Mann
☆    

India,
2018-12-09 11:14
(2295 d 11:46 ago)

Posting: # 19670
Views: 11,479
 

 BE assessment regarding first time point Cmax [Study As­sess­ment]

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Hello Friends,

Can anyone help me with your experience or suggestions considering the below details?

One of BE study (for MHRA, two way, crossover, IR tablet with parent, no active metabolites) with intra-subject CV with 20-25% was conducted in 40 subjects and sampling schedule (0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75,2, 2.25, 2.5, 2.75, 3, 3.5, 4, 6, 8, 10,12, 16 & 24 hr) was designed considering 2hr tmax and 3 hr half life.

2 subjects did not complete the study and hence dropped, eventually 38 subjects completed the study. The concentration vs time profiles revealed the following:
  1. Both test and reference products showed more than one peak (an inherent characteristics of the drug, clear literature evidence)

  2. In reference product, 3 subjects reflected first time point (0.25 hr) as Cmax and 25 subjects in test treatment reflecting first time point Cmax (as per the guidelines, these subjects are not considered for the analysis as there was no reliable Cmax appearance and no single sampling time between 0 to Cmax point).

  3. An outliers analysis (Lund's) confirmed two subjects with an outlier concentration levels.There are no change in concentration levels for the repeat analysis samples as per the SOPs. Hence, we have considered that the overall eligible subjects are 13 of 38 (2 outliers, 23 with first time point Cmax).

  4. With all 36 subjects (excluding 2 outliers), AUCt and AUCinf 90% CI are within 80-125. However, Cmax is out of the boundary (96.56 -133.45) and inta-CV is 24.56.

  5. The final analysis with 13 eligible subjects reflecting all the primary PK parameters within 80-125. Cmax also appearing 99.42 - 122.34. Power for AUCt, AUCinf and Cmax = 100, 100 & 79.7.
My questions for your suggestions are:
  1. Whether final selection of the subjects for BE assessment is correct or not?
  2. The final positive BE result (Total transparent reflection of overall assessment of the analysis in CSR) with 13 subjects with slightly less power for Cmax is acceptable for MHRA?
  3. What other points we need to consider and report?
  4. Anybody had an experience with the similar case?

Thanking you.

Best regards,
Mann
 
Ohlbe
★★★

France,
2018-12-10 00:46
(2294 d 22:14 ago)

@ Mann
Posting: # 19672
Views: 10,360
 

 BE assessment regarding first time point Cmax

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Dear Mann,

First of all, thanks for providing all information needed in this very detailed post :-)

❝ 1. Whether final selection of the subjects for BE assessment is correct or not?


IMHO, no.

❝ [...] as per the guidelines, these subjects are not considered for the analysis as there was no reliable Cmax appearance and no single sampling time between 0 to Cmax point.


That's not what the EMA guideline says. What's written is that the sampling schedule should be planned to avoid Cmax being the first point of a concentration time curve. But first point Cmax is not listed in section 4.1.8 as one of the possible reasons to exclude subjects.

❝ An outliers analysis (Lund's) confirmed two subjects with an outlier concentration levels. [...] Hence, we have considered that the overall eligible subjects are 13 of 38 (2 outliers, 23 with first time point Cmax)


Read again the guideline section 4.1.8:
Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish the formulation effects from other effects influencing the pharmacokinetics.

The only two exceptions listed in the guideline are for lack of measurable concentrations (or very low concentrations) after administration of the reference product, and concentrations higher than 5 % of Cmax in period 2. Full stop.

❝ 2. The final positive BE result (Total transparent reflection of overall assessment of the analysis in CSR) with 13 subjects with slightly less power for Cmax is acceptable for MHRA?


They will not care about the decreased power for Cmax, which is irrelevant (have a look at Helmut's lectures if you want to know why). But they will not accept the exclusion of 25 subjects out of 38.

❝ 3. What other points we need to consider [...]


