Bioequivalence and Bioavailability Forum • Profiles with no measurable concentrations

vezz
☆

Erba (CO), Italy,
2011-10-06 14:45
(4756 d 22:42 ago)

Posting: # 7430
Views: 9,990

Profiles with no measurable concentrations [Outliers]

Dear All,

in a recent study we observed few profiles with no measurable concentrations (i.e., all the concentrations were below the lower limit of quantification). I would like to ask you how these profiles are usually handled in the statistical analysis in your experience.

Someone suggested not to calculate the PK parameters (e.g., AUC C_max, etc.) based on these profiles, but to consider these concentrations only in the calculation of the descriptive statistics by time point in order to determine the mean profiles. I wonder if this approach may be reasonable.

I found that this issue was discussed by the Health Canada Scientific Advisory Committee on Bioavailability and Bioequivalence in a workshop held in 2004. The record of proceeding is available here and the relevant part is reported below.

"Issue discussed: What is an inadequate concentration versus time profile?
Conclusion: If there are no measurable concentrations or just one concentration, that profile is not adequate. If two consecutive measurable concentrations are observed and the second is lower than the first, it is possible to compute a C_max and AUC_T. Although these estimates of C_max and AUC_T may be somewhat inadequate, the profile should nevertheless be included in the analysis.
No consensus was reached on treatment of inadequate profiles, i.e., on whether these profiles may be simply dropped from the analysis."

Thank you in advance for your help.

—
Kind regards,

Stefano

Dr_Dan
★★

Germany,
2011-10-06 16:22
(4756 d 21:05 ago)

@ vezz
Posting: # 7431
Views: 8,329

Profiles with no measurable concentrations

Post reply

Dear Stefano
first of all before discussing how to calculate PK parameters I would suggest to find out the reason for obtaining profiles with no measurable concentrations.

Is the bioanalytical method sensitiv enough?
What about subject compliance?
Has the drug a high inter-subject variability?
Is this phenomenon observed after test and reference application?
Does this phenomenon occur in both periods of a subject or just in one?

Maybe it is worthless to think about statistical evaluation.... :confused:

Kind regards
Dan

—
Kind regards and have a nice day
Dr_Dan

ElMaestro
★★★

Denmark,
2011-10-06 19:45
(4756 d 17:42 ago)

@ Dr_Dan
Posting: # 7437
Views: 8,384

Profiles with no measurable concentrations

Post reply

Dear all,

I have a lot of sympathy for Dr_Dan's post here:
Do we really want to try to conclude a lot about product performances when this happens? Or should we rather stop for a second and start thinking and focus on trial performance instead?

If a subject's PK is just a row of BLQ's then something very basic, whatever it is, went badly wrong (yeah right, he/she could be a supergiga-metaboliser. Not). For me personally, I would not think primarily of product failure (as in a tablet with zero API) - I think other reasons come more realistically to mind, but that's just me and it is said with reference to the rather strict GMP and release criteria in EU.

I know I am going to extremes here but considering eg. ICH E6 2.2 ('Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.') or 2.5 ('Clinical trials should be scientifically sound, and described in a clear, detailed protocol.'), if a trial has a subset subjects having just BLQ's would lead me to think the following:

The trial's outcome itself might be dubious, regardless of product performance.
I want to know why it happened.
I want to know how to prevent it from happening again cf. the quotes above, otherwise there may be a potential element of futility in future trials, and regulators -notably FDA imho- can have a very big problem with that.

I do acknowledge that a reason for mishaps cannot always be identified. But there is no excuse for not trying very very hard, mefinks.

—
Pass or fail!
ElMaestro

d_labes
★★★

Berlin, Germany,
2011-10-06 17:24
(4756 d 20:03 ago)

@ vezz
Posting: # 7433
Views: 8,518

ask the EMA oracle

Post reply

Dear vezz,

❝ in a recent study we observed few profiles with no measurable concentrations (i.e., all the concentrations were below the lower limit of quantification). I would like to ask you how these profiles are usually handled in the statistical analysis in your experience.

The EMA guidance states (page 14)
"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 exceptions to this are:
1) A subject with lack of any measurable concentrations or only very low plasma concentrations for reference medicinal product. A subject is considered to have very low plasma concentrations if its AUC is less than 5% of reference medicinal product geometric mean AUC (which should be calculated without inclusion of data from the outlying subject). The exclusion of data due to this reason will only be accepted in exceptional cases and may question the validity of the trial ..."

A little bit curious for me is the underlined sentence. Taken literally it would not allow to exclude such profiles for the Test formulation :confused:

❝ Someone suggested not to calculate the PK parameters (e.g., AUC C_max, etc.) based on these profiles, but to consider these concentrations only in the calculation of the descriptive statistics by time point in order to determine the mean profiles. I wonder if this approach may be reasonable.

The EMA guidance is not specific in respect to this.
I personally would calculate the PK metrics for such profiles as far as possible but drop them in the statistical analysis.
I would drop these profiles also from the mean curves.

—
Regards,

Detlew

Ohlbe
★★★

France,
2011-10-06 18:31
(4756 d 18:56 ago)

@ d_labes
Posting: # 7436
Views: 8,519

ask the EMA oracle

Post reply

Dear D. Labes,

❝ A little bit curious for me is the underlined sentence. Taken literally it would not allow to exclude such profiles for the Test formulation :confused: .

My understanding is that this is precisely the idea ! Basically, if no concentration is measured after the reference product, EU regulators are ready to assume that the subject did not swallow the product. The reference formulation is considered to be reliable :-|

If the same situation happens after the test product, they consider that they cannot make the difference between a non-compliant subject and a deficient tablet. They will not take any chance.

Regards
Ohlbe

—
Regards
Ohlbe

Helmut
★★★

Vienna, Austria,
2011-10-06 21:14
(4756 d 16:13 ago)

@ vezz
Posting: # 7439
Views: 8,341

Profiles with no measurable concentrations

Post reply

Dear vezz & all!
The never-ending story. :ponder:

It took EMA quite a while to accept the fact that shit happens. Interesting is the beginning of the section D. Labes quoted.

Reasons for exclusion
Unbiased assessment […] requires that all subjects are […] treated according to the same rules. These rules should be independent from treatment or outcome.
(my emphasis)

I agree with Ohlbe’s interpretation. In other words, treatments are not to be treated [sic!] equally.

R: Innocent until proven guilty
T: Guilty until proven innocent

All animals are equal,
but some animals are more equal than others. George Orwell (Animal Farm, 1945)

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
Helmut Schütz

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