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Presentation Outline

Introduction

Sources of Challenge for BE study

Necessity of a BE Study?

Study Design

CRO

Ethics Committee

Regulatory Authority

Sponsor (Personnel or Product)

2 1st MENA Regulatory Conference on BE/BIOWAI/BIOAN/DISS, 23-24. 09.2013, Amman Jordan

CRO – In the middle of all Actions

and Communications

CRO REG/CLIN/

BIAN/SCI

Ethics Committee

Sponsor

Investigator - Other CRO’s


3

Science Science Based

Regulations

Business

Regulatory Affairs

BP-PK Statistics

Pharmacology Pharm.Technology

Medical Advice Documentation,

1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, 23-24. 09.2013, Amman Jordan

Departments of a “ponsor Pharmaceutical Company

Science Business –

Science Based Regulatory

4 1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, 23-24. 09.2013, Amman Jordan

M mmmmmm

1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, 23-24. 09.2013, Amman Jordan 5

BIOEQUIVALENCE

Administrative and summarizing data (Modules I and II) incl. GMP

Pharmaceutical data (Module III)

Preclinical data

(Module IV)

Innovative medicine Experimental data/ Literature

Generic medicine Multisource interchangeable

Clinical data

(Module V)

Bioequivalence – bridging innovators

and generics

Sources of Challenges Necessity of a BE Study?

Study Design

CRO

Ethics Committee




Necessity of a BE Study * Is it really necessary to perform BE study ? * If yes, how many? Grandfather Drugs (FDA separates these drugs as that ones

approved before 1938 and between 1938 – 1962) Special Recommendations of Health Authorities

(http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075207.htm) BCS (Memantine, Levofloxacine, Pregabalin) Bracketing for nonlinear pharmacokinetic showing Active

Substances , for products showing deviation from proportional composition

Local acting not absorbed drugs (Otilonium bromide – in Turkey)

MR Products – how many studies (single unit, multiple unit products)


Source of Challenges Necessity of a BE Study?

Study Design

CRO

Ethics Committee




Study Design

1. • Pharmacokinetic / Pharmacodynamic properties of Active Substance

• Intra-subject variability

2.

• Choice of Reference Product

• Regulations

• Special Recommendations

3

• Pilot Studies

• Kind of Pivotal Studies

4 • Special Products


Golden standard study design Single dose,

two-period,

Crossover

Healthy

volunteers

Reference

(comparator)/

Test (generic)


Tmax, Cmax, T1/2, AUC, Food effect, Linearity

Blood sampling points

Dose to be given - Wash-out period

Inclusion – Exclusion Criterion

11

1.

• Pharmacokinetic / Pharmacodynamic properties of Active Substance



Biological Material

Analytical Method and Analytes to be measured (metabolite – enantiomers)

Study Design

Intra-subject variability

Number of Volunteers

12

1.

• Pharmacokinetic / Pharmacodynamic properties of Active Substance


Plasma, Urine, Serum or Whole Blood

Cross-over, Replicate, Parallel,

etc.


2

Choice of Reference Product

Should be marketed in the EU ?

Which Country?

If not available on EU markets?

If registration in the US is also targeted

Different batches different in vitro profiles of the reference???

13

2. • Choice of Reference Product

Which is your target Market??


Choice of Reference Product RLDs Listed in USA-FDA Orange book

Lists of recommended reference / comparators products available on WHO website.

Innovator product with established Q,S, and E sourced from well regulated market (ICH process countries).

Other reference /comparator products must be justified. Recommended to consult WHO.


• Choice of Reference Product 2.

