Regulatory Considerations in Drug and Device Development: The Process and the Science

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Regulatory Considerations in Drug and Device
DevelopmentThe Process and the Science

• John H. Powers, MD
• Lead Medical Officer
• Antimicrobial Drug Development and Resistance
  Initiatives
• Office of Drug Evaluation IV
• Center for Drug Evaluation and Research
• U.S. Food and Drug Administration

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Introduction

• Background on U.S. Food and Drug Administration
  (FDA)
• mission, goals, and short history
• current structure of FDA
• Process of drug development
• definitions of common terms
• phases of drug development
• Process of device development

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The Scientific Method

• Roger Bacon, monk, philosopher and alchemist
• Described scientific method in 13th century
• Repeating cycle of
• Observation
• Hypothesis
• Experimentation
• Verification/replication
• Regulations are based on GOOD SCIENCE
• Not hurdles
• Not just for licensing

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The Scientific Method

• Science can be an expensive (and dangerous!)
  business
• George Wilhemm Richmann was killed by lightning
  in 1753 attempting to replicate the 1752 kite
  experiment of Benjamin Franklin

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Mission and Goals

• The Food and Drug Administration Modernization
  Act (FDAMA) of 1997 affirmed FDAs public health
  protection role and defined the Agencys mission
  
• to promote public health by promptly and
  efficiently reviewing clinical research and
  taking appropriate action on the marketing of
  regulated products in a timely manner.

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Background

• U.S. Food and Drug Administration regulates a
  wide range of products including foods,
  cosmetics, drugs and medical devices
• FDA regulated products make up 1 trillion dollars
  worth of products and account for 25 of consumer
  spending
• FDA has approximately 10,000 employees
• FDA HQ located in Washington, DC, and across DC
  suburbs but soon to move to White Oak, MD in
  April 2005

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Background

• Regulatory authority comes from Food, Drugs and
  Cosmetic (FDC) Act enacted in 1938 after tragedy
  with Elixir of Sulfanilamide
• Code of Federal Regulations (CFR) is
  interpretation of FDC Act
• Original act specified drug sponsor only had to
  demonstrate safety of drug product
• Kefauver-Harris Amendments in 1962 specified
  that drug product must be effective as well as
  safe after issues with thalidomide
• Medical device regulations enacted in 1976
• FDA determines safety and effectiveness of
  products

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Background

• Executive branch of government
• Department of Health and Human Services (DHHS)
• U.S. Food and Drug Administration (FDA)
• Center for Biologics Evaluation and Research
• Center for Devices and Radiological Health
• Center for Food Safety and Applied Nutrition
• Center for Veterinary Medicine
• National Center for Toxicological Research
• Center for Drug Evaluation and Research (CDER)
• Office of New Drugs (OND)

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Regulation of Drugs
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Background

• CDER mission to oversee research, development,
  manufacture, and marketing of drugs.
• Review clinical trial evidence of safety and
  effectiveness of new drugs before approving them
  for marketing
• Monitors drugs post-marketing performance for
  unexpected health risks
• Ensures that drug labeling, drug information for
  patients, and drug promotion are truthful,
  helpful, and not misleading

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Background

• Each drug reviewed by a multi-disciplinary team
• Project Manager/Consumer Safety Officer
• coordinates team
• point of contact for drug sponsors
• Biopharmacologists
• Chemists
• Clinicians
• Microbiologists
• Pharmacology/toxicologists
• Statisticians
• Review of primary data, validity of data,
  chemistry

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Drug Development ProcessDefinitions

• Drug - any substance used to diagnose, cure,
  mitigate, treat or prevent a disease (FDC Act)
• Disease defined in the dictionary as a condition
  that results in medically significant symptoms
• Effectiveness - impact of drug on outcomes
  clinically relevant to patients, such as how a
  patient feels, functions, or survives
• Direct measurement of clinical endpoints
• Surrogate endpoints proven to predict clinical
  outcomes
• Safety all drugs associated with some harms
• all tests reasonably applicable to evaluate
• describing the adverse events associated with
  administration of drug

