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ratnakar1811 ★ India, 2011-06-11 10:06 (5499 d 13:23 ago) Posting: # 7108 Views: 13,078 |
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Dear Forum Members, As per current EMA guideline with respect to the exclusion of the subject, It states in section Reasons for exclusion that “Unbiased assessment of results from randomised studies requires that all subjects are observed and treated according to the same rules. These rules should be independent from treatment or outcome. In consequence, the decision to exclude a subject from the statistical analysis must be made before bioanalysis.” Now my question is, how much it is acceptable (complying with guideline) to continue the subject in the study having vomiting in period 1 and decision to exclude the subject taken before Bioanalysis? Further in this situation should we analyze the plasma samples of subject who will not be considered for PK and stats? The reason to continue the subject in the study inspite of vomiting is to have data for safety evaluation and second reason is that we have experience of volunteers informing about vomiting (or even sometimes self induced vomiting) so that they can be excluded from the study (with full compensation). Your comments will be highly appriciated. Best Regards, Ratnakar |
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Ohlbe ★★★ France, 2011-06-11 18:00 (5499 d 05:29 ago) @ ratnakar1811 Posting: # 7109 Views: 11,946 |
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Dear Ratnakar, ❝ Now my question is, how much it is acceptable (complying with guideline) to continue the subject in the study having vomiting in period 1 and decision to exclude the subject taken before Bioanalysis? If the subject vomits in Period 1 at a time which would justify his exclusion, I would consider it unethical to dose him in Period 2, expose him to the risk of adverse events and collect blood samples. ❝ Further in this situation should we analyze the plasma samples of subject who will not be considered for PK and stats? Some labs indeed analyse samples already collected to demonstrate vomiting is not due to an unusually high concentration. I can indeed see the logic behind it, at least for the test product. ❝ The reason to continue the subject in the study in spite of vomiting is to have data for safety evaluation Disagreed: what safety information do you really expect to get from a study on 24 subjects ? ❝ and second reason is that we have experience of volunteers informing about vomiting (or even sometimes self induced vomiting) so that they can be excluded from the study (with full compensation). Usually subjects complain of nausea before vomiting... And in such a case I would not expect them to be left alone. Regards Ohlbe — Regards Ohlbe |
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ratnakar1811 ★ India, 2011-06-13 16:06 (5497 d 07:23 ago) @ Ohlbe Posting: # 7114 Views: 11,671 |
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Dear Ohlbe & forum members, Thanks for your information; the term ‘safety evaluation' I used in the same context what you have rightly mentioned; where we may be able to co-relate the PK data with the event (unusually high concentration at the time of event and not the evaluation of the safety of the drug under study). We do analyze plasma samples of all subjects who have been discontinued because of AEs. But my query is as per EU guideline, the decision of exclusion of the subject to be taken before Bioanalysis and if we take the decision to exclude him should we analyze the samples? Which you rightly said that it is unethical but as per FDA (if it is 2 times median Tmax) we have to continue the subject in the study even if he had vomiting in period 1 as we are not aware of the median Tmax of the study drug at that point of time and we get the data only after analyzing the samples and then we take the decision whether to exclude the subject or not. I think this is the right approach? Your views please. Best Regards, Ratnakar |
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Ohlbe ★★★ France, 2011-06-14 01:13 (5496 d 22:16 ago) @ ratnakar1811 Posting: # 7116 Views: 11,692 |
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Dear Ratnakar, ❝ [...] but as per FDA (if it is 2 times median Tmax) we have to continue the subject in the study even if he had vomiting in period 1 as we are not aware of the median Tmax of the study drug at that point of time and we get the data only after analyzing the samples and then we take the decision whether to exclude the subject or not. The FDA guidance recommends not to use data from subjects who vomited at or before 2 times median Tmax. However:
❝ But my query is as per EU guideline, the decision of exclusion of the subject to be taken before Bioanalysis and if we take the decision to exclude him should we analyze the samples? Not discussed in the guideline. I may analyse samples collected before the subject vomits and the decision to exclude him is taken by the investigator. But I would stop collecting samples once the decision to withdraw him is taken. Regards Ohlbe — Regards Ohlbe |
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ratnakar1811 ★ India, 2011-06-14 13:45 (5496 d 09:45 ago) @ Ohlbe Posting: # 7122 Views: 11,593 |
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Dear Ohlbe, Thanks for your inputs, I do agree with your views. Also regarding the FDA guidance, I just wanted to highlight that as per FDA guideline data can be excluded if the vomiting occurs before two times median Tmax and very few references mention median Tmax. Further I had discussed this issue with FDA and I got in writing from FDA that the median Tmax should be considered from the study (for that treatment) and not from the literature as the Tmax depend upon the time points in the study which may vary from study to study. I do have the letter from FDA regarding the same. Best Regards, Ratnakar |
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Helmut ★★★   Vienna, Austria, 2011-06-14 16:11 (5496 d 07:18 ago) @ ratnakar1811 Posting: # 7126 Views: 12,455 |