Obviously you have a shorter Tmax with your formulation compared to the reference. Hence a higher Cmax, this is why you get

❝ Cmax is out of the boundary (96.56 -133.45)


If you remove all subjects with a shorter Cmax and only keep those with a longer Cmax, you will mask this potential difference... which is why regulators will not accept to remove those subjects.

The reason why the guideline asks to plan the sampling schedule in order to avoid first point Cmax is that Cmax is likely to be underestimated if it comes as the first point. In your case, even if underestimated it is higher than with the reference product. It would be even worse with a sample collected at 5 or 10 minutes.

There is no way out. Reformulate. Sorry...
—
Regards
Ohlbe
 
Mann
☆    

India,
2018-12-10 01:28
(2294 d 21:32 ago)

@ Ohlbe
Posting: # 19673
Views: 10,113
 

 BE assessment regarding first time point Cmax

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Dear Ohlbe,

Thank you for your detailed clarification.

Could you please share your views and suggestions from US-FDA and ICH perspective?

Best regards,
Mann
 
Ohlbe
★★★

France,
2018-12-11 01:05
(2293 d 21:55 ago)

@ Mann
Posting: # 19675
Views: 10,108
 

 BE assessment regarding first time point Cmax

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Dear Mann,

❝ Could you please share your views and suggestions from US-FDA and ICH perspective?


There is no ICH guideline on bioequivalence, and I'm not a specialist of FDA regulations and guidelines. I won't comment on the outliers part as I'm not too sure what FDA's current position is on this topic. But the issue remains the same whatever the guideline: you have a shorter Tmax with your product, resulting in a higher Cmax, hence a failure to demonstrate BE. Having an earlier time point would not change this, and may actually make things worse (even higher Cmax with your product). I doubt that any regulator anywhere would approve the exclusion of 23 of 38 subjects on this basis.

If you look at it from a regulator's perspective: they're supposed to have a conservative attitude in order to protect the patients. If your study shows BE but some subjects have a first point Cmax, regulators may challenge it because your estimate of Cmax may not be reliable. But if you fail to show BE, they're not going to challenge that and allow you to exclude the data that make your study fail. Especially if this is obviously due to a different behaviour of your product.

By the way, there is one thing you forgot to say in your first message: did you have anything in your protocol regarding the exclusion of subjects with first point Cmax ? And did the protocol plan for an outlier test to be performed at all ?
—
Regards
Ohlbe
 
mittyri
★★  

Russia,
2018-12-11 17:38
(2293 d 05:22 ago)

@ Mann
Posting: # 19681
Views: 9,996
 

 FDA and outliers

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Dear Mann,

I don't think the position of FDA is different.
Please see this old post.

Do you have any experience of BEQ analysis for submission in FDA/EMA jurisdiction?
Where is the idea of outliers coming from?
Do the results without any outliers analysis also show not-BE?
—
Kind regards,
Mittyri
 
Erkin
☆    

Turkey,
2018-12-28 09:29
(2276 d 13:31 ago)

@ Mann
Posting: # 19717
Views: 9,877
 

 BE assessment regarding first time point Cmax

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Dear Mann,

I've found the following on page 298 of "Generic Drug Product Development - Solid Oral Dosage Forms" by Leon Shargel & Isadore Kanfer":

First point Cmax: Do any of the concentrations vs. time profiles exhibit first-point Cmax (i.e., the first sample collected is the Cmax value)?
If so, were 3 to 5 samples collected within the first hour and was one of these collected between 5 and 15 minutes post-dose?
If these early samples were collected, no change in data analysis is warranted.
If these early samples were not collected, then those subjects with first point Cmax values should be dropped from the primary statistical analysis.

I couldn't find the reference from EMA or FDA about dropping the subjects. I've contacted to Dr. Leon Shargel via e-mail and asked him the same question.

I will post here, as soon as he replied me.

Regards,
Erkin
 
ElMaestro
★★★

Denmark,
2018-12-28 15:32
(2276 d 07:28 ago)

@ Erkin
Posting: # 19718
Views: 9,769
 

 BE assessment regarding first time point Cmax

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Hello Erkin,

❝ If these early samples were not collected, then those subjects with first point Cmax values should be dropped from the primary statistical analysis.

