Ohlbe
★★★

France,
2013-03-15 12:10
(3148 d 09:19 ago)

Posting: # 10199
Views: 26,478

## Draft EMA MR formulations GL published! [Regulatives / Guidelines]

Dear all,

EMA have published today the long-awaited draft of the revised modified release formulations guideline. Consultation is opened till 15 September.

Regards
Ohlbe

Regards
Ohlbe
Helmut
★★★

Vienna, Austria,
2013-03-15 13:28
(3148 d 08:01 ago)

@ Ohlbe
Posting: # 10200
Views: 22,003

## Housekeeping suggestions

Dear Ohlbe,

THX; I didn’t expect it sooo early!

I guess we will have some discussions here. I suggest some rules in order to keep posts short. Don’t paste from the GL unless considered necessary for understanding – give a reference instead, e.g.,
• Section X.Y.Z
• Lines XXX-YYY
• Referring to only part of a sentence: Paste the sentence and highlight the disputable part in blue.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Helmut
★★★

Vienna, Austria,
2013-03-15 14:19
(3148 d 07:10 ago)

@ Ohlbe
Posting: # 10201
Views: 22,019

## Scaling for pAUCs

Dear all!

Lines 800/805:
AUC(0-t) and AUC(0-∞). No truncation (line 788). I’m happy with that. Avoids problems with potential flip-flop PK of CR formulations (EMA’s terminology: prolonged release). I would say if we show BE of AUC(0-∞), BE of AUC(0-t) is of no additional value.1 Furthermore, in a linear system only SD AUC(0-∞) is expected to be equal to MD AUC(0-τ). On the other hand, IMHO for DR AUCt or AUC72 should be sufficient.
No BE of “partial Cmax” like in the Q&A-document Section 11.2 Should be determined (lines 789/790) but not compared (i.e., not stated in lines 800–804). This is now in line with FDA’s requirements.

Lines 807–810:
Scaling is acceptable for HVD/HVDPs – not only for Cmax,ss, but also for Cτ,ss and pAUC. Though I expected Cτ,ss – pAUC is a positive surprise. For the latter I know of one product already passing last year after a scientific advice at EMA (terrible CVWR of the first pAUC was demonstrated in full replicate pilot study).

1. AUC(0-∞) and AUC(0-t) are highly correlated. Since the variability of the former is higher than the one of the latter if a study passes AUC(0-∞) likely it will pass AUC(0-t) as well. Hint: Intersection-Union Tests.
“These recommendations are based on the present Note for guidance on modified release oral and transdermal dosage forms, Section II (CPMP/EWP/280/96) and represent the current regulatory thinking. It should be noted that this guideline is currently under revision hence recommendations regarding these aspects may change in the revised guideline.”

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
ioanam
★

Romania,
2013-03-30 17:54
(3133 d 03:35 ago)

@ Ohlbe
Posting: # 10314
Views: 21,400

## Draft EMA MR formulations GL published!

Dear all

I could not find anything about the topical generic products. The Canadian and US agencies require clinical trials. What about EMA?

Happy Easter!

Regards
Ioana
Helmut
★★★

Vienna, Austria,
2013-03-30 22:51
(3132 d 22:38 ago)

@ ioanam
Posting: # 10315
Views: 21,205

## Topicals → 1995 NfG

Hi Jo,

for topicals CPMP/EWP/239/95 final (1995) is still in force. Only for topicals locally acting in the GIT a concept paper is expected this year. Dermals: no idea.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
ElMaestro
★★★

Denmark,
2013-03-31 19:26
(3132 d 03:03 ago)

@ ioanam
Posting: # 10317
Views: 21,040

## Topicals, generic

Hi ioanam,

further to what Helmut just said I can mention that inhaled and intranasal drugs also somehow are often classified as topicals.
Many inhaled topicals () are regulated by this beauty of a guideline.

In many cases you cannot call them generics (and cannot assume substition is granted like a typical generic) if they are submitted for EU approval. Check directive 2001/83 article 10.3.

Pass or fail!
ElMaestro
ioanam
★

Romania,
2013-04-01 07:51
(3131 d 14:38 ago)

@ ElMaestro
Posting: # 10318
Views: 20,986

## Topicals, generic

Thank you very much for your responses.

I consider that EMA must present a clear guideline for this type of products in order to have the same procedure in all EU countries because in some countries is still possible to obtain MA as a well established use product, while other authorities requires more and more trials. This is not ok.

We are all equal, but some are more equal than others (Sorry for this satirical quote adapted to this situation).

Wish you a beautiful week,
Ioana
The Outlaw Torn
★

Europe,
2013-04-01 08:03
(3131 d 14:26 ago)

@ ioanam
Posting: # 10319
Views: 20,936

## Topicals, generic

Good morning folks,

It seems the new guideline hasn't removed the need to conduct a BE study (for safety reasons) for opthalmic solutions that may contain an ingredient that is absorbed systemically. Has anyone successfully argued against this? It appears it's still fine to obtain a biowaiver for the efficacy part, but not for safety?! To me, this is a WTF moment, but maybe I'm missing out on something. Does that make sense to anyone (for a solution)?

