[PDF] Overview of Comments Received on Draft Guideline on the

View - Download Overview of Comments Received on Draft Guideline on the

Previous PDF

Next PDF

European Medicines Agency

7 Westferry Circus, Canary Wharf, London, E14 4HB, UK

Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 86 13 E-mail: mail@ema.europa.eu http://www.ema.europa.eu

EMEA 2010 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged

London, 20 January 2010

Doc. Ref. EMA/CHMP/EWP/26817/2010

OVERVIEW OF COMMENTS RECEIVED ON

DRAFT GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE

CPMP/EWP/QWP/1401/98 REV. 1

Table 1: Organisations that commented on the draft Guideline as released for consultation

Name of Organisation or individual Country

1 EFPIA 2 European Generic medicines Association (EGA)

3 EUFEPS Network on BABP

4 FIP Special Interest Group on BCS and Biowaiver

5 BPI-German Pharmaceutical Industry Association Germany

6 The Association of the European Self Medication Industry (AESGP)

7 European Federation of Statisticians in the Pharmaceutical Industry

8 European Quality Assurance Confederation

9 International Association for Pharmaceutical Technology Germany

10 BEBAC-Consultancy Services for bioequivalence and Bioavailability

Studies Austria

11 CIPLA LTD. INDIA India

12 Pharmascience Inc. Montreal, Canada Canada

13

Anapharm Canada

14 Lupin Bioresearch Center India

15

MANEESH PHARMACEUTICALS, LTD India

16 MDS PHARMA SERVICES

17 POLFA TARCHOMIN S.A Poland

18

PHAST GmbH Germany

19 Jenson Pharmaceutical Services Ltd

20 Douglas Pharmaceuticals Ltd New Zealand

21

Ratiopharm GmbH

22

Ranbaxy

23 Orion Corp. Orion Pharma

24 Gilead Sciences International Ltd

25 CEPHA s.r.o. Czech Republic

26 H.L. Lundbeck A/S

27

Combino-pharm Spain

28 Bayer Schering Pharma AG/Clinical Pharmacology and Global

Pharmacometrics

29 Quinta Analytica-s.r.o. Czech Republic

30

Hexal AG Germany

31 Synthon BV The Netherlands

32 UCB Pharma S.A.

33 Merck Sharp & Dohme (Europe) Inc

34 ACC GmbH, Analytical Clinical Concepts Germany

35 Slovak National Accreditation Service Slovakia

36 Good Laboratory Practice Monitoring Authority UK

37 Norwegian Accreditation Norway

38 Eye- Care Industries European Economic interest grouping

39 Dr. Nasir Idkaidek Jordan

40

Patrick Nicolas France

41

Atholl Johnston UK

42

Laszlo Endrenyi Canada

43

Aldo Rescigno

44 Carla M Catsmella Italy

45

Salvador Fudio

46 Dr. Kamal K. Midha and Dr. Gordon McKay

47

Swissmedic

Table 2:Discussion of comments GENERAL COMMENTS

Outcome

1) There is a general confusion about the implementation of new guidelines now that interim advice

has been issued. In particular, companies appear to be concerned about the fate of applications entering the system before finalisation. An explic it statement of the date (a) when agreed guidelines will come into force and (b) that regulations will not be applied retrospectively, would be useful. (2) Although there is a wish to examine as much data as is available, it should be stated that submissions for non-EU submissions can be omitted. (3) In the document there is use of general terms such as "same", "similar" and "major" which have a wide range of interpretation. Where ever possible, a numerical guide should be used. For example, a major metabolite might constitute 30% of the dose etc. (4) General definitions, e.g. of bioavailability, bioequivalence, generic medicinal products,

pharmaceutical equivalence etc. should also be included in the new guideline. 1) Once the final guideline has been adopted by CHMP it

will be published for 6 months before coming into operation. The revised guideline should be applied to all applications submitted after the guideline has come into operation, regardless of when the BE studies were conducted. The present guideline and Q&A document are relevant for applications submitted until the new guideline comes into operation. See also EMEA/P/24143/2004. Items 2, 3 and 4) are covered by responses to specific

comments. Over 80 pages of detailed comments from over 16 companies were consolidated into this document.