❝

❝ I couldn't find the reference from EMA or FDA about dropping the subjects. I've contacted to Dr. Leon Shargel via e-mail and asked him the same question.


The whole business of dropping certain subjects, disregarding data, and getting rid of some data data while keeping other data is a discipline in which many companies, CROs and applicants are extremely skilled but not overly successful when facing regulators. If the guideline does not mention the opportunity to drop subjects data in accordance with your decision scheme then perhaps that is because regulators don't want you to drop data that way? Just thinking of this as a remote hypothetical possibility.

Funnily enough, perhaps it is just me hallucinating: Sometimes I get the impression that when CROs and Sponsors try and enter these discussions about getting rid of certain data in ways not stipulated by a protocol it seems always to be about getting rid of data that is unwanted for the purpose of showing BE, and much effort is put into keeping just the data the result in demonstration of BE. Isn't that really, really strange....?
—
Pass or fail!
ElMaestro
 
Erkin
☆    

Turkey,
2018-12-28 21:57
(2276 d 01:03 ago)

@ ElMaestro
Posting: # 19719
Views: 9,796
 

 BE assessment regarding first time point Cmax

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Dear ElMaestro and Mann,

I've got an e-mail from Dr. Leon Shargel & Dr. Patrick Noonan who are the authors of "Generic Drug Product Development - Solid Oral Dosage Forms" about the reference of the sentence:

"If these early samples were not collected, then those subjects with first point Cmax values should be dropped from the primary statistical analysis."

E-mail from Dr. Lean Shargel:
"I am sorry that you can not find the appropriate reference. You can email the FDA office of Generic Drugs, Division of Bioequivalence, However, due to Holidays, you may not get a response for some time. In general, the FDA does not like to drop subjects in a BE study. I have had this problem in the past and unfortunately had to re-do the study with a larger subject population. Very costly."

E-mail from Dr. Patrick Noonan:
Dear Erkin and Leon,

I would agree with Leon in that it would be unlikely that a regulatory agency would permit dropping subjects from a BE study. Upon review of the chapter, written quite a long time ago, I don’t agree with my own text. More likely, if a substantial # of subjects exhibit a first point Cmax and the study design didn’t include a sample between 5 and 15 min, the study design may be regarded as inadequate and the study results suspect. My interpretation is that all subjects would be included in the statistical analysis. The older guidance (from 2003) provides a clearer explanation than that provided in the 2013 guidance.

Best regards,

Pat

Patrick K. Noonan, PhD
PK Noonan Pharmaceutical Consulting, LLC


I hope that after ElMaestro's hallucinations ;-) and Dr. Leon Shargel's reviews, dropping subjects due to first point Cmax subject is closed.

Best Regards & Happy New Year,

Erkin
 
Astea
★★  

Russia,
2019-03-02 19:02
(2212 d 03:58 ago)

@ Erkin
Posting: # 19987
Views: 9,029
 

 regulatory reasons to consider the study inadequate

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Dear Friends!

In the appendix of The Guideline on the Investigation on Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1) there is a Table 3.2 Additional pharmacokinetic data for <analyte> in <study ID>, where it is supposed to put information about the records where Cmax is the first point (as well as records where AUC0-t/AUC0-∞<0.8 and records where pre-dose sample > 5% Cmax). Could the regulators ban the results of the BE study with such data? Did you ever faced with this in your practice? What was the percentage of subjects with such data (for example for 0.8 it is common to suppose more than 20%)? If there is only one or two subjects with Cmax in the first point should we perform additional analysis excluding them in order to show that this doesn't affect the results if it was not stated in the protocol?

