lechia
☆    

C of U,
2015-04-06 18:14
(3279 d 00:10 ago)

Posting: # 14664
Views: 8,913
 

 Submitting a pilot as a pivotal study [Study As­sess­ment]

Hello all,

There have been a number of mentions on the BEBAC forums of using the results of a pilot to submit to regulatory bodies if the study "passes" without going to a pivotal. There are even arguments that it is not ethical to run a pivotal study if the pilot shows equivalence, i.e. why subject more healthy volunteers to a drug if not needed?

My question concerns what is required to actually successfully do this. How should the pilot protocol be written to allow this? Generally, pilot protocols do not have BE criteria specified. I presume this would be a requirement to convert a pilot to a pivotal? Do we need to put any additional text that mentions that if BE criteria are fulfilled no pivotal study will be conducted?

Secondly, is this not in effect cheating? If we use the pilot for submission when the study passes, then in effect we are giving ourselves an extra shot at passing. A free shot, since if the study fails to meet BE criteria we can just run a larger pivotal study that will narrow the 90% CI. The failed pilot will be submitted (with all other studies), but only for informational purposes, so it really has no impact on acceptance by the agencies.

Thank you.


Edit: Category changed. [Helmut]
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2015-04-06 21:24
(3278 d 21:01 ago)

@ lechia
Posting: # 14665
Views: 7,799
 

 Submitting a pilot as a pivotal study

Hi Lechia,

❝ There are even arguments that it is not ethical to run a pivotal study if the pilot shows equivalence, i.e. why subject more healthy volunteers to a drug if not needed?


Yes. In Europe we had a north-south slope. Scandinavian countries and Germany were generall happy with this idea. From Spain the response sometimes was along these lines:

“Thank you for showing the CI to be within the acceptance range. Now submit a properly designed pivotal study.”

Strictly speaking this request is correct. BE should be demonstrated in a reasonably powered pivotal study, whereas a pilot study is exploratory by nature. Generally the GMR and CV are only “guess­ti­mates” and the power low.
Which agency are you targeting?

❝ […] Do we need to put any additional text that mentions that if BE criteria are fulfilled no pivotal study will be conducted?


Exactly.

❝ Secondly, is this not in effect cheating? […]



Maybe. Maybe not. The type I error might be inflated. Consider a recent paper* and download the 16 (!) electronic supplementary PDFs. If you have questions, I guess ElMaestro will be happy to give explanations.


  • Fuglsang A. Pilot and Repeat Trials as Development Tools Associated with Demonstration of Bioequivalence. AAPS J (Epub 3 March 2015) doi 10.1208/s12248-015-9744-6

Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
ElMaestro
★★★

Denmark,
2015-04-06 21:46
(3278 d 20:39 ago)

@ Helmut
Posting: # 14666
Views: 7,707
 

 Submitting a pilot as a pivotal study

Hi Lechia,

I agree with every wise word from Helmut above – I have to say that guy is not as stupid as he looks. :-D

It is almost like two schools of thought. If a pilot trial shows BE can you use the data as pivotal proof? Is it unethical not to?
I am sure someone could make that a philosophical discussion, even.

All things considered I think it is reasonable to write in the protocol that you will consider the result a kind of pivotal proof if you show BE, and then an assessor can later decide if (s)he likes that or not.

Pass or fail!
ElMaestro
Dr_Dan
★★  

Germany,
2015-04-07 13:43
(3278 d 04:42 ago)

@ lechia
Posting: # 14669
Views: 7,804
 

 pilot ≠ pivotal study

Dear Lechia,
I have a little bit different view than Helmut and ElMaestro.

❝ All things considered I think it is reasonable to write in the protocol that you will consider the result a kind of pivotal proof if you show BE, and then an assessor can later decide if (s)he likes that or not.

IMHO pilot BE studies are Proof-of-Concept studies performed with a formulation that might be used for producing validation batches of which one will usually be used to demonstrate BE, i.e. the formulation you use in a pilot study is produced in lab scale and not in commercial scale and can therefore not be used for a pivotal study. Once you got the pilot study results and decided the formulation is o.k. you scale up. If you already have produced validation or commercial scale batches of your formulation you must be pretty sure that this formulation is bioequivalent. So if I you now run a pilot study one could get the impression that you aim at bioequivalence in a first try with a cheap study and still reserve the option for a second try to run a "second pivotal" study.
You should also consider the number of subjects. Usually the number for a pilot study is low (e.g. 12 subjects). If you have a variable drug and power a "pilot" study in such a way that it might become bioequivalent an assessor might become distrustful. The same applies if you need the pilot study for the estimation of variablity. In this case you should think of a two-stage design for a pivotal study.
Kind regards
Dr_Dan

Kind regards and have a nice day
Dr_Dan
Samaya B
☆    

India,
2015-04-07 14:44
(3278 d 03:41 ago)

@ lechia
Posting: # 14670
Views: 7,560
 

 Submitting a pilot as a pivotal study

Dear Lechia,

I do agree with Dr Dan. To submit data of pilot BE study (as a pivotal study), all you need to consider is - test product must be from exhibit batch (submission batch). Secondly, BE study should be conducted on at least 14 subjects (preferably N: 16). This would be possible for drugs with low within subject variability. If pilot BE study data are comfortable, same can be submitted. In my opinion, if you are mentioning all criteria as that of pivotal BE study protocol except small number of subjects, in effect that will not be considered as a cheating.

Regards,
Samaya.
lechia
☆    

C of U,
2015-04-09 20:01
(3275 d 22:24 ago)

@ Samaya B
Posting: # 14678
Views: 7,297
 

 Submitting a pilot as a pivotal study

Thank you all for your comments even if somewhat contradictory, but that's what this forum is for, right? :-)

@Helmut: this is a general question, not related to any specific study we are considering, but I am curious about people's experience using this approach at various agencies: EMA, FDA, TGA, TPD, etc. Any experience with the FDA using this approach? Thanks for the paper, I will have a look.

@Dr_Dan & Samaya: Yes, the assumption is that you do have a commercial batch, otherwise, like you said, this option is not feasible. This would also be considered only in situations where the ISCV is relatively small. I agree that running a pivotal with much more than 16 subjects (assuming a 2wxo) is questionable. But in situations where the ISCV is let's say 20%, we get 80% power at a 5% T/R difference with 20 subjects. That's close to the 12-16 used for pilot studies, which makes it possible the study may pass.
UA Flag
Activity
 Admin contact
22,957 posts in 4,819 threads, 1,638 registered users;
89 visitors (0 registered, 89 guests [including 11 identified bots]).
Forum time: 17:25 CET (Europe/Vienna)

Nothing shows a lack of mathematical education more
than an overly precise calculation.    Carl Friedrich Gauß

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5