Thank you,
Outlaw
Tina
★

India,
2013-05-15 14:19
(3087 d 08:10 ago)

@ Ohlbe
Posting: # 10585
Views: 19,501

## Clarity on waiving multiple dose study

Dear all,

The recently updated MR guideline (EMA/CPMP/EWP/280/96 Corr1) mentions about the possibility of waiving multiple dose study (593-595). However, 612-615 mentions that there isnt sufficient scientific evidence. With the current scenario, would waiving multiple dose study on the basis suggested in 593-595 be a risk? How can a generic company justify scientific evidence for this approach?

593-595

A multiple dose study is needed unless a single dose study has been performed with the highest strength which has demonstrated that the mean AUC(0-τ) after the first dose covers more than 90% of mean AUC(0-∞) for both test and reference, and consequently a low extent of accumulation is expected.

612-615

The discussion of the opportunity of using equivalence in Cτ in single dose studies as basis for waiving the multiple dose study has been recognized. However, there is not considered to be sufficient scientific evidence at the moment to encourage this approach.

Thank the team in advance for clarification.
Helmut
★★★

Vienna, Austria,
2013-05-17 18:49
(3085 d 03:40 ago)

@ Tina
Posting: # 10600
Views: 19,425

## Hey, it is just a draft!

Dear Tina!

» With the current scenario, would waiving multiple dose study on the basis suggested in 593-595 be a risk? How can a generic company justify scientific evidence for this approach?

Let’s split this.

Lines 593–599:

A multiple dose study is needed unless a single dose study has been performed with the highest strength which has demonstrated that the mean AUC(0-τ) after the first dose covers more than 90% of mean AUC(0-∞) for both test and reference, and consequently a low extent of accumulation is expected. In this case bioequivalence needs to be demonstrated for addi­tio­nal parameters representing the shape of the plasma concentration versus time curve in the single dose study […]. An early partialAUC and a terminal partialAUC separated by a pre­de­fined time point, which is usually the half of the dosage interval are recommended, unless otherwise scientifically justified.

I would defend not performing MD studies if low accumulation can be predicted from SD. I succeed in MRPs for more than a decade now.1 My truncation time point for the pAUCs was based on pharmacological reasons; I don’t get the idea why one should truncate at τ/2.2 IMHO – if no PD justification is possible – tmax,ref (+ scaling if necessary) makes more sense.

Right now I would not take the risk for formulations which accumulate (i.e., based on equivalence of Cτ). For some background on the possibility of waiving MD studies see the following papers:
1. Pro
Paixão P, Gouveia LF, Morais JAG. An alternative single dose parameter to avoid the need for steady-state studies on oral extended-release drug products. Eur J Pharm Biopharm. 2012;80(2):410–7. doi:10.1016/j.ejpb.2011.11.001
2. Skeptic
Endrényi L, Tóthfalusi L. Metrics for the Evaluation of Bioequivalence of Modified-Release Formulations. AAPS J. 2012;14(4):813–9. doi:10.1208/s12248-012-9396-8
3. Con
García-Arieta A, Morales-Alcelay S, Herranz M, de la Torre-Alvarado JM, Blázquez-Pérez A, Suárez-Gea MaL, Álvarez C. Investigation on the need of multiple dose bioequivalence studies for prolonged-release generic products. Int J Pharm. 2012;423(2):321–5. doi:10.1016/j.ijpharm.2011.11.022
As I have learned this week at the BABE-conference in Budapest the majority of members of the PK-group were in favor of dropping MD (based on BE of Cτ), whereas the minority is responsible for lines 612–615. Though I was very skeptical myself (especially in the case of DR and flip-flop PK, see this presentation: slides 34–47), I find the simulations of #1 convincing. I think that #2 is a case of “negative cherry-picking” of men on a mission. If five out of sixty studies failed to be discriminatory this doesn’t bother me – especially because these studies were not designed and powered to show BE of Cτ.
Consider attending the EUFEPS Open Discussion Forum on the Revised European Guideline on Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms in June and comment the draft GL yourself.

Act rather than react!

1. We showed BE of concentrations starting at 12 hours and presented PK simulations predicting an accumulation of ~1%. We went to a scientific advice at the RMS who defended our approach in the MRP. Relying only on something stated in a draft GL is never sufficient, IMHO. Sometimes regulators are discordant and publish the draft just to see what might happen (therefore, comments are that important). You never know which party will ‘win’. That’s nice in the EU where development of GLs is rather transparent – contrary to the FDA where drafts appear out of the blue and are considered as binding as final versions.
2. “Usually [sic] τ/2.” What the heck? If somebody knows a single paper where such a truncation is used, please post a reference here. The word “usually” in this context is downright bizarre. Simply another case where regulators invent a metric out of the blue without a scientific rationale. Bad.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Helmut
★★★

Vienna, Austria,
2013-06-29 19:44
(3042 d 02:45 ago)

@ Helmut
Posting: # 10901
Views: 17,982

## Critical review of García-Arieta et al. (2012)

Dear all,

I had a closer look into

García-Arieta A, Morales-Alcelay S, Herranz M, de la Torre-Alvarado JM, Blázquez-Pérez A, Suá­rez-Gea MaL, Álvarez C. Investigation on the need of multiple dose bioequivalence studies for pro­longed-release generic products. Int J Pharm. 2012;423(2):321–5. doi:10.1016/j.ijpharm.2011.11.022.

