Biometrics India, Pfizer Global R & D

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Biometrics India, Pfizer Global R D

• The Concept of Randomization and Blinding in
  Clinical Trials
• Suraj P Anand

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Randomization

• Randomization is the process of assigning
  clinical trial participants to treatment groups.
  Randomization gives each participant a known
  (usually equal) chance of being assigned to any
  of the groups. Successful randomization requires
  that group assignment cannot be predicted in
  advance.

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Why Randomize?

• If, at the end of a clinical trial, a difference
  in outcomes occurs between two treatment groups
  (say, intervention and control) possible
  explanations for this difference would include
• the intervention exhibits a real effect
• the outcome difference is solely due to chance
• there is a systematic difference (or bias)
  between the groups due to factors other than the
  intervention.
• Randomization aims to obviate the third
  possibility.

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Forms of Randomization

• Simple Randomization
• Permuted Block Randomization
• Stratified Block Randomization
• Dynamic (adaptive) random allocation

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Simple Randomization

• Coin Tossing for each trial participant
• Sequence of Random Numbers from statistical
  textbooks
• Computer generated sequence

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Illustrations

• The computer generated sequence
• 4,8,3,2,7,2,6,6,3,4,2,1,6,2,0,.
• Two Groups (criterioneven-odd)
• AABABAAABAABAAA
• Three Groups
• (criterion1,2,3A, 4,5,6B, 7,8,9C
  ignore 0s)
• BCAACABBABAABA
• Two Groups different randomisation
  ratios(eg.,23)
• (criterion0,1,2,3A, 4,5,6,7,8,9B)
• BBAABABBABAABAA..

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Permuted Block Randomization

• Used for small studies to maintain reasonably
  good balance among groups
• In a two group design, Blocks having equal
  numbers of As and Bs (A  intervention and
  B  control, for example) are used, with the
  order of treatments within the block being
  randomly permuted

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Illustration

• With a block size of 4 for two groups(A,B), there
  are 6 possible permutations and they can be coded
  as
• 1AABB, 2ABAB, 3ABBA, 4BAAB, 5BABA, 6BBAA
• Each number in the random number sequence in
  turn selects the next block, determining the next
  four participant allocations (ignoring numbers
  0,7,8 and 9).
• e.g., The sequence 67126814. will produce BBAA
  AABB ABAB BBAA AABB BAAB.
• In practice, a block size of four is too small
  since researchers may crack the code and risk
  selection bias. Mixing block sizes of between 6
  and 12 is better with the size kept unknown to
  the investigator. This precaution maintains
  concealment. Simple randomization should
  determine which block size to use next.

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Stratified Block Randomization

• Stratified block randomization can further
  restrict chance imbalances to ensure the
  treatment groups are as alike as possible for
  selected prognostic variables or other patient
  factors. A set of permuted blocks is generated
  for each combination of prognostic factors
• Typical examples of such factors are age
  group, severity of condition, and treatment
  centre. Stratification simply means having
  separate block randomisation schemes for each
  combination of characteristics (stratum)
• For example, in a study where you expect
  treatment effect to differ with age and sex you
  may have four strata male over 65, male under
  65, female over 65 and female under 65

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Dynamic (adaptive) random allocation

• Simple and block randomization methods are
  defined, and allocation sequences set up, before
  the start of the trial.
• In contrast, dynamic randomization methods
  allocate patients to treatment group by checking
  the allocation of similar patients already
  randomized, and allocating the next treatment
  group "live" to best balance the treatment groups
  across all stratification variables. Biased coin
  randomization and minimisation are two such
  methods.
• Efron(1971) first introduced the idea of
  biased coin randomization as a method for
  adjustment of assigning probabilities. The
  assigning probability for the first patient
  is1/2. After k patients are enrolled, with k(A)
  and k(B)
• patients randomized in groups A and B
  respectively, the idea involves randomizing the
  next patient to group B with probability greater
  than ½ if more patients have been randomized to
  group A at this stage, and vice-versa. If balance
  is achieved, the next patient is randomized to
  either of the groups with probability ½.

