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Marcel ★ 2011-04-13 13:05 (5557 d 22:27 ago) Posting: # 6893 Views: 5,531 |
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Good morning folks of BEBAC, Does anyone know if the EMA has ever accepted the results of a pilot study to access bioequivalence of formulations? For example, lets say we conducted a pilot study in 16 volunteers and the results were within the accepted confidence intervals (and everything else was according to the effective guidelines at the time and it was prespecified in the protocol that the results may be used to access bioequivalence), can this study be considered by the authorities? Specifically, EMA (I believe the FDA has addressed this specifically in their guideline and it's okay with them). Does anyone know of a case where a company has done this is the past with the EMA (in order to have a precedent). And if so, any idea what the product and company is? Do I make sense? Thank you in advance. |
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Helmut ★★★   Vienna, Austria, 2011-04-13 15:36 (5557 d 19:56 ago) @ Marcel Posting: # 6894 Views: 4,829 |
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Dear Marcel! You are right with the FDA. Monica Edholm (MPA) pointed out at several conferences that she would be happy with such a study. But this was before the current GL came into force. I'm not so sure about member states south of the Alps. Personal experience: nil. See also this recent thread. — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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ElMaestro ★★★ Denmark, 2011-04-13 16:36 (5557 d 18:56 ago) @ Marcel Posting: # 6895 Views: 4,815 |
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❝ Good morning folks of BEBAC, Good afternoon, Marcel. ❝ Does anyone (...) study (...) bioequivalence (...)un(...)dressed? ❝ Do I make sense? Yeah, you make a lot of sense, Marcel.  I do recall an innovator getting away with it (late development issue; needed to change something in the CMC and then show eq. to the drug that was tested in the pivotals). My personal opinion is that a drug is bioequivalent if BE is shown, regardless of what's written in the protocol. The drug does not get any better or worse because of a sentence in a protocol somewhere, but this is not always the reasoning of regulators. If this issue hits CMD(h) in a referral I think the chances would be reasonably high for approval. This of course requires that the RMS is willing to approve. So submit it in Sweden? — Pass or fail! ElMaestro |
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Dr_Dan ★★ Germany, 2011-04-13 17:20 (5557 d 18:13 ago) @ ElMaestro Posting: # 6896 Views: 4,987 |
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Dear Marcel I totally agree with ElMaestro. If the results were within the accepted confidence intervals and everything else was according to the effective guidelines at the time then the formulations should be regarded to be bioequivalent regardless of how the study was named (pilot or pivotal) or intended for (sample size estimation etc.). In the clinical overview of the dossier it should be pointed out that it was prespecified in the protocol that the results of the pilot strudy may be used to access bioequivalence. To repeat the study will not lead to a gain in knowledge. Therefore it is unethical to conduct the same study again. A request for a second study would be a offence against the ICH GCP principles (see paragraph 2.2 and 2.3 CPMP/ICH/135/95). If you adresses this point in the right way in the clinical overview then I think it will be hard to find any arguments for a repeat. Please ensure that your test formulation batch is a representative batch. a) The test product should usually originate from a batch of at least 1/10 of production scale or 100,000 units, whichever is greater, unless otherwise justified. b) The production of batches used should provide a high level of assurance that the product and process will be feasible on an industrial scale. In case of a production batch smaller than 100,000 units, a full production batch will be required. c) The characterisation and specification of critical quality attributes of the drug product, such as dissolution, should be established from the test batch, i.e. the clinical batch for which bioequivalence has been demonstrated. d) Samples of the product from additional pilot and / or full scale production batches, submitted to support the application, should be compared with those of the bioequivalence study test batch, and should show similar in vitro dissolution profiles when employing suitable dissolution test conditions (see Appendix I). Comparative dissolution profile testing should be undertaken on the first three production batches. If full scale production batches are not available at the time of submission, the applicant should not market a batch until comparative dissolution profile testing has been completed. The results should be provided at a Competent Authority's request or if the dissolution profiles are not similar together with proposed action to be taken. To my experience this is the critical point. I hope this helps. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Marcel ★ 2011-04-13 17:26 (5557 d 18:07 ago) @ Dr_Dan Posting: # 6898 Views: 4,876 |
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Opps, seems we double posted and I didn't have a chance to thank you too, so thank you. I'm drafting a response for the CMD as we speak. I'll mention something about the "unethicalness" of repeating a study. The rest is up to par. Everything is as it should be, but we are dealing with a very stubborn (and rude) assessor. Cheers. |
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Marcel ★ 2011-06-20 15:09 (5489 d 20:23 ago) @ Marcel Posting: # 7156 Views: 4,322 |
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Update: This is what a CMS state had to say about the referal: We fully endorse the assessment of RMS on this referral and agree with the responses of applicant. This referral should never have been made as the issues as raised by (take a guess) are not related to public health considerations and can never be an issue for refusing an application. We prevailed. (take a guess) withdrew their objection. I would have loved to be a fly on the wall at this referal process. |
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Marcel ★ 2011-04-13 17:22 (5557 d 18:10 ago) @ ElMaestro Posting: # 6897 Views: 4,804 |
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Thank you to both of you. It's already been submitted - in Sweden as RMS!!! They, of course, are on our side, but a country south of the Alps (who have approved the exact same dossier 5 times already) has referred the product to CMD. I'll try to get our person in charge here to throw around some names to the RMS! |
Ing. Helmut Schütz