Helmut
★★★

Vienna, Austria,
2019-11-27 19:08
(611 d 02:42 ago)

Posting: # 20878
Views: 4,922

## ICH M13 [BE/BA News]

Dear all,

The International Council for Harmonisation (ICH) met in Singapore from 16 – 20 November 2019, bringing together over 450 participants from ICH’s sixteen Members and thirty-two Observers. The meeting saw the convening of fourteen ICH Working Groups, which included six new Working Groups who met to progress work on recently approved new topic proposals…

From today’s press release:

Agreement on new ICH harmonisation activities
The Assembly revisited two new topic proposals which it had supported in principle at the last ICH biannual meeting in June 2019. This included the new topic proposal on Bioequivalence for Immediate-Release Solid Oral Dosage Forms (M13) and a proposal for the revision of the ICH Q9 Guideline on Quality Risk Management. The Assembly approved the Concept Paper Outlines for both topics, with the revision of ICH Q9 to have a delayed start time in view of other ongoing quality work, while a new Working Group would be established without delay to initiate work on finalising the concept paper and business plan for the M13 topic.

(my emphasis)

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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ElMaestro
★★★

Denmark,
2019-11-27 21:42
(611 d 00:09 ago)

@ Helmut
Posting: # 20879
Views: 3,909

## ICH M13

Hi Hötzi,

thank you.
It will be interesting to see if they will then harmonize the definition of BE. That little subtle difference between EMA's and FDA's definition makes all the difference between allowing PD to be part of a BE proof, or whether that should rather be called TE with all it entails in relation to the discussion of 10.3's, 10.1/10.2's , 505(b)(2)'s, 505(j)'s and so forth.

I am looking forward to seeing how it pans out.

Elegantly, if this is only about IR SODFs then I guess in all (?) cases PK is the go-to method, so possibly they can avoid discussing the definition altogether. Are there any IR SODF's where it could become tricky? Some of the locally acting anti-diarrheal drugs perhaps or the corticosteroids for Crohn's or Colitis Ulcerosa?

Pass or fail!
ElMaestro
Helmut
★★★

Vienna, Austria,
2019-11-28 12:37
(610 d 09:13 ago)

@ ElMaestro
Posting: # 20883
Views: 3,804

## ICH pushed by GBHI?

Hi ElMaestro,

» thank you.

Should go to Susana Almeida who notified me.

» It will be interesting to see if they will then harmonize the definition of BE. That little subtle difference between EMA's and FDA's definition makes all the difference between allowing PD to be part of a BE proof, or whether that should rather be called TE with all it entails in relation to the discussion of 10.3's, 10.1/10.2's, 505(b)(2)'s, 505(j)'s and so forth.

Agree – the major obstacle will be the legal stuff.

» Elegantly, if this is only about IR SODFs then I guess in all (?) cases PK is the go-to method, so possibly they can avoid discussing the definition altogether.

My impression: ICH-members felt the pressure coming from the GBHI-conferences (Mar 2015 Amsterdam, Sep 2016 Rockville, Apr 2018 Amsterdam).
Biowaivers and IR were topics of the the first two.
• The ICH’s concept paper on biowaivers was published in Oct 2016 and the draft in Oct 2018.
• Sumfink about IR BE was overdue.
Let’s wait what will happen in the next conference (12–13 Dec Bethesda).

» Are there any IR SODF's where it could become tricky? Some of the locally acting anti-diarrheal drugs perhaps or the corticosteroids for Crohn's or Colitis Ulcerosa?

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
Ohlbe
★★★

France,
2019-11-28 14:06
(610 d 07:44 ago)

@ Helmut
Posting: # 20884
Views: 3,765

## ICH pushed by GBHI?

Dear Helmut,

» » It will be interesting to see if they will then harmonize the definition of BE. That little subtle difference between EMA's and FDA's definition makes all the difference between allowing PD to be part of a BE proof, or whether that should rather be called TE with all it entails in relation to the discussion of 10.3's, 10.1/10.2's, 505(b)(2)'s, 505(j)'s and so forth.
»
» Agree – the major obstacle will be the legal stuff.

Don't you expect some lengthy discussions regarding HVD, two-step design, NTID, fed/fasting/both, supporting data from metabolites and stuff like that ? Aren't these significant differences between both sides of the Atlantic ?

» My impression: ICH-members felt the pressure coming from the GBHI-conferences (Mar 2015 Amsterdam, Sep 2016 Rockville, Apr 2018 Amsterdam).
» Biowaivers and IR were topics of the the first two.
• The ICH’s concept paper on biowaivers was published in Oct 2016 and the draft in Oct 2018.