In general, this revision is welcomed and considered to be well written. In particular we welcome the principle of applying 'scientific reasoning ' to guide the choice of design, dose, analysis and acceptance criteria. A few general comments, before line by line specifics are given in the rest of the document.

Several companies asked for additional clarification regarding exactly when the scientific principles

of BE described in the guidance apply to generic substitution (or do not apply). Please consider adding clarification to various sections as to applicability of scientific principles of BE to formulation development versus generic substitution. Could you make reference to the fact that the new document does not cover the topic "bioavailability" and from where guidance on this topic is intended to come? Furthermore, the current NfG on the Investigation of Bioavailability and Bioequivalence includes a number of definitions (e.g. pharmaceutical equivalence, essential

similarity of products, etc.), which are missing in the new draft. Will these definitions be included

in another guideline? There was the typical dichotomy of comments asking for more detail and those asking for less 'prescriptive' guidance. However, in a few specific places, most companies thought that the draft guidance note is overly prescriptive in several areas where there are proposals for alternative approaches, which could be appropriately taken with adequate scientific rationale provided by sponsors, in particular Line 195 (requirements for reference and test product packaging) and Line

989-998 (detailed provision of analytical method parameters). Proposals for alternative wording are

made below within the detailed comments.

Generic substitution is a nati

onal legal issue and is not covered in this EU guideline. The other issues are covered by responses to specific comments.

EMEA 2010 Page 3/248

We welcome the clarification provided on the definition of 'complete absorption' and feel that the appropriate threshold for complete absorption is a topic worth further exploration for consideration in future guidance revisions.

The draft guidance note requests proof of dissolution profile similarity by generation of dissolution

data in 3 buffer systems (e.g. pH 1.2, 4.5 and 6.8). We propose that if changes in formulation and manufacturing process are made within a pre-defined design space, there should be no requirement

for confirmatory dissolution testing beyond the specified dissolution test. We seek greater clarity on

the value added by the 3 pH point dissolution test in the case of an enhanced product/process

understanding and control strategy. We recommend greater incorporation of the principles of enhanced product specific understanding in the selection of dissolution methodology. We believe that once the critical quality attributes impacting drug product performance are identified, monitoring these parameters utilising a

discriminatory or biorelevant dissolution test, would provide a viable alternative to a 3 point dissolution testing in support of biowaiver applications. We are concerned by the apparent constriction in dissolution criteria applied to biowaiver applications. In the original guidance note (CPMP/EWP/QWP/1401/98) it was stated that "in case of exemption from BE studies, in vitro data should demonstrate the similarity of dissolution profile"... and "in cases where more than 85% of the active substance are dissolved within 15 minutes the similarity of dissolution profiles may be accepted as demonstrated" i.e. without further mathematical testing. The current draft guidance indicates that BCS based biowaivers will only be accepted for very rapidly dissolving drug products (lines 917 & 923), i.e. > 85% dissolved within

15 minutes. This is considered overly conservative with respect to scientific understanding of

pharmacokinetics and typical gastric emptying times. For biowaiver applications we strongly recommend consideration of drug products with rapid dissolution where 85% dissolution occurs in

30 minutes (as discussed in lines 792 through 797).

In these cases mathematical testing should be

performed to demonstrate similarity in dissolution profiles. This approach would provide greater scope for alignment with regulatory guidance for other regions. We recommend keeping mathematical methods used to demonstrate dissolution profile similarity as simple as possible so that the key aspect, i.e. what magnitude of difference is important, can be defined in a manner that is readily understood by all and may be related to the practical consequence of failing to meet this requirement. Complex multivariate distance based approaches provide a challenge in interpretation of what constitutes a meaningful difference. We suggest that this is a complex topic requiring further discussion.

EMEA 2010 Page 4/248

Marketed highly variable drugs have been demonstrated to be safe and effective indicating that

individual subjects as well as the general patient population receive benefit despite the large day to

day fluctuations in their exposure. While the proposed criteria recognize this for Cmax, they do not

address the same problem for AUC. Thus, we recommend consideration of a scaled approach to BE criteria (Cmax and AUC) as described in Haidar SH, Makhlouf F, Schuirmann DJ, Hyslop T,We Davit B, Conner D, Yu LX. Evaluation of a Scaling Approach for the Bioequivalence of Highly Variable Drugs. AAPS J. 2008 Aug 26. This method avoids unnecessary exposures to subjects in BE studies who receive no therapeutic benefit while adequately ensuring acceptable product performance. Plasma/serum can be used throughout the guidance or a footnote/comment that for plasma also serum may be read. In general the guidance lacks any information on how to evaluate the results of a chemical entity displaying double peaks in the concentration time profile.