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Drug Development ProcessDefinitions

• Effectiveness
• Requirement for substantial evidence from
  adequate and well controlled trials since 1962
• trials of adequate size and design to determine a
  difference should such a difference exist
• uncontrolled trials are usually not acceptable
• testing a hypothesis in a clinical trial, such as
  drug X is superior to drug Y by Z

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Adequate and Well-Controlled

• Clear statement of objectives of trial
• Study design permits valid quantitative
  comparison with a control
• Select patients with disease (treatment) or at
  risk of disease (prevention)
• Baseline comparability (randomization)
• Minimize bias (blinding, etc.)
• Appropriate methods of assessment of outcome with
  well defined and reliable endpoint
• Appropriate methods of analysis
• 21 CFR 314.126

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Drug Development ProcessDefinitions

• Safety
• no drug is completely safe
• implies concept or risks of adverse effects
  compared to benefits of receiving drug
• takes into account seriousness of disease and
  available alternative therapies and seriousness
  and frequency of adverse effects

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Drug Development ProcessDefinitions

• Safety
• usually NOT testing a hypothesis but providing
  descriptive statistics only
• sample size of clinical trial database often too
  small to determine rare events
• Rule of three - no events in a given sample
  rules out a risk of denominator divided by three
• e.g. no events in 3000 patients rules out risk of
  11000 (compare to risk of hepatotoxicity in
  general population of 11,000,000)

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Drug Development Process Definitions

• Safety
• Important to look at absolute number of patients
  potentially experiencing adverse event as well as
  relative risk
• risk of visual abnormalities
• voriconazole 30 of 5000 patients with invasive
  aspergillosis is 1500 patients and few available
  therapies

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Drug Development Process
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Drug Development ProcessOverall Development Plan

• Overall goal to prove that drug is safe and
  effective in treatment and/or prevention of
  diseases under study
• Decide which indications to pursue and whether
  drug is to treat or prevent disease
• Speak with relevant Division at FDA about overall
  development plan and number of studies required
  for approval

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Development ProcessPhases of Drug Development

• Pre-clinical data
• in vitro data showing biological activity
• carcinogenicity
• animal toxicology (NOAEL) by going to high enough
  dose to observe some effect
• Phase 1
• first introduction of investigational new drug in
  humans usually performed in healthy volunteers
• used to determine absorption, metabolism,
  distribution, elimination in humans

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Development ProcessPhases of Drug Development

• Phase 2
• early controlled clinical trials, dose response
• preliminary efficacy of drug in patients
• determine common short term side effects
• Phase 3
• pivotal information on safety and efficacy
• further information on dose
• adequate and well -controlled trials
• basis for extrapolating results to general
  population and product labeling
• Phase 4 - post-marketing

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Drug Development Process

• Investigational New Drug (IND) Application
• needed whenever a sponsor wishes to study a new
  drug or an approved drug at a new dose, new route
  of administration in a new population
• houses all data prior to submission of NDA
• New Drug Application (NDA)
• information from IND as well as Phase 3 trials
  submitted for application to market a drug

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Drug Development Process
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Drug Development Process

• Fast Track Designation
• products for serious and life threatening
  diseases
• products that have potential to address unmet
  medical need
• sponsor can request at time of submission of IND
  or any time thereafter prior to approval
• schedule of meeting and written correspondence
• eligibility for priority review or accelerated
  approval

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Drug Development Process

• Accelerated Approval (two forms)
• serious and life threatening diseases without
  good alternative therapies
• approval based on surrogate endpoints reasonably
  likely to predict clinical benefit
• contingent on follow-up studies to confirm
  therapeutic benefits to patients
• restricted distribution
• Priority review
• products with significant improvement in safety
  or effectiveness
• not limited to serious and life threatening
  diseases

