Industry created standards Data attributes Accurate validation of instrument
29、ation, software, Complete - “spare the pen and spoil the data” Traceable equivalent to the chain of evidence in law Legible Attributable “who did what” Timely supported & endorsed by the FDA Rigorous Statistical Analysis - the determining factor,Cost of Clinical Trials,a All costs were deated using
30、the GDP Implicit Price Deator. Weighted values were used in calculating means, medians, and standard deviations. b N: number of compounds with full cost data for the phase.,Estimate of costs of development for investigational compounds(US$ million, 2002)a,Journal of Health Economics 22 (2003) 151185
31、,Consumer Perceptions: The Cancer Example,The vast majority of cancer patients do not take part in clinical trials only 4% of cancer patients participate Perception (based on survey) 84% are unaware of clinical trials 58% would never participate because of: Fear of no insurance coverage Less than be
32、st treatment (e.g., placebo) Reality Placebos never used Benefits best std treatment at minimum, patient is taking an active role, Drawbacks side effects, insurance may not cover,Consumers: What to Ask Up Front,Purpose of the study? # of people included in the trial? Kinds of tests and treatments? T
33、reatment side effects? Risks & Benefits of the trial? Length of the trial and follow period? Costs, insurance coverage, financial aid?,The Post-Genomic Era Increasing the complexity of Clinical Trials,Pharmacogenomics determines the inherited variations in genes that dictate drug response SNPs, micr
34、oarray technology, etc. Personalized Medicine Combining the genotype information of an individual patient with pharmacogenomics to target the “right drug to the right patient.” Rational Drug Design apply information about the protein structure of a drug receptor (target) or one of its natural ligand
35、s to identify/create candidate drugs Relenza (antiviral for flu) Viagra,Web Resources,Clinical Trials - Ongoing ClinicalTrials.gov (http:/www.clinicaltrials.gov/) any pharmaceutical company e.g., (http:/ Clinical Trials - Completed ClinicalStudyResults.org (http:/www.clinicalstudyresults.org/) Pharm
36、aceutical Information DrugsFDA (http:/www.accessdata.fda.gov/scripts/cder/drugsatfda/) Medline Plus (http:/www.nlm.nih.gov/medlineplus/druginformation.html) Clinical trials analysis Analysis and statistics tools (http:/www.gfmer.ch/Medical_search/Clinical_tools.htm) Data randomizing (http:/www.rando
37、mizer.org/) Sample size (http:/www.fhcrc.org/science/education/courses/cancer_course/clinical/approaches/size.html) Clinical studies reporting format ICH Guidelines (http:/www.ich.org/MediaServer.jser?_ID=479&_MODE=GLB) Consumer information FDA magazine (http:/www.fda.gov/fdac/default.htm) Classroom Activity NOVA (http:/www.pbs.org/wgbh/nova/teachers/activities/2805_cancer.html),Thank You,www.sdsc.edu,Classwork,Pick a disease Find the drugs and trials under study or Pick a recently approved drug Find completed trials review study report D then Check out Google Earth http:/
