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Master Class

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Title: Master Class


1
Master Class 6Neuraxial agents and spinal
neurotoxicity midazolam, nesacaine, clonidine,
and beyond. What works and how safe is it?
John Butterworth, MD Christopher Bernards,MD
2
The Drug Development Process From IND to NDA
  • The FDA and its obligations
  • The drug approval process
  • Sources of new drugs
  • Preclinical stage
  • Clinical stage
  • Postmarketing surveillance

3
The FDA, Safety, and Efficacy
  • Food and Drugs Act (1906) requires standards of
    purity and strength
  • Food and Drug Act (1938) mandates drug safety
    before marketing
  • Kefauver-Harris Amendment (1962) requires
    evidence of efficacy before marketing
  • Food and Drug Administration Modernization Act
    (1997) promotes pediatric investigations

4
The Drug Approval Process Nonhuman Phase
AfterCompound Identified
  • Animal safety testing
  • Acute toxicity in 2 species (only 1 rodent
    species)
  • Subacute and chronic toxicity in 2 species
  • Reproductive and developmental toxicity
  • Mutagenicity
  • Bioavailability and pharmacokinetic studies
  • Physicochemical properties and stability
  • Good Laboratory Practice (GLP) inspections

5
Elements of an IND(Investigational New Drug)
  • 1. Description of drug
  • 2. List of components
  • 3. Quantitative analysis
  • 4. Source and preparation of all components
  • 5. Strength, quality, purity standards for drug
  • 6. All available clinical, preclinical data
  • 7. All data supplied to PIs
  • 8. Training and experience expected of
    investigators
  • 9. Identity, training and experience of each
    investigator
  • 10. Outline of all phases of proposed studies
    including protocols

6
Elements of an IND-2
  • 11. Statement that FDA will be notified if and
    when studies discontinued
  • 12. Statement that all investigators will be
    notified if NDA approved or studies discontinued
  • 13. If drug to be sold, explanation why no NDA
  • 14. Statement that studies will not begin for 30
    days
  • 15. Environmental impact for EPA, if indicated
  • 16. Statement that GLP regs complied with

7
IND/NDA classification system
  • Therapeutic Potential
  • A. Important therapeutic gain
  • B. Modest therapeutic gain
  • C. Little or no therapeutic gain
  • D. Special situation (e.g., for nonresponders)
  • E. Upgrade to effective
  • Additional Classes
  • M. Marketed abroad
  • P. Packaging or container
  • R. Unique conditions of approval
  • S. Sensitive (newsworthy, Congressional interest)
  • T. Toxicity (carcinogenic)
  • U. Likely use in children

8
Stages of Human Testing
  • Phase 1 20-100 healthy volunteers studied for
    several months focus on safety, tolerance,
    pharmacokinetics maximum tolerated dose 70
    success
  • Phase 2 Up to several hundred subjects selected
    populations studied up to 2 years focus on
    dosing, efficacy, short-term safety 33 success
  • End of Phase 2 conference plan studies needed
    for NDA approval (including pediatric studies)

9
Stages of Human Testing-2
  • Phase 3 Up to several thousand subjects in CTs
    studied for lt4 years safety, efficacy,
    drug-related AEs, specific indications 25-30
    success (20 to market!)
  • End of Phase 3 conference (Pre-NDA) adequacy of
    data, statistics, sufficient Peds studies how
    data to be presented for NDA
  • Phase 4 Studies conducted after approval
    incidence of side-effects long-term results
    differing populations marketing comparisons
    FDAMA Peds

10
Elements of a New Drug Application (NDA)
  • Must contain all R D data categorized,
    tabulated, evaluated, and documented
  • Patients treated dosages and durations signs,
    symptoms, and responses side effects ADRs
  • Chemistry, pharmacology, toxicology, biochemistry
    of the new drug
  • Manufacturing and quality control procedures for
    processing, labeling, and packaging
  • Highly detailed summary (50-200 pages)