The authors reviewed all studies of prolonged release products submitted to the Spanish Agency since 2000. In Table 3 they reported the outcome (single dose and multiple dose) of six cases where the MD study failed on Cmin,ss.1 Values are given for Cτ (SD) and Cmin,ss (MD).

 Case   design     n   CV%     PE        90% CI       Conclusion   BE?  SD/MD agrees?   6  SD  fasted  55  33.05  145.57  131.21  161.50  inequivalent   no      yes            MD  fasted  33  60.13  146.30  125.48  170.59  inequivalent   no                  7  SD  fasted  34  47.48  125.15  103.99  150.62  inconclusive   no      yes            MD  fasted  34  38.11   83.86   72.09   97.56  inconclusive   no                  8  SD  fasted  35  45.50  119.37  100.15  142.27  inconclusive   no      yes            MD  fasted  42  27.84  120.32  108.83  133.03  inconclusive   no                  9  SD  fed     24  49.57   89.31   70.79  112.67  inconclusive   no      yes            MD  fed     24  54.32   80.38   62.47  103.42  inconclusive   no                 10  SD  fasted  28  50.33  112.28   90.40  139.41  inconclusive   no      yes            MD  fasted  59  35.32  119.19  107.25  132.46  inconclusive   no                 11  SD  fed     23  23.96   92.08   81.67  103.82  equivalent    yes       no            MD  fed     28  38.49   84.43   71.27  100.02  inconclusive   no               

Interesting that in case 6 (MD fasted) the sample size does not agree with the overview given in Table 1 (33 vs. 35). Is this a typo or why were two subjects in this study dropped from the com­parison? I recalculated the CV from the reported CI & sample size of all studies. One discrepancy is evident: Case 6, MD (reported 60.13%, calculated 38.05%).2

I am not a friend of post-hoc power, but evidently none [sic] of the studies was sufficiently powered ($$\tilde{x}$$ 11.84%, quartiles: 3.25–13.35%) to demonstrate BE of minimum con­cen­tra­tions – not unexpected, since at the time of submission Cmin was not a strict requirement. Even if designed for an expected ratio of 95%, only three of the studies would have a power of ≥80%. In five of six cases Cτ (SD) correctly predicted the result of Cmin,ss (MD). In case 11 variability after MD in­creased substantially (from SD 24% to 38%). We cannot conclude the product is bio­inequivalent in steady state; it would only need an extremely large sample size of 260 subjects to demonstrate BE in a 2×2 cross-over (or 78 in a 4-period full replicate with reference-scaling). In other words the failed prediction of BE from SD might be a false positive as well.
Although in case 7 both SD and MD failed, the deviation of the ratio from 100% reversed (SD 125%, MD 84%). Would be interesting which type of formulation this one was. Never seen anything like this in 30+ years. Or a coding error?3

The authors concluded that Cτ (SD) is a poor predictor of Cmin,ss (MD):

[…] in […] six cases […] the multiple dose study was the only design [sic] able to detect the differences and, therefore, it was essential when comparing the in vivo performance of prolonged release products.
Regarding the predictive value of Cτ, one case in Table 3 shows that it is predictive of the bioequivalence failure of Cmin,ss, but in the other ﬁve cases, the results are not predictive or as sensitive as Cmax,ss or Cmin,ss.

On the contrary, I would say all studies – except case 11 – failing on Cτ (SD) failed on Cmin,ss (MD) as well. The re­main­ing case was extremely underpowered. Actually, the authors confirmed (‼) in real examples that Cτ is indeed a reliable predictor of multiple dose performance of prolonged release formulations. It might not have been the authors’ intention, but in fact, these findings do not refute but rather support the work by Pai­xão et al.4 I consider it bad science if conclusions contradict the data.
IMHO, a clear case for commenting lines 612–615 of the draft guideline.

1. Would have been nice to know how many studies passed. Without this number the relevance of the authors’ findings cannot be set into perspective, i.e., estimate the false positive rate.
2. library(PowerTOST) cat(sprintf("%.2f%%", 100*CI2CV(lower=1.2548, upper=1.7059, n=33)), "\n")
3. Edit March 2018: Acc. to an e-mail exchange with Alfredo: No.
4. Paixão P, Gouveia LF, Morais JAG. An alternative single dose parameter to avoid the need for steady-state studies on oral extended-release drug products. Eur J Pharmaceut Biopharmaceut. 2012;80(2):410–7. doi:10.1016/j.ejpb.2011.11.001.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Helmut
★★★

Vienna, Austria,
2013-06-21 19:24
(3050 d 03:05 ago)

@ Ohlbe
Posting: # 10858
Views: 18,202

## SD vs. MD, partial AUCs

Dear all,

some comments on this week’s workshop in Bonn.