Regulations

Should be followed according to the target market

Turkey follows EU regulations

Special Recommendations

Every country own recommendations

FDA

(http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075207.htm)

15

2. • Regulations • Special Recommendations


Regulatory Recommendations for

MR products-BA/BE Studies

Type of MR Product

Single Unit

3 studies (fasting, fed and Steady state/multiple dose)

to the highest strength

Single dose fasting for each strength

(or Bracketing)

Multiple Unit

3 studies (fasting, fed and steady state/multiple dose)

to the highest strength


http://www.google.com.tr/imgres?imgurl=http://images.habervitrini.com/haber_resim/ilachap33930.jpg&imgrefurl=http://www.habervitrini.com/haber.asp?id=291391&usg=__eDT1RGD7WSKTGxlq_GzXeEF7Dlk=&h=230&w=230&sz=8&hl=tr&start=14&itbs=1&tbnid=dZQ2d5vv81oqVM:&tbnh=108&tbnw=108&prev=/images?q=tablet+ila%C3%A7&hl=tr&gbv=2&tbs=isch:1

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As all we know Especially important for MR products

Very important not only to plan pivotal studies but also for post approval variations

To be planned in both conditions (fasting and fed)

Different test formulations to be used (IVIVC)

17

3

• Pilot Studies


EXAMPLE : Pilot study

18

T1-R in-vitro

Study Code: IDE04206-TI05-PK301-1 1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, 23-24. 09.2013, Amman Jordan

19

Study Code: IDE04206-TI05-PK301-1

Test 1

Test 2

Test 3

Reference

T2-R in-vivo

EXAMPLE : : Pilot study: Study Code: IDE04206-TI05-PK301-1


Statistical Results EXAMPLE : : Pilot study: Study Code: IDE04206-TI05-PK301-

1

20 Study Code: IDE04206-TI05-PK301-1 1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, 23-24. 09.2013, Amman Jordan

Deconvolution Graph of in vivo Absorption

EXAMPLE : : Pilot study: Study Code: IDE04206-TI05-PK3011

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Study Code: IDE04206-TI05-PK301-1 1st MENA Reg Conf on BE/BIOWAI/BIOAN/DISS, 23-24. 09.2013, Amman Jordan

22

Positive pivotal study under fasting conditions

Test 2 Reference

Test 2

Reference




23

Test 2 Reference

Test 2

Reference

Fed pivotal study failed




EXAMPLE : : Pilot study: Study Code:

IDE04206-TI05-PK301-1

Study Type Fasting Fed

Pilot + -

Pivotal + + (Failed)


Condition ( Fed – Fasting) – according to SmPC

Composition of Meal – according to SmPC

Timing of administration of the drug product in relation to food intake – according to SmPC

Multiple Dose

Period Design

Volunteer Number

25

3

Challenges of Pivotal Studies

Metformin is adviced to be administered

under fed conditions

only

Standardized or high fat breakfast

30 minutes after meal

Replicate, Crossover,

Parallel

)ntrasubject Variability , 6…90


Endogenous Substances

Factors that may influence the endogenous baseline levels should be controlled if possible (e.g. strict control of dietary intake)

Administration of supra-therapeutic doses if possible

Different doses should be studied in pilot or pivotal studies

Baseline correction

Attention to the wash-out period – hard to see carry-over

26



BCS if no absorption in oral cavity

BE study if absorption in oral cavity:

With-out water if Reference used in both conditions

With water if Reference used in only this condition

3 treatment, 3 period, 6 sequence design if the reference medicinal product is taken only in one way (e.g. only with water), and the test product is intended for additional ways of administration

27


Oral Dispersible Tablets


Fixed Dose Combinations EU Turkey

2 way

A+B Reference

(A/B) Test combination

Pharmacological Interaction should be investigated from literature or experimentally

Like EU if literature data available.