11
Does this highly complex, extraordinarily
expensive process protectpatients from risk?
12
Does this highly complex, extraordinarily
expensive process protectpatients from
risk?Incompletely
13
What else aside from the FDA protects research
subjects from unethical investigations?
14
Key US Regulations Governing the Conduct of
Clinical Research
Regulations directed toward protection of human
research subjects 21 CFR Part 50 Informed
Consent 21 CFR Part 56 IRB Regulations These
are nearly identical to the Common Rule
governing protection of human subjects in
federally funded research 45 CFR Part 46
15
Consensus documents, ethics,and clinical research
  • Primum Non Nocere First do no harm (Hippocrates
    Epidemics)
  • Nuremberg Code
  • Declaration of Helsinki (International Conference
    on Harmonisation)
  • Belmont Report
  • See
  • http//www.fda.gov/oc/gcp/regulations.html
  • http//ohsr.od.nih.gov

16
Declaration of Helsinki (1964-)Basic Principles
I
  • 1. Conform to accepted scientific principles
  • 2. Design formulated in experimental
    protocol
  • 3. Conducted by qualified persons
  • 4. Importance in proportion to inherent risk
  • 5. Assessment of risks vs. benefits

17
Declaration of HelsinkiBasic Principles II
  • Concern for the interests of the subjects must
    always prevail over the interests of science and
    society

18
Declaration of HelsinkiBasic Principles III
  • 6. Safeguard subjects integrity (privacy)
  • 7 . Abstain unless hazards are predictable
  • 8. Preserve accuracy when publishing
  • 9. Adequately inform/right to withdraw
  • 10. Obtain true informed consent
  • 11. Reliance on legal guardian
  • 12. State compliance with Declaration

19
Declaration of HelsinkiClinical Research
  • In any medical study, every patient--including
    those of a control group, if any--should be
    assured of the best proven diagnostic and
    therapeutic method. This does not exclude the use
    of inert placebo in studies where no proven
    diagnostic or therapeutic method exists.

20
Ethical Safeguards
Clinical Equipoise Uncertainty whether
treatment is better than control Informed
consent Institutional review board (ethics
committee) review Independent Data and Safety
Monitoring Board Reviews protocol Monitors
data May recommend trial termination
21
Safeguards Informed Consent-Mandatory Elements
  • Compensation/
  • treatment for injury
  • Contact for questions
  • Contact for research subjects rights
  • Right to refuse/ withdraw
  • Research
  • Purpose
  • Description
  • Experimental Procedure
  • Risks/benefits
  • Alternatives
  • Confidentiality

22
Unethical Study-HIV Transmission
  • Zidovudine reduces HIV transmission from mother
    to child by 2/3 (1994)
  • Complex/costly Tx regimen
  • Shorter regimen probably effective
  • 15 of 16 placebo-controlled trials in developing
    countries 9 U.S. funded (1997)
  • Heated debate re ethics of new trials

23
Unethical Treatment of Human Subject-Gene
Transfer Trial
  • Jesse Gelsinger, 18 yr. old
  • Ornithine transcarbamylase deficiency controlled
    with drugs and diet
  • Gene-therapy study to determine safety, not
    efficacy
  • Virus vector killed animals
  • Inadequate discussion of risks
  • Conflict of interest
  • 4 days after therapy, patient brain-dead 17 Sep
    99

24
Hexamethonium challenge study
  • Normal subjects inhaled hexamethonium as
    pulmonary vasodilator
  • Many publications on toxicity (before 1966)
  • Subject 1 with flu not reported to IRB
  • Subject 3, 24 years old died of respiratory
    failure 2 June 2001

25
What prevents a doctor from prescribing an
approved agent in way not specified by the label?
  • Clinical judgment
  • Fear of litigation
  • Potential loss of medical license
  • Potential loss of hospital staff privileges
  • Fear of adverse publicity

26
What prevents a doctor from studying an approved
agent in way not specified by the label?
  • Clinical judgment
  • Fear of litigation
  • Institutional Review Board/Ethics Committee
  • Need for FDA IND if seeking a new indication

27
Some spinal drugs with FDA-reviewable
preclinical data
  • Morphine
  • Clonidine
  • Levobupivacaine
  • Neostigmine
  • Amitryptyline

28
Spinal drugs without FDA-reviewable preclinical
data
  • Midazolam
  • Chloroprocaine
  • Plain 0.5 bupivacaine
  • Ketamine
  • Insert your favorite agent here!