»The BfArM still sleeping at 5 a.m.«

1. SD vs. MD

Status:
• The U.S. FDA generally does not require MD studies (exception: studies in patients under therapy due to unacceptable safety profile in healthy subjects).
• Japan’s NIHS requires SD studies, although “multiple dose studies may be employed for drugs which are repeatedly administered to patients.”
• Brazil’s ANVISA does not require MD studies.
• Canada’s HPFB/TGD requires MD studies only if substantial accumulation is expected, i.e.,
AUCt > 80% AUC.
• The EMA currently requires MD additionally to SD in all cases.
• According to the draft MD studies might be waived under certain circumstances:
• AUCt > 90% AUC and
• BE demonstrated in SD for additional PK metrics, e.g., pAUCs (Cτ under discussion).
Obviously the EMA does not trust in the empiric evidence of no problems in other countries (“absence of evidence is not evidence of absence”). The leap from ‘always’ to ‘never’ is not for cowards. Like in many other places the drafting party followed Canada’s rules, but not without tightening the thumbscrews.
As Alfredo García-Arieta pointed out “The 10% residual AUC are arbitrary; we could have used 20% or 5% as well.” OK, Canada is successfully applying the 20% for more than two decades [sic] now…
I love arbitrary values.

The suggested procedure starting with the SD study is as following:
• If AUCt ≤ 90% AUC target metrics are AUC, AUCt, and Cmax. Whether AUC is primary for controlled release and AUCt for delayed release is under discussion. pAUCs for multiphasic profiles.
MD mandatory (waiving criterion not fulfilled).
• If AUCt > 90% AUC target metrics as above + additional metrics describing the shape of profiles (pAUCs, t75%?).
• If additional metric(s) pass BE, a MD study might be waived.
• If the additional metric(s) fail, a MD study is required.
• If the MD study passes with the conventional metrics (AUCτ, Cmax, Cmin) the fact that ‘shape’ metric(s) failed in SD will not lead to rejection of the application (rationale: BE demonstrated with conventional metrics both in SD and MD).
Now it is up to us to challenge the 90% criterion (empiric evidence from Canada). Furthermore, BE of Cτ makes sense, IMHO. Will be a tough job to convince Alfredo García-Arieta claiming: “I don’t believe in simulations.”

He was asked how achievement of steady state can be demonstrated and whether a statistical test is required. The answer was “A test is not expected. Reporting of pre-dose concentrations and plots are sufficient.” All other members of the drafting party nodded in agreement.

2. partialAUC (if applicable)

Status:
• The U.S. FDA requires pAUCTmax,ref as a measure of early exposure if clinically relevant. Tmax,ref is the population median. Conventional acceptance range.
• The U.S. FDA requires pAUCs in some product-specific guidances (methylphenidate: ER capsules, ER tablets; zolpidem ER tablets). The truncation time point ‘T’ is a priori set based on PD and might be different for fasting/fed or applicable to one state only. Example: MPH (3 h fasting, 4 h fed), zolpidem (1.5 h fasting only).
Required metrics: AUC0-T, AUCT-t, AUC0-∞, and Cmax; conventional acceptance range.
• HPFB/TGD requires pAUCTmax,ref as a measure of early exposure if clinically relevant. Tmax,ref is defined as the individual’s value. Relative mean within the conventional acceptance range (no CI).
• EMA Q&A Ref.4 (02/2012): Pre-specified truncation time point. AUC0-T, AUCT-t, Cmax,0-T, Cmax,T-t; conventional acceptance range.
• MR draft (lines 787–792): Pre-specified truncation time point. AUC0-t, AUC0-∞, Cmax, tmax, AUC0-T, AUCT-t, Cmax,0-T, Cmax,T-t, tmax,0-T, tmax,T-t. Yippee! Ten characteristics. That’s a lot. IMHO, only descriptive.
Statistical evaluation (lines 800–805): AUC0-t, AUC0-∞, Cmax, AUC0-T, AUCT-t; conventional acceptance range or scaling (lines 807–810).
There was a short discussion whether for delayed release AUC0-T & AUCT-t and for prolonged release AUC0-T & AUCT-∞ would be sufficient (dropping the respective other AUC-metrics). No consensus was reached.

Presentations of the workshop will be available for some limited time in a couple of weeks at EUFEPS’ website.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Shuanghe
★★

Spain,
2013-06-25 17:22
(3046 d 05:07 ago)

@ Helmut
Posting: # 10879
Views: 17,889

## SD vs. MD, partial AUCs

Greeting to all (after loooong weekend on the beach )!

» some comments on this week’s workshop in Bonn.

Man. It's nice to be your own boss. lucky you. I used all my budget for the conference on BA/BE/BW in Budapest last May so I won't be anywhere later this year.

» According to the draft MD studies might be waived under certain circumstances:
» — AUCt > 90% AUC and
» — BE demonstrated in SD for additional PK metrics, e.g., pAUCs (Cτ under discussion).

You meant AUCτ, not AUCt, right? The same goes for the following procedure in your post.

Just to make sure I didn't misunderstand the PK parameters in the guideline, let's say one Reference product has to be taken twice a day so dose interval would be 12 hours. In single dose BE study let's say sampling is up to 18 hours.
Then AUCτ is AUC0-12 (and Cτ, in case we are allowed to use it to replace MD study in the future, would be C12 hours), AUCt would be AUC0-18.

In order to avoid MD study, I would firstly just do single dose study with all necessary PK parameters defined in the protocol such as pAUCs (assuming that AUC0-4 and AUC4-18 are wonderful choices for the sake of argument).

