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raghavendra_s ★ 2010-11-25 05:29 (4895 d 04:55 ago) Posting: # 6212 Views: 6,620 |
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Dear Madam/Sir, I have foolowing few queries: What happens when the assay percentage of Investigational product (between test and reference) is more than 5% in conducting a Bioequivalence study? Why healthy volunteers are taken for BA/ BE study? What is basic qualification required for Principal Investigator? Can a MBBS doctor be a Principal Investigator? Is this accepted by regulatory (India)? Kind regards, |
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manan ☆ Ahmedabad, 2010-11-25 11:43 (4894 d 22:42 ago) @ raghavendra_s Posting: # 6220 Views: 6,061 |
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Dear Mr. Raghvendra I would like to share my ideas on your other two querries here. usually, the BA BE studies are carried out in normal healthy volunteers. however, some olass of drugs like anti cancer needs to be carreid out in patients. Enrolling healthy volunteers minimizes any trial releated problems and is well mentioned in almost all the guidlines. the physiological conditions of diseased person is obivoulsy dieffernet from that of a normal healthy volunteer. Secondly, as per the ICH, GCP guidline, section 4.1 an Investigator MUST BE QUALIFIED BY EDUCATION, TRAINING AND EXPERIENCE TO ASSUME RESPONSIBILITY FOR PROPER CONDUCT OF TRAIL. i guess a MBBS cna become a PI or a Co-I provided he has a good experience and is trained. Edit: Please don't shout, and see this post. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2010-11-25 16:44 (4894 d 17:40 ago) @ raghavendra_s Posting: # 6230 Views: 6,150 |
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Dear Raghavendra! ❝ What happens when the assay percentage of Investigational product (between test and reference) is more than 5% in conducting a Bioequivalence study? Not a good idea. See one of my lectures concerning the main assumptions in BE testing: AUC = Dose × Fraction absorbed / Clearance This equation holds for both test and reference. We assume constant Clearances in (a delusion - especially for Highly Variable Drugs) and equal doses. Only based on these assumptions we may equalize the equations and shorten the fraction in order to estimate Ftest/reference as AUCtest/AUCreference.The only country curently recommending a potency correction is Canada (since 1992) - but according to 2010's draft it will be removed from the GL. WHO recommended a potency correction in 1995, but removed it in 2006. Regulators were concerned about possible fraud. A study is not BE and assays were repeated until (due to analytical variability) the potencies came out in such a way that the study miraculously proved BE... Therefore e.g. according to EMA's GL products must not differ more than 5% (unless justified) and the results of the assay have to be given already in the protocol. That’s for the background. Now for your question in particular. Imagine the result of your study are borderline bioequivalent at the lower limits (let's say 81.1%-111.1%, 'true' Frel 95%). If the T/R based on the content is 110% (= test 10% higher than reference), the potency corrected BE would be 73.7%-101.3%. In other words you were only BE, because the test had a higher potency. You are not allowed to perform such a calculation, but be sure that regulators will! ❝ Why healthy volunteers are taken for BA/ BE study? If there are no clinical concerns (main effect or AEs of the drug, which will call for studies in patients) the main assumption in BE is that similar plasma profiles are a surrogate of concentrations at the biosite (i.e., the receptor). Healthy subjects allow for better standarization (we are interested in minimizing variability!) and therefore smaller sample sizes. For some background see EMA's GL (Section 4.1.3): The subject population for bioequivalence studies should be selected with the aim of permitting — 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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d_labes ★★★ Berlin, Germany, 2010-11-26 11:38 (4893 d 22:47 ago) @ Helmut Posting: # 6237 Views: 6,134 |
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Dear Helmut, dear Raghavendra! ❝ ❝ What happens when the assay percentage of Investigational product ❝ ❝ (between test and reference) is more than 5% in conducting a ❝ ❝ Bioequivalence study? ❝ ❝ Not a good idea. See one of my lectures concerning the main ❝ assumptions in BE testing: ❝ AUC = Dose × Fraction absorbed / Clearance ❝ This equation holds for both test ... ❝ ... You are not allowed to perform such a calculation, but be sure ❝ that regulators will! Helmut, full ACK with your points, especially from the teaching point of view  . But sometimes life is more complicated. And sometimes even regulators are aware of this  .The EMA guidance states under Point 4.1.8 Evaluation page 13: "In bioequivalence studies, the pharmacokinetic parameters should in general not be adjusted for differences in assayed content of the test and reference batch. However, in exceptional cases where a reference batch with an assay content differing less than 5% from test product cannot be found (see section 4.1.2) content correction could be accepted. If content correction is to be used, this should be pre-specified in the protocol and justified by inclusion of the results from the assay of the test and reference products in the protocol." — Regards, Detlew |