Final guideline (Step 4) adopted at the last meeting, according to the press release you linked in your first message.

Regards
Ohlbe
Helmut
★★★

Vienna, Austria,
2019-11-28 14:23
(610 d 07:28 ago)

@ Ohlbe
Posting: # 20886
Views: 3,817

## “Lively” discussions

Dear Ohlbe,

» Don't you expect some lengthy discussions regarding HVD, two-step design, NTID, fed/fasting/both, supporting data from metabolites and stuff like that ? Aren't these significant differences between both sides of the Atlantic ?

Absolutely. Were main topics at the previous meetings. The discussions were, well, cough, lively.1

There are more things to sort out: Highest strength (EMA) vs. highest dose (FDA), multiple dose for controlled release (EMA practically2[sup][/sup] always, FDA practically never, HC rarely)…

» Final guideline (Step 4) adopted at the last meeting, according to the press release you linked in your first message.

Yep. Not on the ICH’s website yet.

1. Harmonization is always a compromise. The EMA tried to convey the message to possess the philo­sopher’s stone in its approaches. IMHO, arrogant and not helpful.
2. IMHO, this “option” to waive the multiple dose study if the residual AUC beyond the intended dosing interval in the single dose study is <10% is rather hot air. Never ever seen such a case. If someone knows an example, let me know.

Dif-tor heh smusma 🖖
Helmut Schütz

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

France,
2019-12-04 11:26
(604 d 10:25 ago)

@ Helmut
Posting: # 20916
Views: 3,734

## M9 step 4 now published

Dear Helmut,

» » Final guideline (Step 4) adopted at the last meeting, according to the press release you linked in your first message.
»
» Yep. Not on the ICH’s website yet.

Now it is, along with a Q&A.

Regards
Ohlbe
Helmut
★★★

Vienna, Austria,
2019-12-04 11:42
(604 d 10:09 ago)

@ Ohlbe
Posting: # 20918
Views: 3,660

## And Japan?

Hi Ohlbe,

» Now it is, along with a Q&A.

THX! Added to the collection. I guess, the following (in the Q&A) was a concession to Japan for not accepting biowaivers.

Q: Why does the guideline allow for regional differences in applications for BCS-based biowaivers for generic products?
A: The guideline focuses on BCS-based biowaiver principles to be applied for bioequivalence purposes provided they are supported by a sound scientific rationale. The provision in the guideline that accommodates exceptions to existing regulations that do not permit BCS-based biowaivers for generic product applications, at this time, does not disqualify implementation of these harmonized technical requirements to demonstrate BCS based biowaivers for other product applications unless explicitly stated.

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,
2019-12-04 14:43
(604 d 07:07 ago)

@ Helmut
Posting: # 20923
Views: 3,626

## And Japan?

Wow,

» A: The guideline focuses on BCS-based biowaiver principles to be applied for bioequivalence purposes provided they are supported by a sound scientific rationale. The provision in the guideline that accommodates exceptions to existing regulations that do not permit BCS-based biowaivers for generic product applications, at this time, does not disqualify implementation of these harmonized technical requirements to demonstrate BCS based biowaivers for other product applications unless explicitly stated.

I tried to read that answer 10 times now and I am none the wiser. Do they mean "The guideline will deal with BCS-based biowaivers, but it is acknowledged that some countries might not accept those." ??

Pass or fail!
ElMaestro
Helmut
★★★

Vienna, Austria,
2019-12-04 15:42
(604 d 06:09 ago)

@ ElMaestro
Posting: # 20925
Views: 3,633

Hi ElMaestro,

» I tried to read that answer 10 times now and I am none the wiser. Do they mean "The guideline will deal with BCS-based biowaivers, but it is acknowledged that some countries might not accept those." ??
»

My interpretation as well. I expected that (since Japan had/has always a certain way of thinking).

We had that already in ICH E9 of 1998. The draft followed closely the European one of 1993. Japan insisted to have a “global assessment” in the GL. Quote:

In some cases, 'global assessment' variables […] are developed to measure the over­all safety, overall efficacy, and/or overall usefulness of a treatment. This type of variable integrates objective variables and the investigator’s overall impression [sic] about the state or change in the state of the subject […]
Global assessment variables generally have a subjective component. […]

Japanese investigator approaches the volunteer and asks “How do we feel today?”
Volunteer – unsuccessfully – tries to remove a nasal tube: “Hmpfl…”
Investigator turns away (mumbling “well, very very well…”) and ticks ☑ good in the CRF.

Dif-tor heh smusma 🖖
Helmut Schütz

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