So I'd compare AUC0-12/AUC0-∞ to see if the ratio is >90%. If I'm lucky, then I can do ANOVA on the rest of the parameters (Cmax, AUC0-4, AUC4-18, AUC0-18, AUC0-∞). And if I'm lucky again, no MD study. (ok, instaed of saying lucky I should probably use "my formulation's good" )

By the way, one doubt here.

What if AUCτ/AUC0-∞ is <90% for reference but >90% for test? So reference has risk of accumulation but test does not. Can we waive MD study?
I wish that we could but probably not if "less food effect contradictory to the definition of generic... " is any indication. But I'd like to hear all thoughts from forum members anyway.

While we were talking about parameter, I have another question.
Since there're several Cmin to choose (predose, post dose, true Cmin...), Cmin was defined as "the concentration at the end of the dose interval" (in steady state). However the guideline defined the Cτ,ss as such as well. So what's the difference between them?

» If the MD study passes with the conventional metrics (AUCτ, Cmax, Cmin) the fact that ‘shape’ metric(s) failed in SD will not lead to rejection of the application (rationale: BE demonstrated with conventional metrics both in SD and MD).

Nice. Is this a consensus and will be written in the final guideline or just our wish?

» There was a short discussion whether for delayed release AUC0-T & AUCT-t and for prolonged release AUC0-T & AUCT-∞ would be sufficient (dropping the respective other AUC-metrics). No consensus was reached.

No kidding. I was under the impression that pAUC will not be required for delayed-release formulation. I remembered that Dan Seiler (or someone else?) said so during the panel discussion on the 2nd day in the Budapest conference. Or I misunderstood it? D***, that would affect many of my projects.

All the best,
Shuanghe
Helmut
★★★

Vienna, Austria,
2013-06-25 19:15
(3046 d 03:14 ago)

@ Shuanghe
Posting: # 10880
Views: 17,983

## SD vs. MD, partial AUCs

Hi Shuanghe!

» Man. It's nice to be your own boss. lucky you.

Great that my boss pays for me. Stupid personal union.

» » According to the draft MD studies might be waived under certain circumstances:
» » — AUCt > 90% AUC and
» » — BE demonstrated in SD for additional PK metrics, e.g., pAUCs (Cτ under discussion).
»
» You meant AUCτ, not AUCt, right? The same goes for the following procedure in your post.

Oops, sure. AUC(0-τ) – lines 593–595.

» […] let's say one Reference product has to be taken twice a day so dose interval would be 12 hours. In single dose BE study let's say sampling is up to 18 hours.
» Then AUCτ is AUC0-12 (and Cτ, in case we are allowed to use it to replace MD study in the future, would be C12 hours), AUCt would be AUC0-18.

Exactly. My mistake.

» In order to avoid MD study, […]

Correct interpretation.

» What if AUCτ/AUC0-∞ is <90% for reference but >90% for test? So reference has risk of accumulation but test does not. Can we waive MD study?

Nope. See lines 594–595: “[…] demonstrated that the mean AUC(0-τ) after the first dose covers more than 90% of mean AUC(0-∞) for both test and reference…”

» I wish that we could but probably not if "less food effect contradictory to the definition of generic... " is any indication. But I'd like to hear all thoughts from forum members anyway.

Consensus amongst the members of the drafting group: “Better” is not “equivalent”. Article 10(3) instead of 10(1).

» While we were talking about parameter, I have another question.
» Since there're several Cmin to choose (predose, post dose, true Cmin...), Cmin was defined as "the concentration at the end of the dose interval" (in steady state). However the guideline defined the Cτ,ss as such as well. So what's the difference between them?

In a generic application you always have to show BE of Cτ,ss. With a new formulation (first MR product or comparison with IR) the global Cmin will be more interesting (that’s also the one you should use in the calculation of %PTF if you want).

» » If the MD study passes with the conventional metrics (AUCτ, Cmax, Cmin) the fact that ‘shape’ metric(s) failed in SD will not lead to rejection of the application (rationale: BE demonstrated with conventional metrics both in SD and MD).
»
» Nice. Is this a consensus and will be written in the final guideline or just our wish?

This was a consensus. Difficult to predict whether it will be that clearly stated in the final version. But there is a logic behind. You try to pass with the additional metrics in order to apply for a waiver. Imagine two applications:
• In the first the additional metrics were tried, failed, but passed the MD study.
• The other one didn’t try at all and went straight for the MD.
So at the end both showed BE with conventional metrics in SD and MD. Rejecting the first application would be difficult to defend.

» » There was a short discussion whether for delayed release AUC0-T & AUCT-t and for prolonged release AUC0-T & AUCT-∞ would be sufficient (dropping the respective other AUC-metrics). No consensus was reached.
»
» No kidding. I was under the impression that pAUC will not be required for delayed-release formulation. I remembered that Dan Seiler (or someone else?) said so during the panel discussion on the 2nd day in the Budapest conference. Or I misunderstood it? D***, that would affect many of my projects.