For immediate release products double peaks is expected to be a rare phenomenon. In the context of this guideline, bioequivalence for immediate release products, Cmax (the highest concentration, regardless if this is reached with the

first or second peak) is considered appropriate. No change to

the guideline is needed. The EGA welcomes the release of the draft revision of the bioequivalence guideline as a great step forward. Generally, the presence of greater detail and more flow charts achieves the clarification level which was deemed necessary by both generic medicines companies and assessors. The EGA also welcomes the perspective of a harmonised approach to BCS-biowaivers applications. This approach will certainly limit the degree of variation in interpretation of bioequivalence

requirements in Europe. Member states will need to show political will to implement these provisions harmoniously. In spite of this notable progress, the EGA would qualify this guidance document as very demanding

in light of the prescriptive requirements it contains and of the number of new acceptance criteria it

introduces. In addition, the EGA has identified a number of topics which would still deserve additional

clarification or information. The EGA would generally note that, contrary to other initiatives in the

world, European regulators are moving in the introduction of additional requirements for steady- state studies in the case of immediate release dosage forms. The EGA is of the opinion that this

does not contribute significantly to better proof of bioequivalence. This move must have its roots in

an overestimation of the added value of steady-state studies in those cases. Additionally, the guideline is rather extensive and tends to cover numerous topics and issues. The The present guideline is interpreted differently by different member states with some member states considering bioequivalence as a "quality" issue and are very reluctant e.g. to accept widening of the acceptance criteria based on justification that this does not affect efficacy or safety, while

others are more open to this and have a more "clinical relevance" approach. This has lead to a large number of applications being referred to CMDh/CHMP. One aim of the revision of the guideline was to provide more clear guidance with less risk for different interpretation and fewer application procedures leading to CMDh/CHMP referrals. Hence, before the revision was initiated it was agreed between member states to revise the guideline towards a "quality" approach and leave less room for justifications from clinical efficacy and safety perspective. The development of the draft guideline therefore focused on providing recommendations for design and conduct of bioequivalence studies that would assure essentially similar biopharmaceutical quality between test and reference. At the

EMEA 2010 Page 5/248

EGA would require that those chapters which remain general in nature and do not particularly add any new information be removed in order to improve readability. Although in general the requirements seem well defined, the clarity of the text is undermined by the use of non-specific and undefined terms and phrases such as 'markedly high', 'may be acceptable' or 'sufficient'. same time, the draft guideline was written with the ambition to cover all clinically relevant situations where a simple design evaluating parent compound after single dose administration would potentially not be sufficient to conclude bioequivalence between test and reference products. Hence, the request for e.g. multiple dose studies in certain cases of dose-and time dependent pharmacokinetics or the evaluation of active metabolite that contributes significantly to the efficacy when use of metabolite data may be more sensitive to detect differences between formulations. It has become evident from the comments received that the draft guideline is difficult to interpret and may lead to new situations with different interpretation between industry and regulatory agencies and also between different member states. Hence, there is a clear need for simplification of the guideline. As described in responses to th e comments below, a major revision of the guideline has been made, with the ambition that the guideline will be easier to interpret. There is no precise indication of how the guideline is to be implemented once it has been adopted. As it contains several changes in terms of strategy and approach to demonstrating bioequivalence, it is important to consider the practical aspects of implementation.quotesdbs_dbs35.pdfusesText_40

[PDF] étude de bioéquivalence pdf

[PDF] les differents types de microfinance

[PDF] difference entre mission but et objectif

[PDF] vision mission valeurs

[PDF] mitose meiose 3eme

[PDF] l'opinion est elle un obstacle ? la recherche de la vérité

[PDF] ressemblance vraisemblance arts plastiques

[PDF] difference entre poeme et poesie

[PDF] comparaison dictature démocratie

[PDF] les roms en france

[PDF] formule étendue tableur

[PDF] rapport interdécile ses

[PDF] exemple dobjectif dune entreprise

[PDF] plan de l'orchestre symphonique

[PDF] orchestre classique