Edit: Appendix IV linked. [Helmut]
—
"Being in minority, even a minority of one, did not make you mad"
 
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2019-03-03 20:42
(2211 d 02:18 ago)

@ Astea
Posting: # 19990
Views: 8,903
 

 Good question, next question

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Hi Nasty,

❝ […] information about the records where Cmax is the first point (as well as records where AUC0-t/AUC0-∞<0.8 and records where pre-dose sample > 5% Cmax). Could the regulators ban the results of the BE study with such data? Did you ever faced with this in your practice? What was the percentage of subjects with such data (for example for 0.8 it is common to suppose more than 20%)? If there is only one or two subjects with Cmax in the first point should we perform additional analysis excluding them in order to show that this doesn't affect the results if it was not stated in the protocol?


OK, let’s have a look at the guideline:

Sampling times

  • The sampling schedule should include frequent sampling around predicted tmax to provide a reliable estimate of peak exposure. In particular, the sampling schedule should be planned to avoid Cmax being the first point of a concentration time curve.
  • The sampling schedule should also cover the plasma concentration time curve long enough to provide a reliable estimate of the extent of exposure which is achieved if AUC(0-t) covers at least 80% of AUC(0-∞).

Reasons for exclusion

  • Subjects with non-zero baseline concentrations > 5% of Cmax. Such data should be excluded from bioequivalence calculation (see carry-over effects below).
    The above can, for immediate release formulations, be the result of […] an insufficient wash-out period, […] and should as far as possible be avoided […] by designing the study with a sufficient wash-out period. The samples from subjects excluded from the statistical analysis should still be assayed and the results listed.
    If there are any subjects for whom the pre-dose concentration is greater than 5 percent of the Cmax value for the subject in that period, the statistical analysis should be performed with the data from that subject for that period excluded. In a 2-period trial this will result in the subject being removed from the analysis. The trial will no longer be considered acceptable if these exclusions result in fewer than 12 subjects being evaluable.
  • AUC(0-t) should cover at least 80% of AUC(0-∞). Subjects should not be excluded from the statistical analysis if AUC(0-t) covers less than 80% of AUC(0-∞), but if the percentage is less than 80% in more than 20% of the observations then the validity of the study may need to be discussed.
My personal summary:
  • First-point Cmax “should be avoided”. Though not elaborated in the section about exclusion, I would state it in the protocol. See also what Ohlbe wrote above. I would gather that excluding >20% of subjects will lead to troubles (similar to high residual AUC).
    Note that the FDA is more generous: If you have data from a pilot study showing that the sampling schedule in the pivotal was adequate, you don’t have to worry (just bad luck, data acceptable).
  • Subjects with carry-over can be excluded (hopefully ≥12 left). No discussion needed if procedure stated in the protocol. Do it better next time.
  • High residual AUC. Clearly stated in the GL, though I would be happy to discuss “the validity of the study”. For IR products sampling far beyond 2×tmax is scientifically questionable.
If nothing is stated in the protocol, assessors love a sensitivity analysis. However, if the full data set fails and the one after exclusion passes, don’t hope for too much. Then it depends on the “whole body of evidence”. If this is one study of an entire set, chances for approval are still there. If not, very unlikely.
—
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Helmut Schütz
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Astea
★★  

Russia,
2019-03-03 22:42
(2211 d 00:19 ago)

@ Helmut
Posting: # 19991
Views: 8,953
 

 first point Cmax: trouble waiting to happen?

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Dear Helmut!

Thank you very much for your response!

That's understandable that the sampling schedule should be planned to avoid Cmax being the first point. But if it has just happened for some (or even for the majority) subjects? "It happens... sometimes" (Forrest)

❝ My personal summary: First-point Cmax “should be avoided”. Though not elaborated in the section about exclusion, I would state it in the protocol. See also what Ohlbe wrote above. I would gather that excluding >20% of subjects will lead to troubles (similar to high residual AUC).


Can assessors ban the whole study for this reason? So far I was lucky enough not to get any questions from russian assessors, but we are planning to deal with the regulators from other countries. Contrary to the Mann's situation the full data set is BE. I would like to know if there were any precedents of this kind.
—
"Being in minority, even a minority of one, did not make you mad"
 
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