29
The chloroprocaine controversy
  • Introduced (1952), used for 433 spinal
    anesthetics without reported problems
  • Wide popularity in obstetrics
  • 2 reports of 8 patients with persisting paresis
    and perineal anesthesia after accidental spinal
    anesthesia (1980)
  • Most had total spinal rapid injection of large
    volume hypotension

Anesth Analg 198059399-400, 447-51, 452-4 Reg
Anesth Pain Med 200126558-64
30
Case Presentation
  • 26 year old woman with a Papanicolau smear
    suggestive of cervical carcinoma
  • Scheduled for cold knife conization
  • Caudal catheter placed
  • Surgery delayed by an emergency
  • Now urgent need to establish anesthesia
  • 20 ml 3 2-chloroprocaine given

31
Case Presentation
  • Onset of sacral and lumbar anesthesia within 20
    min
  • Total spinal anesthesia at 25 min
  • Partial recovery over 2 hours
  • Residual weakness and anesthesia in sacral roots
  • Incomplete bowel and bladder control 5 years
    later

32
Neurotoxic effects of LAs2-chloroprocaine
  • Metabisulfite
  • Acidic pH
  • Toxicity disappeared when 2-CP reformulated
  • Toxicity returns with generic versions of old
    formulation!

Gissen. Reg Anesth 19849124-134 135-145 Wang.
Anesth Analg 198463445-7
33
Neurotoxic effects of LAs2-chloroprocaine
  • Metabisulfite
  • Acidic pH
  • Toxicity disappeared when 2-CP reformulated
  • Toxicity returns with generic versions of old
    formulation!

Gissen. Reg Anesth 19849124-134 135-145
34
Neurotoxic effects of LAs2-chloroprocaine
  • Metabisulfite
  • Acidic pH
  • Toxicity disappeared when 2-CP reformulated
  • Toxicity returns with generic versions of old
    formulation!

35
Neurotoxic effects of LAs2-chloroprocaine
  • Metabisulfite
  • Acidic pH
  • Toxicity disappeared when 2-CP reformulated
  • Toxicity returns with generic versions of old
    formulation!
  • Those who cannot rememember the past are
    condemned to repeat it.
  • Santayana G. The Life of Reason Reason in Common
    Science. New York, 1903

Winnie Nader. Reg Anesth Pain Med 200126558-64
36
Is 2 2-CP a satisfactory substitute for 2
lidocaine?
  • 8 volunteers
  • 40 mg
  • Comparable onset, peak, tourniquet tolerance
  • 7/8 have TNS (lido) 0/8 (2-CP)

Lidocaine
2-chloroprocaine
Plt.01
Anesth Analg 20049870-4, 75-80, 81-8, 89-94,
Time (min)
37
Is it the 2-CP or the bisulfite?
  • Rats received IT infusions (1 ?L/min x 2 hr) of
    3 2-CP, bisulfite, 3 2-CP bisulfite, or
    saline
  • Sensory loss at 7 days measured by tail flick
    latency
  • 2-CP injury lessened by bisulfite

max possible sensory loss
Taniguchi. Anesthesiology 2004 10085-91
38
Is it the 2-CP or the bisulfite?
  • Rats received IT infusions (1 ?L/min x 2 hr) of
    3 2-CP, bisulfite, 3 2-CP bisulfite, or
    saline
  • Nerve injury at 7 days
  • 0 normal
  • 1 mild injury
  • 2 moderate injury
  • 3 severe injury
  • 2-CP injury lessened by bisulfite

Mean nerve injury score
Taniguchi. Anesthesiology 2004 10085-91
39
Questions
  • Do the available animal testing results support
    clinical testing of chloroprocaine spinal
    anesthesia?
  • If the available clinical results show that there
    have been no major AEs in 2000 subjects (2
    patients with TNS) should we use chloroprocaine
    for spinal anesthesia?

40
Midazolam Questions
  • What is the responsibility of journal editors
    regarding publication of intrathecal drug
    studies?
  • Acceptance for publication?
  • Communication with the home IRB?
  • Responsibility to the research subjects

41
Thank you!
See http//www1.wfubmc.edu/ anesthesiology/resear
ch/ faculty_presentations.htm
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