Biometrics India, Pfizer Global R & D The Concept of Randomization and Blinding in Clinical Trials Suraj P Anand

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. The idea of randomisation, first introduced in the design of agricultural experiments by R.A.Fisher, ensured that true treatment effect could be separated from other effects arising from differences in experimental conditions or differences in the subjects studied. Randomisation did not feature in clinical trials until Bradford Hill introduced it formally in a trial of streptomycin for tuberculosis in 1948. Today randomisation is regarded as an essential feature of a well conducted clinical trial.

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.

Forms of Randomization Simple Randomization Permuted Block Randomization Stratified Block Randomization Dynamic (adaptive) random allocation

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

Illustrations The computer generated sequence: 4,8,3,2,7,2,6,6,3,4,2,1,6,2,0,……. Two Groups (criterion:even-odd): AABABAAABAABAAA…… Three Groups: (criterion:{1,2,3}~A, {4,5,6}~B, {7,8,9}~C; ignore 0’s) BCAACABBABAABA…… Two Groups: different randomisation ratios(eg.,2:3): (criterion:{0,1,2,3}~A, {4,5,6,7,8,9}~B) BBAABABBABAABAA…….. Some advantages of unequal randomization include the opportunity to place more patients in a less expensive arm, or to place more patients in an arm where there is concern about effects and side effects, i.e. an arm in which more data are needed.

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

Illustration With a block size of 4 for two groups(A,B), there are 6 possible permutations and they can be coded as: 1=AABB, 2=ABAB, 3=ABBA, 4=BAAB, 5=BABA, 6=BBAA 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.

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

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. Efron(1971) first introduced the idea of biased coin randomisation 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.

Characteristic Treatment A Treatment B Site 1 7 8   Site 2 10 9 ER+ 5 6 ER– 12 11 Premenopausal Postmenopausal Total 17 The next participant (no. 35) is from Site 2, ER+, postmenopausal. Subtotals for treatment allocation to this profile of characteristics are 10 + 5 + 9 = 24 for Treatment A and 9 + 6 + 8 = 23 for Treatment B (note subjects are counted more than once). Participant no. 35 would therefore be allocated to Treatment B. When the tallies on A and B are equal within a profile, the next participant is randomly allocated. This process is equivalent to a permuted block size of two within the profile. 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 Characteristic Treatment A Treatment B Site 1 7 8 Site 2 10 9 ER+ 5 6 ER– 12 11 Premenopausal Postmenopausal Total 17 The next participant (no. 35) is from Site 2, ER+, postmenopausal. Subtotals for treatment allocation to this profile of characteristics are 10 + 5 + 9 = 24 for Treatment A and 9 + 6 + 8 = 23 for Treatment B (note subjects are counted more than once). Participant no. 35 would therefore be allocated to Treatment B. When the tallies on A and B are equal within a profile, the next participant is randomly allocated. This process is equivalent to a permuted block size of two within the profile.

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

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. For example, suppose that an investigator creates an adequate allocation sequence using a random number table. However, the investigator then affixes the list of that sequence to a bulletin board, with no allocation concealment. Those responsible for admitting participants could ascertain the upcoming treatment allocations and then route participants with better prognoses to the experimental group and those with poorer prognoses to the control group, or vice versa. Bias would result. Inadequate allocation concealment also exists, for example, when assignment to groups depends on whether a participant's hospital number is odd or even or on translucent envelopes that allow discernment of assignments when held up to a light bulb. Allocation concealment should not be confused with blinding. Allocation concealment concentrates on preventing selection and confounding biases, safeguards the assignment sequence before and until allocation, and can always be successfully implemented (1, 2). Blinding concentrates on preventing study personnel and participants from determining the group to which participants have been assigned (which leads to ascertainment bias), safeguards the sequence after allocation, and cannot always be implemented (1-7).

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

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

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  

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

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

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.

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

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.

Hierarchy of Blinding open label: no blinding single blind: patient (usually;occasionally 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

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. Even though the open label studies are not recommended for comparative trials, under certain circumstances, these are necessarily conducted. e.g. in order to provide some potentially promising medications to the patients with severely debilitating or life-threatening disease, clinical trials conducted under compassionate plea protocols may be open labeled. Clinical trials for evaluation of safety and effectiveness of a new surgical procedure are usually conducted in an open-label fashion because it is clearly unethical to conduct a double-blind trial with a concurrent control group in which patients are incised under a general anesthesia to simulate the surgical procedures.

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

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

Double Blinding:Techniques 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

Double Blinding:always 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

Double Blind Studies:stumbling 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

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

Complete Blinding:Techniques 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) In this case, along with the patient and the investigator, all members of the clinical project team of the sponsor including CRA, statistician, programmer, and data coordinator are blinded. In practice, although the project clinician, CRA, statistician, programmer, and data coordinator usually have the access to the individual patient’s data, they are usually not aware of the treatment assignment for each patient. In addition, the overall treatment result, if any e.g..(interim analysis), will not be made available to the patient, project clinician, CRA, statistician, programmer, and data coordinator until a decision is made at an appropriate time. To maintain the integrity of blindness throughout the study, it is helpful to provide in-house training/education to all personnel related to the clinical trial, including those in the analytical laboratory or in pharmaceutical science R&D.