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CDRH Organization
CBER
OSM
FDA
CFSAN
OSB
CDRH
CVM
OHIP
ODE
CDER
OST
OIVD
DOED
DRARD
DAGID
DGRND
DCD
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Office of Device Evaluation
OFFICE OF THE DIRECTOR
Division of Reproductive, Abdominal, ENT
Radiological Devices
Division of Ophthalmic Devices
Division of General, Restorative Neurological
Devices
Division of Anesthesiology, General Hospital,
Infection Control, and Dental Devices
Division of Cardiovascular Devices
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Device Regulations

• FFDC Act (21 U.S.C 301 et seq.)
• Device Defined in Sec 201(h)
• Intended to diagnose, cure, mitigate, treat, or
  prevent a disease or condition
• or
• Affects the function or structure of the body
• and
• Does not achieve intended use through chemical
  action in/on body and is not metabolized to
  achieve purpose

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Center for Devices and Radiological Health
Pre-Marketing Review

• Devices divided into Classes for purposes of
  review
• For Class III Devices
• Premarket Approval Application (PMA) similar to
  NDA for new drugs
• Requires clinical trials
• For Class I, II and a few Class III Devices (for
  which a predicate device exists)
• Premarket Notification (510k)
• Comparison to previously approved device

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FDA APPROVES / DISAPPROVES MARKETING CLEARANCE
FOR FINISHED PRODUCTS (DRUGS, DEVICES, BIOLOGICS)

• not technologies
• not materials
• not processing techniques
• not additives

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Combination Product

• Combination Product (21 CFR 3.2(e))
• a product comprised of two or more regulated
  components that are physically, chemically or
  otherwise combined or mixed as a single entity
• two or more separate products packaged together
  (e.g., drug and device products) or
• provided separately but intended for use together
  where both are required to achieve the intended
  use, indication, or effect and where mutually
  conforming labeling is needed.

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Office of Combination Products (Established
December 24, 2002)

• Assignment of combination products to lead
  center based on primary mode of action
• Inter-center consultation/collaboration
• Ensure timely and effective premarket review
• Consistent and appropriate postmarket regulation
• Dispute resolution (timeliness vs. substance)
• Review/update guidance, agreements, practices

P. L. 107-250 -- enacted 10-26-02
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Examples Antimicrobial Agents in Cleared /
Approved Devices

• silver, silver cpds
• chlorhexidine cpds
• triclosan
• nitrofurazone
• bacitracin zinc
• minocycline
• polymyxin B sulfate

• rifampin
• methylene blue
• crystal violet
• dicloxicillin
• combinations of these

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Examples Device TypesCleared / Approved

• catheters - intravascular, urological,
  peritoneal, etc.
• wound care products - dressings, etc.
• dental - toothbrush, floss, instrument covers
• implanted devices - surgical mesh, orthopedic
  fixation, ear tube, heart valve

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Contact Information Office of Combination
Products

• Mark D. Kramer
• Director, Office of Combination Products
• 15800 Crabbs Branch Way (HFG-3)
• Rockville, MD 20855
• [phone]
• combination_at_fda.gov
• http//www.fda.gov/oc/combination/default.htm

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Contact Information for Devices

• Bob Gatling
• Program Operations
• Center for Devices and Radiological Health
• 9200 Corporate Boulevard (HFZ-450)
• Rockville, MD 20850
• [phone]

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Product Development Process

• Critical Path Initiative
• released by FDA in 2004
• goal to find better tools to streamline drug
  development process
• better predict safety and efficacy of products
• FDA can provide guidance on what tools may be
  most helpful
• www.fda.gov/oc/initiatives/criticalpath

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Conclusions

• Communication is one of keys to drug development
  process
• Take advantage of opportunities to discuss
  options with FDA
• Failing to plan is planning to fail
• Develop future tools during current trials