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Example of randomization using the minimisation
method in a trial of chemotherapy for breast
cancer, with stratification factors of clinic
site, estrogen receptor status (ER or ER) and
menopausal status
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Inappropriate randomisation methods

• Assigning patients alternately to treatment group
  is not random assignment
• Assigning the first half of the population to
  one group is not random assignment
• Assignments by methods based on patient
  characteristics such as date of birth, order of
  entry into the clinic or day of clinic
  attendance, are not reliably random

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Allocation Concealment

• It is very important that those responsible
  for recruiting people into a trial are unaware of
  the group to which a participant will be
  allocated, should that subject agree to be in the
  study. This avoids both conscious and unconscious
  selection of patients into the study.
• For multicentre clinical trials, central
  randomization by telephone, interactive voice
  response system, fax or the Internet are ideal
  methods for allocation concealment. The clinician
  or data manager at the participating site
  assesses eligibility, gains consent, and makes
  the decision to enroll a patient, then calls the
  randomization service to get the treatment
  allocation.
• For single-centre clinical trials, it is usually
  possible to identify a staff member not involved
  with the trial who can keep the randomization
  list or envelopes. They should be instructed to
  keep the list private, and to only reveal a
  treatment allocation after receiving information
  demonstrating that the patient is eligible and
  has consented to the trial.
• In situations where remote randomization may not
  be feasible or desirable, a set of tamper-evident
  envelopes may be provided to each participating
  site. The envelopes should look identical, and
  each should have the trial identification and a
  sequential number on it. Inside is the treatment
  allocation and usually a trial identifier for the
  patient (e.g., unique sequential number). After
  assessing eligibility and consent, the next
  envelope in sequence is opened. Care needs to be
  taken that the envelopes are opaque and well
  sealed, and that the sequence of opening the
  envelopes is monitored regularly.

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Issues leading to Blinding

• Most investigators have firm views about which of
  a range of alternative treatments is more
  effective and often, which is more appropriate
  for particular groups of patients. As a result,
  there is a strong temptation by investigators to
  channel particular groups of patients to
  particular treatments (channeling effect )
• There is also a risk of the investigators
  subconsciously losing their objectivity in their
  assessments of treatment effects simply because
  of their clear preference for particular
  treatments
• There is a risk of having other forms of bias,
  which can be satisfactorily controlled by proper
  blinding

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Bias

• Bias is said to have occurred if the results
  observed reflect other factors in addition to (or
  even instead of) the effect of the treatment
• Some potential sources of bias
• Patient bias
• Care Provider bias
• Assessor bias
• Laboratory bias
• Analysis and Interpretation bias

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Patient Bias

• the patient's knowledge that the patient is
  receiving a "new" treatment may substantially
  affect the patient's subjective assessment
• there is a subject x disease interaction in at
  least some diseases (and virtually all diseases)
• thus, the patient's knowledge of the treatment
  being received may affect the outcome of the
  study
•  

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Care Provider Bias

• the care provider's knowledge of which treatment
  a patient is receiving may affect the way the
  provider
• deals with the patient
• treats the patient
• these differences may give the patient
  information (even if incorrect) about the
  treatment the patient is receiving, which then
  may affect the outcome of the study

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Assessor Bias

• the assessor's knowledge of which treatment the
  patient is receiving may affect the way the
  assessor assesses outcome
• such a bias would directly affect the validity of
  the conclusions of the study
• if the assessment is done while the patient is
  still receiving treatment, this may provide the
  patient with information about the treatment
  being received

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Laboratory Bias

• the knowledge of which treatment the patient
  received may affect the way in which the test is
  run or interpreted, or be retested.
• although this is most severe with subjectively
  graded results (pathology slides, photographs,
  ECG, etc.), this can also be a problem with
  "objective tests" such as laboratory assays which
  may be run subtly differently by the technician.

