TeacherTECH Summer Science

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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

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Objectives for Todays 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

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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

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Drugs vs. Biologics

• Small molecules
• low molecular weight (typically lt10kD)
• organic and inorganic compounds
• Regulated by FDA Center for Drug Evaluation and
  Research (CDER)

• Therapeutic Proteins and peptides
• (large molecules)
• high Mol. Wt. ( typically gt10 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

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Traditional Drugs are small

• FLUDARA (fludarabine phosphate)
• Chronic lymphocytic leukemia
• Molecular weight 365.2 daltons
• Chemical formula C10H13FN5O7P

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Biological Drugs are BIG!

• RITUXAN (rituximab)
• B-cell non-Hodgkins lymphoma
• Molecular weight 145,000 daltons
• Chemical formula (non-glycosylated IgG1k)
  C3264H5002N840O998S20

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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
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Making Money from Drugs
Drug Development Timeline
Cost Recovery
Patent Life (17 years up to 5 years for drug
approval time losses)
RD 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)

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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

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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

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Drug Development Timeline
2-4 yrs
3-6 yrs
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Source FDA
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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

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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

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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

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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 labs,
  protocol labs)

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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

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

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Cost of Clinical Trials
Estimate of costs of development for
investigational compounds (US million, 2002)a
Testing Phase Out of pocket Mean cost Nb Probability of entering the Phase Cost adjusted for risk of failures Cost adjusted for risk, and capital costs
Pre Clinical 121.0 335.0
Clinical
Phase I 15.2 66 .215 70.7 141.4
Phase II 23.5 53 .303 77.6 139.7
Phase III 86.3 33 .685 126.0 163.9
Total 125.0 281.9 444.9
Animal Studies 5.2 20 .685 7.60 13.7
Total pre-clinical and clinical costs Total pre-clinical and clinical costs Total pre-clinical and clinical costs 402.9 793.7
a All costs were de?ated using the GDP Implicit
Price De?ator. 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) 151185
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Consumer PerceptionsThe 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

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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?

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The Post-Genomic EraIncreasing the complexity of
Clinical Trials

• Pharmacogenomics
• determines the inherited variations in genes that
  dictate drug response
• SNPs, 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

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Web Resources

• Clinical Trials - Ongoing
• ClinicalTrials.gov (http//www.clinicaltrials.gov/
  )
• any pharmaceutical company e.g.,
  (http//www.novartisclinicaltrials.com/etrials/hom
  e.do?pl_idbmretk000019)
• Clinical Trials - Completed
• ClinicalStudyResults.org (http//www.clinicalstudy
  results.org/)
• Pharmaceutical Information
• Drugs_at_FDA (http//www.accessdata.fda.gov/scripts/c
  der/drugsatfda/)
• Medline Plus (http//www.nlm.nih.gov/medlineplus/d
  ruginformation.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/educatio
  n/courses/cancer_course/clinical/approaches/size.h
  tml)
• Clinical studies reporting format
• ICH Guidelines (http//www.ich.org/MediaServer.jse
  r?_at__ID479_at__MODEGLB)
• Consumer information
• FDA magazine (http//www.fda.gov/fdac/default.htm)
  
• Classroom Activity
• NOVA (http//www.pbs.org/wgbh/nova/teachers/activ
  ities/2805_cancer.html)

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Thank You
www.sdsc.edu
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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//earth.google.com/