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Dear Ratnakar & Ohlbe, ❝ Also regarding the FDA guidance, I just wanted to highlight that as per FDA guideline data can be excluded if the vomiting occurs before two times median Tmax and very few references mention median Tmax. @Ohlbe: I think you mixed up FDA’s Guidance and EMA’s draft GL. FDA’s states on ![[image]](img/uploaded/IAsmall.png) early exposure:We recommend that the partial area be truncated at the population median of Tmax values for the reference formulation. And on vomiting:We recommend that data from subjects who experience emesis during the course of a BE study for immediate-release products be deleted from statistical analysis if vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time during the labeled dosing interval can be deleted. Since in FDA’s terminology ‘population’ is always referring to subjects in a particular study, no reference is made to the label (median tmax, which is rarely – if ever – given). EMA’s draft was confusing, since it stated about early exposure: For products where rapid absorption is of importance, partial AUCs can be used as a measure of early exposure. The partial area can in most cases be truncated at the population median of tmax values for the reference formulation. However, an alternative time point for truncating the partial AUC can be used when clinically relevant. The time point for truncating the partial AUC should be pre-specified and justified in the study protocol. Whilst the second sentence call for a truncation time obtained from study’s data, the third called for a prespecification (from the SmPC‽). The entire section was dropped in the final GL (see also the commentary document pp87-89).When it comes to exclusion, it’s up to the applicant to specify limits in the protocol: Examples of reasons to exclude the results from a subject in a particular period are events such as vomiting and diarrhoea which could render the plasma concentration-time profile unreliable. […] The permitted reasons for exclusion must be pre-specified in the protocol. If one of these events occurs it should be noted in the CRF as the study is being conducted. Exclusion of subjects based on these pre-specified criteria should be clearly described and listed in the study report. In my studies for EMA I’m using FDA’s rules (IR: 2× tmax,ref, MR: τ) and never had any problems. ❝ Further I had discussed this issue with FDA and I got in writing from FDA that the median Tmax should be considered from the study (for that treatment) and not from the literature as the Tmax depend upon the time points in the study which may vary from study to study. I do have the letter from FDA regarding the same. Yes, this is consistent with their guidance, IMHO. — 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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ratnakar1811 ★ India, 2011-06-15 08:49 (5495 d 14:40 ago) @ Helmut Posting: # 7128 Views: 11,528 |
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Dear HS and Ohlbe, Thanks for prompt reply; ❝ In my studies for EMA I’m using FDA’s rules (IR: 2× tmax,ref, MR: τ) and never had any problems. Were there any queries from any of the regulatory authority from EU, after recent guideline has been implemented, as one of our sponsors is not very satisfied with the approach and asking to withdraw a subject from the study during clinical phase only if there is any vomiting during clinical phase? Best Regards, Ratnakar |
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Helmut ★★★ Vienna, Austria, 2011-06-15 14:03 (5495 d 09:26 ago) @ ratnakar1811 Posting: # 7130 Views: 11,584 |
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Dear Ratnakar! ❝ ❝ In my studies for EMA I’m using FDA’s rules (IR: 2× tmax,ref, MR: τ) and never had any problems. ❝ Were there any queries from any of the regulatory authority from EU, after recent guideline has been implemented, […] No. ❝ […] as one of our sponsors is not very satisfied with the approach and asking to withdraw a subject from the study during clinical phase only if there is any vomiting during clinical phase? I’m sorry – I (still) don’t get the sponsor’s point. Reading the entire thread again I can only give you my procedure:
— 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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ratnakar1811 ★ India, 2011-06-20 08:37 (5490 d 14:52 ago) @ Helmut Posting: # 7155 Views: 11,402 |
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Dear HS, Thanks for your inputs; ❝ Withdraw a subject if vomiting occurs according to FDA’s rules. Analyze samples – regardless the treatment. ❝
My concern is current EU guideline specifically mention about the decesion to withdraw a subject should be taken before analysis & this should not creat any issues later on, as I got a study where withdrwing a subject at statistical analysis stage reverse the results of the study? Best Regards, Ratnakar |
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Helmut ★★★ Vienna, Austria, 2011-06-20 15:41 (5490 d 07:49 ago) @ ratnakar1811 Posting: # 7157 Views: 11,665 |
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Dear Ratnakar! ❝ My concern is current EU guideline specifically mention about the decesion to withdraw a subject should be taken before analysis & this should not creat any issues later on, as I got a study where withdrwing a subject at statistical analysis stage reverse the results of the study? I think you go in circles. The GL is pretty clear (as is your original post). Reasons for exclusions have to be stated in the protocol, and if one of the conditions are applicable, the subject has to be exluded before statistics (see the quote in this post). As Ohlbe said, the subject has to be discontinued from the study (no more samples drawn after the event), but samples analyzed and presented (GL 4.1.8 Evaluation / Presentation of data): Drop-out and withdrawal of subjects should be fully documented. If available, concentration data and pharmacokinetic parameters from such subjects should be presented in the individual listings, but should not be included in the summary statistics. If the subject erroneously was kept in the study (noncompliance of the investigator – I’ve seen that), report it as a protocol deviation. According to the protocol the primary analysis is without the subject – you may present the full data set as a sensitivity analysis. The GL is pretty clear about exclusion of outliers – not based on statistics alone.I would consider it bad practice to
— 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