Well, according to the draft Appendix III (lines 1170–1176) for DR no MD is required. However, this question was raised. The main concern is AUCT-∞ instead of AUCT-t for PR. Higher variability and not consistent with US/CAN. Whatever the outcome will be (and I don’t think MD will be required for DR) it will affect projects starting 1½ years from now (my guess about the timeline).

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Shuanghe
★★

Spain,
2013-06-27 11:07
(3044 d 11:23 ago)

@ Helmut
Posting: # 10891
Views: 17,747

## SD vs. MD, partial AUCs

Hi Helmut, Thanks!

» » What if AUCτ/AUC0-∞ is <90% for reference but >90% for test? So reference has risk of accumulation but test does not. Can we waive MD study?
»
» Nope. See lines 594–595: “[…] demonstrated that the mean AUC(0-τ) after the first dose covers more than 90% of mean AUC(0-∞) for both test and reference…”

I know the guideline said both test and reference (I actually copied the phrase but somehow got deleted ).
What I was trying to ask is if anyone mentioned this point so we might get generic product with AUCτ/AUC0-∞ is <90% for reference but >90% for test. It's a long shot I know.

» Consensus amongst the members of the drafting group: “Better” is not “equivalent”. Article 10(3) instead of 10(1).

OK. What about "better alcohol effect" ?

We know in vitro dissolution with alcohol (0, 5, 10, 20%, and maybe 40% as well as FDA did) will be required and the "criterion" is "similar effect".
But for alcohol, maybe "better" and "equivalent" is not that contradictory? Not like the accumulation mentioned above, which I had doubt myself; for alcohol I'd say it should be allowed to have generic product release less in alcohol than reference. Anyone mentioned this in the discussion?

» Imagine two applications:
» In the first the additional metrics were tried, failed, but passed the MD study.
» The other one didn’t try at all and went straight for the MD.
» So at the end both showed BE with conventional metrics in SD and MD. Rejecting the first application would be difficult to defend.

When you put it this way, it's crystal-clear. thanks.

» Well, according to the draft Appendix III (lines 1170–1176) for DR no MD is required.

My bad. I didn't state it clearly. No MD study for DR dosage form, that's clear from the guideline (unless they change their mind of course).
What I meant to say was that Line 800 indicated that Cmax, AUC0-t, AUC0-∞ and partialAUC will be required for MR formulation in single dose study. My argument is that only the former 3 parameters should be required for DR formulation and all 4 parameters required for prolonged-release formulation in single dose study. That's impression I got from Budapest conference.

» However, this question was raised. The main concern is AUCT-∞ instead of AUCT-t for PR. Higher variability and not consistent with US/CAN. Whatever the outcome will be (and I don’t think MD will be required for DR) it will affect projects starting 1½ years from now (my guess about the timeline).

Not sure if I understood your message correctly, you mean that pAUC (in single dose study) will be required for DR formulation as well?

All the best,
Shuanghe
Helmut
★★★

Vienna, Austria,
2013-06-27 14:38
(3044 d 07:51 ago)

@ Shuanghe
Posting: # 10893
Views: 17,946

## pAUCs, alternative metrics, alcohol

Hi Shuanghe!

» I know the guideline said both test and reference.
» What I was trying to ask is if anyone mentioned this point so we might get generic product with AUCτ/AUC0-∞ is <90% for reference but >90% for test. It's a long shot I know.

Nobody raised this question. In my understanding you will get an approval, only the MD study will be mandatory. Up to you to send a comment to the EMA.

» OK. What about "better alcohol effect" ?
» We know in vitro dissolution with alcohol (0, 5, 10, 20%, and maybe 40% as well as FDA did) will be required and the "criterion" is "similar effect".

I didn’t take notes, so we have to wait for the presentations at EUFEP’s website. Maybe Dan does remember? In a recent line extension we were asked for 0, 5, 20, and 40% at pH 1.2 for two hours.

» But for alcohol, maybe "better" and "equivalent" is not that contradictory? […] for alcohol I'd say it should be allowed to have generic product release less in alcohol than reference.

I would support that.

» Anyone mentioned this in the discussion?

Not that I recall. However, there was a lengthy discussion whether the GL should concentrate on “intended use” or “misuse”. Food effects and alcohol-related dose dumping are different.
• Independent from what is stated in the SmPC (no food effect, without/with food, or even specific type of food, e.g., light breakfast) in real life administration contrary to the SmPC will happen regularly. So this is a very important issue.
• Intake together with alcohol might range from “possible” to “almost never”. As you know this issue has its origin in the oxycodone-story. Quite often terminal cancer patients take opiates together with strong spirits. On the other hand chances that this might happen with a pediatric formulation are close to nil.
I would say the requirement should be case-by-case and not a general one. Another point to comment.

» » Imagine two applications:
» When you put it this way, it's crystal-clear.

Sometimes I fail to make myself clear in the first place. Sorry.

» […] No MD study for DR dosage form, that's clear from the guideline (unless they change their mind of course).
» What I meant to say was that Line 800 indicated that Cmax, AUC0-t, AUC0-∞ and partialAUC will be required for MR formulation in single dose study. My argument is that only the former 3 parameters should be required for DR formulation and all 4 parameters required for prolonged-release formulation in single dose study. That's impression I got from Budapest conference.

