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
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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

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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

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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

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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

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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

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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

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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)

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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

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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)

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Does this highly complex, extraordinarily
expensive process protectpatients from risk?
12
Does this highly complex, extraordinarily
expensive process protectpatients from
risk?Incompletely
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What else aside from the FDA protects research
subjects from unethical investigations?
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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
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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

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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

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Declaration of HelsinkiBasic Principles II

• Concern for the interests of the subjects must
  always prevail over the interests of science and
  society

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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

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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.

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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
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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

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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

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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

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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

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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

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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

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Some spinal drugs with FDA-reviewable
preclinical data

• Morphine
• Clonidine
• Levobupivacaine
• Neostigmine
• Amitryptyline

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Spinal drugs without FDA-reviewable preclinical
data

• Midazolam
• Chloroprocaine
• Plain 0.5 bupivacaine
• Ketamine
• Insert your favorite agent here!

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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
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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

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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

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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
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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
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Neurotoxic effects of LAs2-chloroprocaine

• Metabisulfite
• Acidic pH
• Toxicity disappeared when 2-CP reformulated
• Toxicity returns with generic versions of old
  formulation!

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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
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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)
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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
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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
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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?

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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

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