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Mikkabel ☆ Belgium, 2024-11-20 10:00 (61 d 18:54 ago) Posting: # 24281 Views: 1,740 |
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Dear All, I have a question regarding the interpretation of the ICHM13A for the high-risk products. As far as I understood and confirmed by the Q|A, two studies should be performed for high-risk products: One in fed and one in fasting conditions. Recently (Before the finalisation of the ICHM13A), we performed a study comparing two high-risk products and the reference product should be administered with according to its SPC. Therefore, the study was performed in fed conditions and the BE was concluded. Following a DCP, the assessor request a study in fasting condition according to the ICHM13A. My question is do we have to demonstrate the BE for this study even if the two products will have to be administered with food in clinical use? (SPOILER ALERT, we will be not BE in that conditions and most probably we will have a lower BA). Thanks in advance for your answers! |
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Helmut ★★★   Vienna, Austria, 2024-11-21 10:23 (60 d 18:31 ago) @ Mikkabel Posting: # 24282 Views: 1,523 |
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Hi Mikkabel, ❝ Recently (Before the finalisation of the ICHM13A), we performed a study comparing two high-risk products and the reference product should be administered with according to its SPC. Therefore, the study was performed in fed conditions and the BE was concluded. ❝ Following a DCP, the assessor request a study in fasting condition according to the ICHM13A. My question is do we have to demonstrate the BE for this study even if the two products will have to be administered with food in clinical use? ❝ (SPOILER ALERT, we will be not BE in that conditions and most probably we will have a lower BA). Some ideas; not sure whether they would help.
— 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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Mikkabel ☆ Belgium, 2024-11-21 11:38 (60 d 17:16 ago) @ Helmut Posting: # 24283 Views: 1,511 |
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❝ 1. Although ICH M13A was adopted by the CHMP on 25 July 2024, it will come into effect on 25 January 2025. A six month transition period is common for the EMA in order to give applicants the opportunity to adapt the design of studies to the new requirements. ❝ Tell the assessor in a polite way that (a) at the time being ICH M13A is not in effect and (b) you had no crystal ball and thus, performed the study according to the (then) applicable guideline of 2010. ❝ 2. For high-risk products the clinical use of the comparator is not relevant, sorry. You were aware of the Q&A document. Read #2.4 and #2.5 again. We are dealing with an IR product. Why should it be administered with food? Bad tolerability in fasting state? If yes, you can try to give that as a justification for not performing another study in fasting state. Or did the originator some evergreening to make your life miserable? See the GL 2.1.5, second paragraph for alternatives. IMHO, belonging to the realm of science fiction. ❝ If all (esp. idea #1) fails, I’m afraid you have to reformulate in order to pass in fasting state as well. Thanks Helmut for your swift reply! We will indeed try to answer that the study was performed according to the guideline in force at that time but not sure it will convince the assessor  Concerning your comment that the clinical use of the comparator is not relevant, you mean that even if the comparator is labelled to be taken only with food, we have to perform two PK studies in both conditions (fed and fasting). In our case, the comparator should be administered with food according to its SMPC as it is a low solubility drug. Then, there is a clinically relevant food effect observed in PK. However, the manufacturing technology used in the test and the comparator are different leading to a more food effect for the test and then, a lower BA observed for the test in fasting conditions. To be honest, I still not understand why we should be BE in fasting condition if the products shoudl be taken with food in clinical practice. |
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Ohlbe ★★★ France, 2024-11-21 12:49 (60 d 16:05 ago) @ Mikkabel Posting: # 24284 Views: 1,480 |
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Dear Mikkabel, ❝ We will indeed try to answer that the study was performed according to the guideline in force at that time but not sure it will convince the assessor Not just "at that time": still today. What matters actually is not which guideline was in force when you did the study, but when you submitted the marketing authorisation application, according to the introduction of Annex I to Directive 2001/83/EC. ❝ To be honest, I still not understand why we should be BE in fasting condition if the products should be taken with food in clinical practice. Well... The problem is, whatever instructions they receive, you have absolutely no control over what the patients will do in real life, and what type of food they will be taking the product with if any: light breakfast (coffee and a slice of bread), or a full fatty lunch ? A fasting study represents the worst case scenario. — Regards Ohlbe |
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Mikkabel ☆ Belgium, 2024-11-21 16:26 (60 d 12:28 ago) @ Ohlbe Posting: # 24288 Views: 1,472 |
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Thanks Ohlbe for your advice! I can understand the potential lack of efficacy if the treatment is taken off label by the patient. Just for my information, what would be the expectation of the regulators if after having performed the study in fasted state, the test product present an higher BA (but still less than in fed condition) than the comparator demonstrating a less food effect from the test product? Do you think that it will be an issue for the assessor that the BE is not demonstrated in both condition in that case? 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 #5! [Helmut] |
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Ohlbe ★★★ France, 2024-11-22 11:51 (59 d 17:03 ago) @ Mikkabel Posting: # 24289 Views: 1,425 |
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Dear Mikkabel, ❝ what […] if after having performed the study in fasted state, the test product present an higher BA (but still less than in fed condition) than the comparator demonstrating a less food effect from the test product? Well, at least you have a lower risk of a lack of efficacy if the patient takes the product in the fasting state (contrary to the SmPC/package insert) or with a very light meal. The concern could be switchability: if the patient used to take the reference product, or another generic bioequivalent to the reference in the fed and fasting states, and then switches to yours, he will suddenly get higher concentrations which could cause adverse reactions. Particularly if the doctor prescribed a higher dose due to a lack of efficacy. ❝ Do you think that it will be an issue for the assessor that the BE is not demonstrated in both condition in that case? Who can predict their reactions ?  Impossible to say without any information on the molecule, and even with information I would not try my luck. — Regards Ohlbe |
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Helmut ★★★ Vienna, Austria, 2024-11-22 14:17 (59 d 14:37 ago) @ Ohlbe Posting: # 24293 Views: 1,394 |
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Dear Ohlbe & Mikkabel, without quoting from the previous posts: By definition generics have to be equivalent to the comparator, not better. ❝ Who can predict their reactions ? ❝ Impossible to say without any information on the molecule, and even with information I would not try my luck. If a product is considered better than the comparator (e.g., less food effects, whatsoever), one may only opt for the hybrid route (acc. to Art. 10(3)). How much additional – clinical – data is required has to be discussed with the agency. Important: Once the procedure has started, one cannot switch from to 10(1) to 10(3). — Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Ing. Helmut Schütz