Gotcha. Does partialAUC in line 800 mean only the first one (singular; like the FDA’s/TGD’s early exposure)? Seems so, because for prolonged release (line 805) the EMA uses the plural: “early and terminal partialAUCs”. Another ambiguity which calls for a comment. There was some dis­cussion whether this section should be extended to:

“AUC(0-t), AUC(0-∞), Cmax and a representative parameter of the shape of the curve, e.g., (early and terminal partialAUCs)

Depending on the formulation pAUCs might not be optimal metrics. Example: Flat profiles with ill-defined tmax. Henning and I voted for the plateau time1 or HVD.2 Unfortunately we have only few published data of pAUCs (especially AUCT-t; exception: some multiphasic for­mu­la­tions). On the other hand for MR theophylline we have a lot of data about t75%. Hen­ning gave the FDA’s example of requiring all MR studies to be performed in a replicate design in order to explore the subject-by-formulation interaction. This requirement was in force for ~two years. After reviewing the data, the FDA concluded that S×F is unlikely and lifted the requirement. Hen­ning suggested to have additional metrics3 as exploratory ones for a limited period of time (should not lead to rejecting an application if failed) and after reviewing the performance clari­fy­ing requirements. No need to update the GL; could be done in the Q&A document. Perso­nally I’m skeptic whether the EMA will follow this track…

» » However, this question was raised. The main concern is AUCT-∞ instead of AUCT-t for PR. Higher variability and not consistent with US/CAN. Whatever the outcome will be (and I don’t think MD will be required for DR) it will affect projects starting 1½ years from now (my guess about the timeline).
»
» Not sure if I understood your message correctly, you mean that pAUC (in single dose study) will be required for DR formulation as well?

For DR I guess only the first pAUC will be required (line 800); see also what I wrote above.

1. Plateau time (t75%) or Peak Occupancy Time (POT-25): Time period during which concentrations are within 25% of Cmax.
2. Half-value duration (HVD), POT-50: Time period during which con­cen­trations are within 50% of Cmax. According to László Endrényi (EUFEPS, Barcelona 2010) more stable than POT-25.
3. Besides #1 and #2, other metrics suggested in Barcelona:
Capical: Average of concentrations within POT.
AUCapical: Average of AUCs within POT.
MDT: Median duration time.
For the cut-off time point of early exposure Endrényi et al. (1998) suggested the earlier tmax calculated for each subject.
• Endrényi L, Csizmadia L, Tóthfalusi L, Balch AH, Chen M-L. The Duration of Measuring Partial AUCs for the Assessment of Bioequivalence. Pharm Res. 1998;15(3):399–404. doi:10.1023/A:1011916113082

Dif-tor heh smusma 🖖
Helmut Schütz

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Helmut
★★★

Vienna, Austria,
2013-06-22 01:15
(3049 d 21:14 ago)

@ Ohlbe
Posting: # 10860
Views: 18,219

## tmax (DR & multiphasic)

Dear all,

another goody. Lines 811–814

[…] A formal statistical evaluation of tmax is not required. However, there should be no appa­rent difference in median tmax and its range between test and reference product.

That’s truly clever. OK, we all learned in nursery school that nonparametric statistics are poisonous. (Concerning risks and adverse effects read the SmPC and ask your physician or pharmacist.)1
The IR GL states:

However, […] there should be no apparent difference in median tmax and its variability between test and reference product.

Do you get the subtle distinction? I was always wondering what the variability of the median might be in the EMA’s opinion (without applying nonparametric statistics this generally ended up in more or less eloquent ). Now I’m enlightened. It is the range! Splendid idea! A statistical parameter with a breakdown point2 of zero. Not even a dyed-in-the-wool nonparametrician on the maximum allowed dose of Schützenafil® would ever compare data based on their ranges. Maybe the IQR performs better?3

2. The breakdown point of an estimator is defined as the number of incorrect values which will not lead to a biased result.
• The arithmetic mean has a breakdown point of 1: Imagine an (even infinitely large) set of identical values (say 1). Now change a single original value to ∞. The arithmetic mean of the new set is ∞.
$$x_1=1,x_2=1,\ldots, x_{i=n}=1\rightarrow \bar{x}=\frac{1}{n}\sum_{i=1}^{i=n}x_i=1$$
$$x_1=1,x_2=1,\ldots, x_{i=n}=\infty\rightarrow \bar{x}=\frac{1}{n}\sum_{i=1}^{i=n}x_i=\infty \; \small{\square}$$
• The median has a breakdown point of 50%. You would need to change 50% of values to ∞ in order to contaminate the median. Therefore, the median is a robust estimator of location.
• Unfortunately the range performs just as bad as the arithmetic mean. Only two values of the entire data set (min & max) are used. Everything else is ignored. Imagine two (if you like very large) ranked sets:
  R  {1, …, 1, 2} median 1, range 1   T1 {1, …, 1, 3} median 1, range 2 → apparent difference
Or more weird:
  T2 {1, …, 1, 1} median 1, range 0 → superior?
3. Duno. Try:
t   <- c(0.5, 0.67, 0.83, 1, 1.33, 1.67, 2) p   <- c(0.025, 0.1, 0.15, 0.45, 0.15, 0.1, 0.025) n   <- 24 set.seed(1234567) R   <- sample(t, size=n, replace=TRUE, prob=p) T   <- sample(t, size=n, replace=TRUE, prob=p) med <- c(median(R), median(T)) rng <- c(range(R), range(T)) iqr <- c(IQR(R), IQR(T)) f   <- "%s%3.2f%s%3.2f%s%+3.2f%s" op  <- par(no.readonly = TRUE) par(family="mono") boxplot(R, T, range = 0, names = c("R", "T"), ylim = c(0, max(t)), las = 1) legend("bottomright", box.lwd = 0, box.col = "white", legend = paste(   sprintf(f, " Medians: R=", med[1], ", T=", med[2],              " (\u2206=", med[2]-med[1], ")"), "\n",   sprintf(f, "Ranges : R=", rng[1], ", T=", rng[2],              " (\u2206=", rng[2]-rng[1], ")"), "\n",   sprintf(f, "IQRs   : R=", iqr[1], ", T=", iqr[2],              " (\u2206=", iqr[2]-iqr[1], ")"), "\n"), cex = 0.9,   title = "Statistics of Tmax") points(x = jitter(rep(1, n), 10), R) points(x = jitter(rep(2, n), 5), T) box() par <- op
BTW, what’s “no apparent difference”?

