Bioequivalence and Bioavailability Forum

Dear Pharma_88,

❝ ❝ In the design I have in mind, the group/cohort is completed with 3+3 patients, not just 3. And you enrol new patients in each cohort (if you only use the same patients who have a good tolerability, you have some bias).

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❝ Yes. but initial cohort (means first one) is started with 3 patients only. subsequent cohort will have 3+3 patients. Right?

No. The initial cohort is started with 3 patients. If you have 0 or 1 DLT, you enrol 3 more in the same cohort. If you meet the pre-defined criteria, the DMC will allow you to move to the next cohort. There you go through the same process: start with 3, if you have 0 or 1 DLT you add 3 more, and so on until you reach the highest tolerated dose or the highest dose defined in your protocol. All cohorts are treated equally, including the first one.

❝ ❝ ❝ Further, in next cohort suppose 1 patient is withdrawn or have some AE then its compulsory to add 3 more patients to inline with multiplication of 3?

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❝ ❝ If a patient is withdrawn due to a DLT, see my first paragraph. The patient is not replaced. If he is withdrawn for another reason: you really have to be extra-sure it is really totally unrelated to a DLT. You may decide to replace that patient (meaning, only 1 extra-patient). Make sure this is properly defined in your protocol. I would not use 3 patients to replace just 1.

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❝ So, in this case, total 4 patients are required to enroll (1 for replacement and 3 others). Correct?

Two possible situations:

• the withdrawn subject was one of the first 3. If the other 2 patients each had a DLT, no need to replace him: you have reached your maximum tolerated dose anyway. If the other 2 had 0 or 1 DLT: you may replace the patient, if allowed by your protocol. Then look at the number of DLT in your 3 patients and see whether you can add 3 more;
  
• the withdrawn subject was one of the last 3. If your stopping criteria are met: no need to replace him. If they are not met, and if allowed by your protocol: you may replace him. Then the DMC will see whether you can move to the next cohort. But don't add 3 more to the same cohort (3 + 3 + 3).