If no data available:

4 way

• A Reference

• B Reference

• A+B Reference

• (A/B) Test combination

28



Highly variable drugs or drug products

Cmax ANOVA CV ≥% 30

Replicate design(3 or 4 periods)

Literature support

AUC remains unchanged 80 % - 125%

Cmax can be enlarged up to(69.84 %- 143.19 %) – geometric mean ratio between 80 % - 125 %

29



Enlarged acceptance ranges

according to EMA

The extent of the widening is defined based upon the within-subject variability seen in the bioequivalence

study using scaled-average-bioequivalence according to

[U, L] = exp [±k·sWR]

30

(L) (U)



Study Design

CRO

Ethics Committee




CRO

The Guide of the Study Planning of the study – study design

Clinical Part Investigator and study team

Human factor - volunteers

Analytical Part

Reporting Part – support during marketing

authorisation


CRO

The Guide of the Clinical part • Investigator and study team

• well experienced, know how to handle in problematic cases


CRO

The Guide of the Clinical part • Observer, monitor for Human factors

• Volunteers/Human subjects-Human factor – Hard to control


EXAMPLE # 1: Volunteer didn’t swallow the

pantoprazole test product


EXAMPLE # 2:Volunteer took a double dose of

Escitalopram 72 hours post test product


EXAMPLE # 3: Volunteer, most probably, vomitted

after repaglinide administration but no records


Outlier

• Explanation for Example #3

In principle any reason for exclusion is valid provided it is specified in the protocol (vomiting, diarrhoea,

concomitant medication) and the decision to exclude is made before bioanalysis.

However the exclusion of data should be avoided, as the power of the study will be reduced and a minimum of

12 evaluable subjects is required.


Outlier Explanation for example #3 • Exclusion of data cannot be accepted on the basis of

statistical analysis or for pharmacokinetic reasons. alone.

• The exceptions to this are:

• A subject with lack of any measurable concentrations or only very low plasma concentrations for reference medicinal product.

• Subjects with carry-over effect.


EXAMPLE # 4: Volunteer vomited 1h 17min

post Lisinopril administration

Kusma ile ilgili örnek

41

Reference

Test


CRO The Guide for Reporting Very important if different markets are in target

Report should be planned to cover all possible requests of all target market authorities

Hard and soft copies of report and all related data

CRO should continue consultancy during Marketing Authorisation Application



Study Design

CRO

Ethics Committee




Regulatory Authority and

Ethics Committee Regulatory Authority Reviews CT Application

- Quality, Safety, Efficacy/- Authorises trial

- Continued oversight of ongoing trial/- Transparency

- Reviews amendments/- Oversight of Safety

- Up to end of trial/- Maintenance of safety and CT

Databases/- Inspection/- Sanctions/- GMP

Ethics Committee Reviews CT Application

-Relevance of protocol and design/-Anticipated benefit outweighs

risk/-Investigator staff and facilities/-Information to

subjects/recruitment/ Compensation/indemnity/insurance/-Cont’nd

oversight of ongoing trial/-Reviews amendments, safety updates, new

information to subjects/-Up to end of trial


Ethics Committee and Regulatory

Authority

Ethics and Regulatory evaluation is very important but

Time is the most important factor – time is money

for the sponsor.

That’s why the sponsor prefer countries where the approval procedures are faster .


Approval Procedures in Turkey 1994 - Turkish BE Guideline is published

1995 - Turkish Good Clinical Practice Guide is published 2009 – New, ICH-GCP adopted Turkish Good Clinical

Practice Guide is published A lot of burocratic problems arised since 2009 with the new

ICH-GCP adopted regulations. Since August 2011 the problems are solved and with the new

Turkish Drug and Medical Device Institution a section in the Clinical Trials Department is established for the examination for only BE studies. This has fasten the

approval process: 1 week EC approval + 2 weeks MoH approval



Study Design

CRO

Ethics Committee




Sponsor

Sponsor is the most important part of all kind of

clinical trials including BE studies

Personnel of the Sponsor should be well

educated in terms of Regulations and Science

Sponsor’ Total Quality should guarantee a good

Quality and documentation over all the study


Summary Choice of an experienced CRO is the most important

point for sponsor companies

Choice of the type of pilot and pivotal studies should be evaluated carefully by sponsor companies on the advise of CRO

Choice of the Country of the Clinical CRO may shorten the approval period and speed up the study

Setting the needs according to the target Market(s)


Thank you for your attention! [email protected]

www.ide-cso.com


mailto:[email protected]




http://www.ide-cso.com/




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