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Helmut
★★★

Vienna, Austria,
2013-07-15 15:50
(3026 d 06:39 ago)

@ Ohlbe
Posting: # 10977
Views: 17,579

## Presentations of the EUFEPS meeting

Dear all,

below links to presentations of the EUFEPS meeting in Bonn last June:

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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Helmut
★★★

Vienna, Austria,
2013-08-16 16:41
(2994 d 05:48 ago)

@ Ohlbe
Posting: # 11294
Views: 13,642

Dear all,

friendly reminder.

Send your comments until 15 September using this M\$-Word template to [email protected].

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Helmut
★★★

Vienna, Austria,
2013-08-26 11:28
(2984 d 11:01 ago)

@ Helmut
Posting: # 11344
Views: 12,681

Dear all,

fantastic! EMA removed the commentary form from its website. One gets only a nice

URL no longer exists

A search for the internal reference “WC500004016.doc” is not successful as well.

Jean-Michel Cardot asked the EMA what’s going on and the answer was

Thank you for contacting the European Medicines Agency.
We hereby acknowledge receipt of your request for information, which was received on 17 August under reference number RFI-2013 No 08-324.
We will respond to your request in due course but no later than two months from the date of receipt.

Edit: The EMA corrected the link in the draft. The template’s new URI is
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2009/10/WC500004016.doc

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
Compliance
★

India,
2013-08-26 12:04
(2984 d 10:25 ago)

(edited by Compliance on 2013-08-26 12:36)
@ Ohlbe
Posting: # 11345
Views: 12,484

## Food effect

Dear All,

I was reviewing this revised guidance of EU for modified release formulation and i have one problem of understanding in the process mentioned in line 362, 363 and 364 about conduction of food effect study with compare to line 365, 366 & 367.

As per line 362 to 364, Food effect study is only require to conduct if the effect of the same is observed on Immediate formulation. I interpret it as only fasting is enough if the effect of food is absence or only fed is requires to be perform.

But as per the line 365 to 367, fast and fed both are suggested to be performed by default. Is it mean that fast and fed is necessary to perform in all cases however only fed is requires if effect of food is known as per IR formulation.

Please clear me on this to get the correct understanding about when to perform fasting and when to conduct fasting and fed both.

Thank you.

Regards,

Compliance

Edit: Subject line changed and moved to the suitable thread. [Helmut]
Dr_Dan
★★

2013-08-26 16:48
(2984 d 05:41 ago)

@ Compliance
Posting: # 11351
Views: 12,558

## Food effect

Dear Compliance
This was a topic at the EUFEPS meeting in Bonn followed by an intensive discussion. Andrzej Dzierbicki from Polpharma pointed out that a food effect study of the new MR formulation should be considered sufficient as food effect related to drug substance/IR formulation is known. Such food effect study results of the new MR formulation can be compared with historical/published data of food effect of an IR formulation irrespective of whether clinically significant food effect was observed for the IR formulation or not. Studies are sufficiently standardized to allow for rough estimation of effect size. However, it is not clear how the PK working group will react on this objection. We need to see the final version of the guideline.
Kind regards
Dan

Kind regards and have a nice day
Dr_Dan
Helmut
★★★

Vienna, Austria,
2013-09-12 15:23
(2967 d 07:06 ago)

@ Ohlbe
Posting: # 11485
Views: 11,288

## Variability (MR vs. IR)

Dear all,

one goody slipped trough my attention, namely lines 340–344:

The inter-individual variability of the pharmacokinetic parameters of interest should be deter­mined in the single dose or multiple dose studies […] and should be compared between the modified and immediate release formulation. The variability of the modified release formulation should preferably not exceed that of the immediate release formulation.

OK, but how to do that? I guess one-sided (non-superiority) of inter-subject variance is meant. But the inter-subject variance is only accessible in a crossover or a paired design: If we have a SD and a MD study we can only assess the total (pooled) variance.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes