Uncovering the Mystery of Clinical Drug Trials

1. Uncovering the Mystery of Clinical Drug Trials TeacherTECH Summer Science July 1, 2005 Dr. Joseph M. Cleary Project Manager, San Diego Supercomputer Center, UCSD Adj. Assoc. Professor, Biology Department, SDSU

2. Objectives for Today’s Presentation • Cover the basics on drugs • Describe clinical trials (types, history process , cost, players , timelines, etc.) • Examine types of web accessible information • Explore resources for information on specific clinical trials and drugs

3. The Big Picture for New Drugs • Identify the Disease Target for Treatment • Conduct Preclinical Research - pharmacology • File for using 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

4. Small molecules low molecular weight (typically <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), Immunomodulators (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, 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) Drugs vs. Biologics

5. Traditional Drugs are small… • FLUDARA® (fludarabine phosphate) • Chronic lymphocytic leukemia • Molecular weight 365.2 daltons • Chemical formula C10H13FN5O7P

6. Biological Drugs are BIG! • RITUXAN® (rituximab) • B-cell non-Hodgkin’s lymphoma • Molecular weight 145,000 daltons • Chemical formula (non-glycosylated IgG1k) C3264H5002N840O998S20

7. The Place of Drugs in Healthcare(US Sources and Spending (2003) Where it went Where it came from "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 & Medicaid Services, Office of the Actuary, National Health Statistics Group

8. Making Money from Drugs Drug Development Timeline Cost Recovery Patent Life (17 years + up to 5 years for drug approval time losses) R&D Timeline (5 – 20 years, AVG = 9 years) Date of patent application “Launch” date (drug is marketed publicly) Expiration of patent • Drug development cost • 1998 - $500 million • 2001 - $650 million • 2005 - $900 million + • US Drug Market • Total Revenue - $220 Billion (2003) • Growth – 12-15%/yr (2000-2003)

9. Clinical Trials: Testing New Medicines • Large Scale Experiments – application of the scientific method to the 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 results = Good clinical science + good statistical design + sound ethical conduct + thorough data analysis

10. 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 Nebuchadnezzar II, stayed healthy. • First clinical trial of a novel therapy: 1537 - Ambroise Parè 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 - 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– 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 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: 1945 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

11. Drug Development Timeline 2-4 yrs 3-6 yrs

12. Source: FDA

13. 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 – 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) • Routes 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 of human dose for safety margin • Good Laboratory Practices (GLP) Compliance • Documentation, instrument validation, records, records, records……

14. 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 humans • 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 IV – Post Marketing Studies • Risks, benefits, optimal use

15. 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 (lab 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, research plan, authorization

16. 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, gov’t labs) • Industry (medical organizations, testing labs, protocol labs)

17. 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 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 or test had an effect

18. Randomization: Essential for Statistical Validity Most trials are divided into two arms (but occasionally three or more

19. Clinical Data • Data Quality is Paramount • Good Clinical (Research) Practices (GCP) • Industry created standards Data attributes • Accurate – validation of instrumentation, 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

20. Cost of Clinical Trials Estimate of costs of development for investigational compounds (US$ million, 2002)a a All costs were deflated using the GDP Implicit Price Deflator. Weighted values were used in calculating means, medians, and standard deviations. b N: number of compounds with full cost data for the phase. Journal of Health Economics 22 (2003) 151–185

21. 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 best 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

22. Consumers: What to Ask Up Front • Purpose of the study? • # of people included in the trial? • Kinds of tests and treatments? • Treatment side effects? • Risks & Benefits of the trial? • Length of the trial and follow period? • Costs, insurance coverage, financial aid?

23. The Post-Genomic EraIncreasing the complexity of Clinical Trials • Pharmacogenomics • determines the inherited variations in genes that dictate drug response • SNP’s, microarray 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 ligands to identify/create candidate drugs • Relenza (antiviral for flu) • Viagra

24. Web Resources • Clinical Trials - Ongoing • ClinicalTrials.gov (http://www.clinicaltrials.gov/) • any pharmaceutical company e.g., (http://www.novartisclinicaltrials.com/etrials/home.do?pl_id=bmretk000019) • Clinical Trials - Completed • ClinicalStudyResults.org (http://www.clinicalstudyresults.org/) • Pharmaceutical Information • Drugs@FDA (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.randomizer.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)

25. Thank You www.sdsc.edu

26. 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 Earthhttp://earth.google.com/