BEBAC  Ing. Helmut Schütz


The EMA promotes consistent development of bio­equi­va­lence studies through product-specific guidance

On 15 Nov 2013 the EMA released its first product-specific guidance on the demonstration of bioequivalence for 16 active substances (dated 24 October 2013) for a three-month public consultation period (i.e., until 15 February 2014).

This is the first wave of product-specific bioequivalence guidance, and the Agency intends to continue developing this type of guidance, which is based on the general principles set out in the Agency’s overarching Guideline on the investigation of bioequivalence, with another wave planned in 2014.*
The aim is to enable a consistent approach to the assessment of applications supported by bioequivalence data, particularly generic applications, across all authorisation routes i.e. centralised, decentralised, mutual-recognition and national authorisation procedures.
The guidance is intended to help companies design study programmes that meet the expectations of European Union regulators, allowing for better transparency and predict­ability of the scientific assessment during the authorisation process.

For each medicine, the document provides guidance in the form of a table on:

Guidances by active substance(s), date of publication of the draft, end of consultation, and dates of adoption and coming into effect. Click the columns’ header to sort (JavaScript required):

# active substance(s) published consultation adopted effective
1Capecitabine (draft, adopted, comments) 2013-11-152014-02-152015-05-212015-12-01
2Carglumic acid (draft, adopted, comments) 2013-11-152014-02-152015-04-082015-10-01
3Dasatinib (draft, adopted) 2013-11-152014-02-152014-11-202015-06-01
4Emtricitabine/Tenofovir Disproxil (draft, adopted) 2013-11-152014-02-152014-11-202015-06-01
5Erlotinib (draft, adopted) 2013-11-152014-02-152014-11-202015-06-01
6Imatinib (draft, adopted, comments) 2013-11-152014-02-152015-04-082015-10-01
7Memantine (draft, adopted, comments) 2013-11-152014-02-152015-04-082015-10-01
8Miglustat (draft, adopted) 2013-11-152014-02-152014-11-202015-06-01
9Oseltamivir (draft, adopted, comments) 2013-11-152014-02-152015-04-082015-10-01
10Posaconazole suspension (draft, adopted, comments) 2013-11-152014-02-152015-04-082015-10-01
11Repaglinide (draft, adopted) 2013-11-152014-02-152014-11-202015-06-01
12Sirolimus (draft, adopted, comments) 2013-11-152014-02-152015-05-212015-12-01
13Sorafenib draft, adopted, comments) 2013-11-152014-02-152015-05-212015-12-01
14Tadalafil (draft, adopted, comments) 2013-11-152014-02-152015-05-212015-12-01
15Telithromycin (draft, adopted, comments) 2013-11-152014-02-152015-05-212015-12-01
16Voriconazole (draft, adopted, comments) 2013-11-152014-02-152015-05-212015-12-01
17Sunitinib (draft, adopted, comments) 2013-12-042014-03-032015-05-212015-12-01
18Asenapine (draft, adopted) 2015-07-152015-11-012016-04-012016-11-01
19Prasugrel (draft, adopted) 2015-07-152015-11-012016-04-012016-11-01
20Sitagliptin (draft, adopted) 2015-07-152015-11-012016-04-012016-11-01
21Zonisamide (draft, adopted) 2015-07-152015-11-012016-04-012016-11-01
22Entecavir (draft, adopted) 2015-10-062016-01-012016-04-012016-11-01
23Rivaroxaban (draft, adopted) 2015-10-062016-01-012016-04-012016-11-01
24Lenalidomide (draft, adopted) 2015-10-062016-01-012016-04-012016-11-01
25Tacrolimus (draft, adopted) 2015-10-062016-01-012016-04-012016-11-01
26Ticagrelor (draft, adopted) 2015-10-062016-01-012016-04-012016-11-01
27Everolimus (draft, adopted) 2016-05-022016-07-312016-12-152017-07-01
28Fingolimod (draft, adopted) 2016-05-022016-07-312016-12-152017-07-01
31Levodopa/Carbidopa/Entacapone (draft, adopted) 2016-05-022016-07-312016-12-152017-07-01
29Paliperidone (Rev. 1 adopted, draft, adopted) 2016-05-022016-07-312018-05-312018-12-31
30Pazopanib (draft, adopted) 2016-05-022016-07-312016-12-152017-07-01
31Crizotinib (draft, adopted) 2016-12-222017-03-312017-06-222018-01-01
32Dabigatran (draft, adopted, comments) 2016-12-222017-03-312018-05-312018-12-01
33Elvitegravir / cobicistat / emtricitabine / te­no­fovir disoproxil (draft, adopted) 2016-12-222017-03-312017-06-222018-01-01
34Elvitegravir (draft, adopted) 2016-12-222017-03-312017-06-222018-01-01
35Emtricitabine, rilpivirine, tenofovir, disopro­xil (draft, adopted) 2016-12-222017-03-312017-06-222018-01-01
36Vortioxetine (draft, adopted) 2016-12-222017-03-312017-06-222018-01-01
37Dolutegravir (draft) 2017-07-282017-10-31  
38Dronedarone (draft) 2017-07-282017-10-31  
39Paracetamol (draft) 2017-07-282017-10-31  
40Rilpivirine (draft) 2017-07-282017-10-31  
41Dimethyl fumarate (draft, adopted) 2017-08-032017-10-312018-05-312018-12-01
42Ibuprofen (draft, adopted) 2017-08-032017-10-312018-05-312018-12-01
43Prasugel (Rev. 1 draft) 2017-08-032017-10-31  
44Tadalafil (Rev. 1 draft) 2017-08-032017-10-31  
45Agomelatine (draft, adopted) 2018-01-312018-04-302018-07-262019-02-01
46Cholic acid (draft, adopted) 2018-01-312018-04-302018-07-262019-02-01
47Ledipasvir/sofosbuvir (draft, adopted) 2018-01-312018-04-302018-07-262019-02-01
48Posaconazole tablet (draft, adopted) 2018-01-312018-04-302018-07-262019-02-01
49Vismodegib (draft, adopted) 2018-01-312018-04-302018-07-262019-02-01
50Aliskiren (draft) 2018-06-272018-09-30  
51Apixaban (draft) 2018-06-272018-09-30  
52Gefitinib (draft) 2018-06-272018-09-30  
53Lapatinib (draft) 2018-06-272018-09-30  
54Octreotide acetate (draft) 2018-06-262018-09-30  
55Pegylated liposomal doxorubicin (draft) 2018-07-052018-09-30  