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Analysis and Interpretation bias

• knowledge of the treatment group may affect the
  results of the analysis of the data by
• seeking an explanation of an "anomalous
  finding when one is found contrary to the study
  hypothesis
• accepting a "positive" finding without fully
  exploring the data
• knowledge of the treatment group may affect the
  decisions made by external monitors of a study by
• terminating a study for adverse events because
  they fit the expectations of the monitors
• terminating a study for superiority of
  treatment because it fits the expectations of the
  monitors

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Blinding

• All of these potential problems can be avoided
  if everyone involved in the study is blinded to
  the actual treatment the patient is receiving.
• Blinding (also called masking or concealment
  of treatment) is intended to avoid bias caused by
  subjective judgment in reporting, evaluation,
  data processing, and analysis due to knowledge of
  treatment.

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Hierarchy of Blinding

• open label no blinding
• single blind patient (usuallyoccasionally may
  be assessor) blinded to treatment
• double blind patient and assessors (who often
  are also the health care providers and data
  collectors) blinded to treatment
• complete blind everyone involved in the study
  blinded to treatment

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Open Label Studies

• These may be useful for
• pilot studies
• dose ranging studies
• However, even these applications may be
  substantially biased by knowledge of the
  treatment given and may result in
• toxicity over (or under) reported
• efficacy over estimated
• Even a small fraction of patients assigned at
  random to placebo will reduce these potential
  problems substantially.

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Single Blind Studies

• single blind studies are usually done to blind
  the patient to the treatment given. Health care
  providers and assessors
• usually know the actual treatment given
• justification is usually that double-blind is
  "impractical" because of need to adjust
  medication, medication affecting laboratory
  values, potential side effects, etc.
• a single blind study should be used only when it
  would be
• unacceptable ethically to give an appropriate
  placebo treatment to a patient, and in such a
  case, the assessor (not the patient) should be
  the one blinded to the treatment

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Double Blind Studies

• When both the subjects and the investigators are
  kept from knowing who is assigned to which
  treatment, the experiment is called double
  blind"
• Serve as a standard by which all studies are
  judged, since it minimizes both potential patient
  biases and potential assessor biases
• Should be used whenever possible, which is
  whenever it is ethically
• permissible to blind a patient

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Double BlindingTechniques

• Coded treatment groups
• Placebo for each possible treatment
• - tablets identical in physical appearance
• - tablets with similar taste and smell
• - IV infusions would normally be the same
  carrier as used for active
• medications
• Other treatments "shammed" as far as
• possible
• minimal power ultrasound therapy when
  testing effect of physical therapy in back pain
• breathing exercises when assessing the
  effect of conditioning exercises

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Double Blindingalways feasible??

• Situations when double blinding might not be
  possible
• it might not be ethically permissible to blind a
  patient. As an example, it is unlikely that sham
  surgery would be considered ethical in a study
• it might not be possible to blind a patient. For
  example, it would be hard to blind a patient to
  the therapy given in an exercise study
• it might not be possible to blind a patient while
  comparing utility of different invasive
  procedures

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Double Blind Studiesstumbling blocks

• Side effects
• side effects (observable by patient) are much
  harder to blind
• in general, there are significant ethical
  problems using placebos to induce side effects in
  patients
• side effects are, in fact, one of the major ways
  in which blinding is broken
• a way to avoid it is that the side effects of all
  the potential therapies be combined into a single
  list, so that knowledge of side effects would not
  indicate therapy (at least to patient)
• Efficacy
• a truly effective treatment can be recognized by
  its efficacy in patients
• although rare, some new treatments truly are
  major leaps. when this happens, it is usually
  very clear which treatment a patient is
  receiving, at least for the health care providers
  involved in the trial

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Complete Blinding

• probably the best approach which can be used, but
  requires two groups for data processing, one
  group to encode the
• data/analysis and one group to perform the
  analysis
• normally only available in major drug company
  studies, and not routinely used even then

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Complete BlindingTechniques

• analysis uses coded treatment groups
• analysis uses coded side effects (e.g., side
  effects coded using non-standard scheme, with
  only numeric codes available at time of analysis)
• analysis uses coded laboratory tests (e.g., name
  of test coded numerically at time of analysis,
  using non-standard code)