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Helmut ★★★ Vienna, Austria, 2010-11-26 15:18 (4893 d 19:07 ago) @ d_labes Posting: # 6239 Views: 5,970 |
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Dear D. Labes, thanks for pointing this out! It might not be possible to obtain a suitable number of batches of the reference to select from. If the difference is >5%, shit happened. In other words that's a justification according to Section 4.1.2 and the statement in Section 4.1.8 makes sense. Clever guys.  — 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 |
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Marcel ★ 2011-06-24 17:19 (4683 d 18:06 ago) @ Helmut Posting: # 7169 Views: 5,197 |
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❝ ❝ Why healthy volunteers are taken for BA/ BE study? ❝ ❝ If there are no clinical concerns (main effect or AEs of the drug, which will call for studies in patients) the main assumption in BE is that similar plasma profiles are a surrogate of concentrations at the biosite (i.e., the receptor). Healthy subjects allow for better standarization (we are interested in minimizing variability!) and therefore smaller sample sizes. For some background see EMA's GL (Section 4.1.3): The subject population for bioequivalence studies should be selected with the aim of permitting ❝ detection of differences between pharmaceutical products. In order to reduce variability not related to differences between products, the studies should normally be performed in healthy volunteers unless the drug carries safety concerns that make this unethical. This model, in vivo healthy volunteers, is regarded as adequate in most instances to detect formulation differences and to allow extrapolation of the results to populations for which the reference medicinal product is approved (the elderly, children, patients with renal or liver impairment, etc.). (my emphasis)Hi Helmut, When choosing a dose for the conduct of a bioequivalence study, is it your understanding that one should move from highest dose to lowest dose (or highest tolerable dose) in healthy subjects before moving to patients? As well, can you expand on your statement that healthy volunteers allow for better standardization? Thanks you, as always. |
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Helmut ★★★ Vienna, Austria, 2011-06-24 17:40 (4683 d 17:45 ago) @ Marcel Posting: # 7171 Views: 5,160 |
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Dear Marcel! ❝ When choosing a dose for the conduct of a bioequivalence study, is it your understanding that one should move from highest dose to lowest dose (or highest tolerable dose) in healthy subjects before moving to patients? I’m not sure what you mean by ‘…before moving to patients’. While in the draft GL EMA suggested to assess BE in the highest dose stated in the innovator’s SmPC, the current GL (Section 4.1.6) recommends (if linear PK applies) the highest strength. For highly soluble drugs a lower strength is also acceptable. For non-linear PK, it depends on the type of non-linearity; see the respective section. ❝ As well, can you expand on your statement that healthy volunteers allow for better standardization? Essentially two points:
— 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 |
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Marcel ★ 2011-06-24 18:03 (4683 d 17:21 ago) @ Helmut Posting: # 7172 Views: 5,146 |
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❝ I’m not sure what you mean by ‘…before moving to patients’. For example, take a drug like Gastroenteriticus XL which could be considered a safety concern to dose to healthy volunteers at high doses (20 and 40 mg). Let's say we want to develop it as a single unit delivery system. Technically, we should be conducting a BE study at all strengths, but for safety reasons we only feel that we can expose healthy volunteers to the 10 mg strength. Do you think it would be sufficient to only conduct the 10 mg studies on healthy volunteers or should we be planning to conduct these studies on patients with the highest strengths? It seems to me EMA prefers healthy subjects, but the wording in the guideline appears to be up to interpretation. Thanks for you responses. |
Ing. Helmut Schütz