Comments should be provided using this template and sent no later than the respective end of consultation to [email protected].

Update 1

APIs requested by the PKWP for review in 2014 so far: asenapine, prasugel, sitagliptin, tacrolimus, and zonisamide (thanks to Jan Welink/MEB for sharing this information).

Update 2

The “Compilation of individual product-specific guidance on demonstration of bioequivalence” (EMA/CHMP/736403/2014) dated 17 Dec was published by the EMA on 19 Dec 2014.

This guideline provides a compilation of product-specific guidance on the demonstration of bioequivalence for individual products authorised within the EU. The procedure for publication is as follows:

Update 3

This […] batch of individual guidance (EMA/CHMP/736403/2014 Rev 1) dated 8 April 2015 replaces the “Compilation of individual product-specific guidance on demonstration of bioequivalence” EMA/CHMP/736403/2014.
New Annex B: Carglumic acid, imatinib, memantine, oseltamivir, and posaconazole. Date for coming into effect: 1 October 2015.

Update 4

EMA/CHMP/736403/2014 Rev 2 dated 21 May 2015 (published on 7 July 2015) replaces EMA/CHMP/736403/2014 Rev 1.

Guidances for capecitabine, sirolimus, sorafenib, sunitinib, tadalafil, telithromycin, and voriconazole were adopted by the CHMP on 21 May 2015.
New Annex C: For products mentioned above. Date for coming into effect: 1 November 2015.

Update 5

New draft guidances for asenapine, prasugrel, sitagliptin, and zonisamide (dated 25 June 2015, published on 15 July 2015).

Update 6

New draft guidances for entecavir, lenalidomide, rivaroxaban, tacrolimus, and ticagrelor (dated 24 September 2015, published on 6 October 2015).

Update 7

EMA/CHMP/736403/2014 Rev 3 dated 1 April 2016 (published on 7 April 2016) replaces EMA/CHMP/736403/2014 Rev 2.

Guidances for asenapine, entecavir, lenalidomide, prasugrel, rivaroxaban, sitagliptin, tacrolimus, ticagrelor, and zonisamide were adopted by the CHMP in April 2016.
New Annex D: For products mentioned above. Date for coming into effect: 1 November 2016.

New draft guidances for everolimus, fingolimod, levodopa / carbidopa / entacapone, paliperidone, and pazopanib (dated 1 April 2016, published on 7 April 2016).

Update 8

Guidances for everolimus, fingolimod, levodopa / carbidopa / entacapone, paliperidone, and pazopanib were adopted by the CHMP in December 2016. Date for coming into effect: 1 July 2017.

New draft guidances for crizotinib, dabigatran, elvitegravir / cobicistat / emtricitabine / tenofovir disoproxil, elvitegravir, and vortioxetine (dated 15 December 2016, published on 22 December 2016).

Update 9

Guidances for crizotinib, elvitegravir / cobicistat / emtricitabine / tenofovir disoproxil, elvitegravir, and vortioxetine were adopted by the CHMP in June 2017. Date for coming into effect: 1 January 2018.

Update 10

New draft guidances for dolutegravir, dronedarone, ibuprofen, paracetamol, rilpivirine, dimethyl fumarate, prasugrel, and tadalafil were adopted by the CHMP for public consultation in June 2017.

Update 11

New draft guidances for agomelatine, cholic acid, ledipasvir / sofosbuvir, posaconazole, and vismodegib were adopted by the CHMP for public consultation in December 2017.

Update 12

Guidances for dabigatran and dimethyl fumarate were adopted by the CHMP in May 2018. Date for coming into effect: 1 December 2018.

New draft guidances for aliskiren, apixaban, gefitinib, lapatinib, octreotide acetate, and pegylated liposomal doxorubicin.

Update 13

Guidances for agomelatine, posaconazole, ledipasvir/sofosbuvir, cholic acid, and vismodegib were adopted by the CHMP in July 2018. Date for coming into effect: 1 February 2019.