Peregrin
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Russia,
2015-07-24 16:24
(3169 d 20:39 ago)

Posting: # 15142
Views: 4,545
 

 Simultaneous conduct of a BE study [Regulatives / Guidelines]

Dear all,

According to section 4.1.1, first paragraph, of the EMA guideline on bioequivalence, 'The study should be designed in such a way that the formulation effect can be distinguished from other effects'.
Moreover, in section 4.1.8, subsection ‘Subject accountability’, second paragraph, of the same guideline, it is stipulated that ‘It is not acceptable to have a protocol which specifies that ‘spare’ subjects will be included in the analysis only if needed as replacements for other subjects who have been excluded.’
Does this imply that the study should be conducted simultaneously in the whole study population? If so, can you please cite the source where this requirement is provided explicitly, perhaps in the scientific guidelines of other regulatory bodies.
I would be very thankful for providing any response.

Kind regards,
Peregrin
Helmut
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Vienna, Austria,
2015-07-24 20:34
(3169 d 16:28 ago)

@ Peregrin
Posting: # 15144
Views: 3,995
 

 “Spare subjects”, multiple groups

Hi Peregrin,

❝ Does this imply that the study should be conducted simultaneously in the whole study population?


Not at all. It means that you shouldn’t replace dropouts. You estimate the sample size (based one the expected T/R-ratio & CV, desired power) and take the expected dropout-rate into account. See this post. If the actual dropout-rate is lower than expected, fine. You get a reward (lower producer’s risk). If it is higher, you will loose some power. Example for 2×2 crossover, CV 25%, T/R 0.95, desired power 80%, expected dropout-rate 10%: You estimate the desired sample size with 28 (power 80.7%), and dose 32 (uprounded):

nel  doact (%)  power (%)
 32     0.0      85.7
 31     3.1      84.6
 30     6.3      83.4
 29     9.4      82.1
 28    12.5      80.7
 27    15.6      79.2
 26    18.8      77.6

nel are the eligible subjects and doact the actual dropout-rates.

[image]The GL is talking about this idea: You desire 28, dose 32, have just 2 dropouts (say #27/28), and analyze #1–#26/#29/#30 (you don’t analyze #31/#32). Though that would safe some money in bioanalytics, there were regulatory concerns about this approach in the past:
  • It is not ethical to potentially have data which will not be used.
  • Doubts about the transparency of the procedure. The easiest rule would be “analyze the next ID”. Some people thought to be very clever and fiddled around with a “ran­dom” pick. Now doubts may rise: Is it possible that all ”spare” subjects were analyzed (undocumented, of course) and the “best” are picked? Yes, that’s plain fraud, but…
It is perfectly fine to perform a study in multiple groups (say for logistic reasons). Whether or not you have to modify the statistical model is a gray zone. Search the forum for “group effect”.
See also FDA’s 2001 guidance, Section VII.A.

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Peregrin
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Russia,
2015-07-25 16:31
(3168 d 20:31 ago)

@ Helmut
Posting: # 15145
Views: 3,842
 

 “Spare subjects”, multiple groups

❝ Whether or not you have to modify the statistical model is a gray zone. Search the forum for “group effect”.

❝ See also FDA’s 2001 guidance, Section VII.A.


Dear Helmut,

Thank you so much! This is the exact thing I've been looking for!
Several more questions have arised when I was considering your answer:
Should the sponsor explicitly state in the protocol that the study for logistical reasons will be carried out in two or more groups?
If the study has been conducted in several groups without statistical arrangements, should the sponsor at least provide some reasons for not doing so?

Kind regards,
Peregrin
Helmut
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Vienna, Austria,
2015-07-25 22:53
(3168 d 14:09 ago)

@ Peregrin
Posting: # 15146
Views: 3,743
 

 “Spare subjects”, multiple groups

Hi Peregrin,

❝ Should the sponsor explicitly state in the protocol that the study for logistical reasons will be carried out in two or more groups?

❝ If the study has been conducted in several groups without statistical arrangements, should the sponsor at least provide some reasons for not doing so?


Two times yes. Always state in the protocol what you plan to do and why.

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Peregrin
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Russia,
2015-07-26 11:36
(3168 d 01:27 ago)

@ Helmut
Posting: # 15147
Views: 3,639
 

 “Spare subjects”, multiple groups

❝ Two times yes.


Thank you!:cool:
sciguy
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Canada,
2015-08-11 06:03
(3152 d 07:00 ago)

@ Helmut
Posting: # 15219
Views: 3,222
 

 “Spare subjects”, multiple groups

Hi everyone,

Here is a slightly different but related scenario for an EMA study:

Regulatory has imposed some recruiting restrictions on our BE study which has forced us to dose in 2 groups due to an inability to recruit a sufficient number in a single group within the current timeframe.

Say we estimate we need to enroll 60 to complete 50 (~17% dropout rate) so we say in the protocol that Group 1 and Group 2 will have 30 subjects each. Can we do the following:
  1. Dose Group 1 with 30 subjects.
  2. Wait for Group 1 to complete Period 2 and assess the dropout rate. Let's say the dropout rate is higher than expected and 9 dropout during the study (ie: 30% dropout rate).
  3. Amend the protocol at this point to enroll 45 more subjects for Group 2 to account for the higher than expected dropout rate and in hopes of meeting the final complete target of 50.
If this is even acceptable, do we need to state how many subjects are planned to be dosed in each group a priori in the protocol knowing that Group 2 size may need to change? I have doubts that we could say something like: 30 subjects will be dosed in Group 1 and a sufficient number dosed in Group 2 to complete with 50 subjects.

Thanks for your valuable opinions!
Helmut
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Vienna, Austria,
2015-08-11 16:06
(3151 d 20:57 ago)

@ sciguy
Posting: # 15229
Views: 3,148
 

 Avoid amendments

Hi sciguy,

I would avoid amendments if ever possible (time consuming, nasty to read, …). You already know beforehand that
  • you need 50 subjects for the desired power, and
  • the dropout-rate is estimated with ~17% (50/60).
I understand your example, but would you decrease the second group size if you had less than the expected five dropouts in the first? I don’t think so. IMHO, amendments make only sense if something has to be adjusted which was not foreseeable. That’s not the case here. Instead, I would state a decision tree in the protocol:
  • If the dropout rate is lower than expected, still dose 30 in the second group. The lower drop­out-rate in the first group might be pure chance and your estimate was done for 50.
  • If more than five subjects drop out, increase the size of the second group. State an upper limit! Other­wise the IEC will not accept the protocol.
However, dealing with dropouts is in the regulatory gray zone. If the dropout-rate is higher than expected you will loose power. Doesn’t bother regulators in the first place (mainly interested in the patient’s risk). However, ICH-E9 has something to say about power. Is it ethical to continue with a group size based on an estimate when you have new information? Sounds that we need a Bayesian statistician* to answer that. ;-)
BTW, I developed R-code in order to keep the pooled dataset in two-stage designs as balanced a possible (see here). Should be easy to modify it to your needs.


  • All statisticians are Bayesians. Frequentist simply don’t know it.

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