Pharma_88
☆    

China,
2020-01-07 08:09

Posting: # 21062
Views: 923
 

 3+3 Design [Design Issues]

Hello All,

This is regarding 3+3 design for Phase-I trial. I have searched online and found some articles on design. My Question is that once the group/cohort is completed with 3 patients, whether same patients will be enrolled in next cohort or new patient will be enrolled? Further, in next cohort suppose 1 patient is withdarwn or have some AE then its compulsory to add 3 more patients to inline with multiplication of 3?

Thanks,
Pharma_88
Ohlbe
★★★

France,
2020-01-07 11:25

@ Pharma_88
Posting: # 21063
Views: 600
 

 3+3 Design

Dear Pharma_88,

» This is regarding 3+3 design for Phase-I trial.

Are you referring to Phase I trials in patients, mostly in oncology ? My experience in such trials is that you start each cohort with 3 patients, if you have 0 or 1 patient experiencing a dose-limiting toxicity (DLT) after e.g. 1 month you can enrol 3 more. Depending on the total number of DLT in these 6 patients you may then progress to the next dose level. If 2 or 3 of the first 3 patients have a DLT you stop there and you don't increase the dose to the next cohort. Is this what you have in mind ?

» My Question is that once the group/cohort is completed with 3 patients, whether same patients will be enrolled in next cohort or new patient will be enrolled?

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).

» Further, in next cohort suppose 1 patient is withdrawn or have some AE then its compulsory to add 3 more patients to inline with multiplication of 3?

If a patient is withdrawn due to a DLT, see my first paragraph.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 If he is withdrawn for another reason: you really have to be extra-sure it is really totally unrelated to a DLT.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.

Regards
Ohlbe
Pharma_88
☆    

China,
2020-01-08 09:55

@ Ohlbe
Posting: # 21065
Views: 546
 

 3+3 Design

» Are you referring to Phase I trials in patients, mostly in oncology ? My experience in such trials is that you start each cohort with 3 patients, if you have 0 or 1 patient experiencing a dose-limiting toxicity (DLT) after e.g. 1 month you can enrol 3 more. Depending on the total number of DLT in these 6 patients you may then progress to the next dose level. If 2 or 3 of the first 3 patients have a DLT you stop there and you don't increase the dose to the next cohort. Is this what you have in mind ?

yes. Same design.

» 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).

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

» » 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?
»
» 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.

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


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe]
Ohlbe
★★★

France,
2020-01-08 10:41

@ Pharma_88
Posting: # 21068
Views: 561
 

 Subject replacement

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).
»
» 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?
» »
» » 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.
»
» 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).

Regards
Ohlbe
Helmut
★★★
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Homepage
Vienna, Austria,
2020-01-07 12:18

@ Pharma_88
Posting: # 21064
Views: 597
 

 Dose escalation and DMC

Hi Pharma_88,

I agree with what Ohlbe wrote.

Note that the decision on whether or not to proceed to the next cohort must not be done at the clincal site but by an external Data Monitoring Committee (DMC). See also the EMA’s Guideline.

Cheers,
Helmut Schütz
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Pharma_88
☆    

China,
2020-01-08 09:56

@ Helmut
Posting: # 21066
Views: 564
 

 Dose escalation and DMC

Thank you Helmut


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe]
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