Hey, it is just a draft! [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2013-05-17 20:49 (4044 d 15:51 ago) – Posting: # 10600
Views: 20,816

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.

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