Clinical Trials: Understanding Biostatistics

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Clinical Trials Understanding Biostatistics

• Joseph Massaro
• Harvard Clinical Research Institute
• Boston University Department of Biostatistics
• March 21, 2008

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Outline

• Clinical trial definition and types of trials
• Phases of pharmaceutical/biotech trials
• Medical device trials
• Major stat considerations for clinical trials

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Clinical Trial Definition

• any form of planned experiment which involves
  patients and is designed to elucidate the most
  appropriate treatment of future patients with a
  given medical condition.
• Pocock, from Clinical Trials A Practical
  Approach (1984)

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Types of Clinical Trials

• Clinical Trials are performed in
• Pharmaceutical Products (Synthetic Drugs)
• Biotechnology Products (products made from human
  cells/tissues for example, such as vaccines,
  blood products)
• Devices (e.g., cardiac stents, pacemakers)

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Phases of Pharmaceutical/Biotechnology Clinical
Trials

• Pre-Clinical (in vivo, in vitro)
• Investigational New Drug (IND) Application
• Phase I - First time in humans
• Phase II - Exploratory
• Phase IIb
• Phase II/III
• Phase III - Confirmatory
• New Drug Application (NDA)/Product License
• Application (PLA)
• Phase IV - Post Marketing

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Phases of Pharmaceutical/Biotechnology Clinical
Trials

• FDA Center for Drug
• Evaluation and Research Handbook at
• http//www.fda.gov/cder/handbook/index.htm
• click on (a) New Drug Development and Review
  ? IND Review Process
• click on (b) New Drug Development and Review
  ? New Drug Development Process
• FDA Center for Drug Evaluation and Research
• general web site at http//www.fda.gov/cder
• FDA Center for Biologics Evaluation and Research
• general web site at http//www.fda.gov/cber

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Phase I Pharm/Biotech Trials

• First time in humans
• Objectives
• Assess pharmacology/pharmacokinetics
• How drug flows through body
• How drug is excreted and how long (half-life)
• Assess toxicology (safety)
• Adverse events, Labs, EKGs, Vital Signs, Physical
  Exams
• Determine maximum tolderated dose (MTD)
• Performed usually in 15-20 subjects
• No interest in efficacy
• Descriptive Analysis

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Phase II Pharm/Biotech Trials

• Performed in usually 50-200 patients
• Sample often based on time, cost considerations
• Concentrate on safety, but also look at efficacy
• Often exploratory in terms of efficacy
• Find parameters on which product is efficacious?
• Find magnitude of the products effect on these
  parameters?
• Contains control group (placebo/active)

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Phase II Pharm/Biotech Trials

• Multiple doses
• Find dose with best safety profile and best
  efficacy profile (not always the highest dose)
• Use results to design confirmatory Phase III
  trials
• Not necessarily required to obtain statistical
  significance (plt0.05) in Phase II in order to
  move to Phase III

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Phase III Pharm/Biotech Trials

• Objective
• Confirm efficacy of new drug seen in Phase II
• Determine safety of new drug (especially for
  uncommon adverse events).
• Often called Pivotal trials

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Phase III Pharm/Biotech Trials

• Often performed in 2 treatment groups
• Study drug vs. Control
• Control may be Active or Placebo
• Some suggest both Active and Placebo control
• If Active-controlled, not necessary to show
  superiority, but non-inferiority or
  equivalence
• FDA has no official rules about control group

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Phase III Pharm/Biotech Trials

• Sample size based heavily on statistics
• If treatment works in population, we want a
  sample large enough to represent population
• I.e., Want a high probability treatment works in
  sample
• FDA usually requires 2 phase III studies, with
  plt0.05 for efficacy (if superiority trial)
• For large simple trials (e.g., CV) only one
  large study may suffice (with, say, plt0.01 or
  plt0.001).

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Phase II/III Pharm/Biotech Trials

• Phase IIb, Phase II/III Trials
• Exploratory, but less so than Phase II
• State a specific analysis if successful,
  consider study as one of the Phase IIIs
  (pivotal)
• If not successful, then consider as exploratory
  analysis for planning Phase III

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New Drug Application (NDA)

• The data gathered during the animal studies and
  human clinical trials of an Investigational New
  Drug (IND) become part of the NDA. (From FDA
  Center for Drug Evaluation and Research Handbook
  at http//www.fda.gov/cder/handbook/index.htm
  click on New Drug Development and Review, New
  Drug Application (NDA) Review Process)
• Biologic equivalent is PLA (Product License
  Application)

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Clinical Trials in Medical Devices

• For further information, see FDA Center for
  Devices and Radiological Health (CDRH) web site
  at http//www.fda.gov/cdrh/index.html.

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International Conference on Harmonisation

• The International Conference on Harmonisation
  (ICH), as quoted at at http//www.ich.org,
• is a unique project that brings together the
  regulatory authorities of Europe, Japan and the
  United States and experts from the pharmaceutical
  industry
• The purpose is to make recommendations on ways
  to achieve greater harmonisation in the
  interpretation and application of technical
  guidelines and requirements for product
  registration in order to reduce

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Statistical Issues in Clinical Trials

• Efficacy variables
• Phase III (Confirmatory)
• 1-2 Primary efficacy variable e.g. Respiratory
  Distress Syndrome (RDS) in premature infants has
  2 primary endpoints
• RDS 24 hours after birth
• 28-day survival
• Show Rx effect in both endpoints (alpha0.05 for
  each)
• Show Rx effect in at least 1 endpoint
  (alpha0.025 for each).

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Statistical Issues in Clinical Trials

• Efficacy variables
• Phase III (Confirmatory)
• Usually several secondary endpoints
• In RDS trial Fi02, Mean Airway Pressure,
  All-cause mortality, Incidence of
  Bronchopulmonary Dysplasia
• How you split the alpha depends on objective of
  secondary endpoints (e.g. for label? just
  exploratory?)

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Statistical Issues in Clinical Trials

• Blindness
• Double-blind neither investigator nor patient
  know treatment patient is receiving
• Ideal situation
• Removes potential bias
• Still sometimes easy to ascertain the treatment
  patient is receiving (e.g., ALS study, lipid
  lowering study)

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Statistical Issues in Clinical Trials

• Blindness
• Single-blind investigator knows treatment
  patient is receiving
• Open-label patient and investigator know the
  treatment patient is receiving
• Such trials occur in cases when comparing, say,
  chemotherapy with surgery
• Have a blinded evaluation of patient outcome
  (someone not involved in treatment administration
  nor care of the patient).

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Statistical Issues in Clinical Trials

• Single-center or multi-center
• Choice often depends on logistical issues
• Can you obtain enough subjects in a
  single-center?
• If so, can you obtain enough in an allotted
  amount of time
• Is a single center representative of the
  population as a whole?

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Treatment-by-Center Interaction

• (Snapinn, 1998)
• Why multiple centers?
• Increase enrollment
• Increase generalizability of results to
  population
• Potential issue with multiple centers
• Center demographics/center study conduct may
  affect treatment performance
• Treatment-by-center (or treatment-by-clinic)
  interaction A treatment difference that varies
  significantly across study centers
• FDA would like assurance such an interaction does
  not exist so patients across centers can be
  pooled into one group for analysis

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• Interpreting Interaction The classical approach
  (Snapinn, 1998)
• Means by treatment group and center under various
  scenarios