The Challenges of Performing In Vivo Studies

for Taste/Acceptability During the Development

of Paediatric Formulations
Joanne Bennett (Pfizer), Hannah Batchelor (Univ. Birmingham)
Paediatrics Consortium Co-funded by Innovate UK

Aims
Acceptability definition and regulatory view
Current challenges for establishing an acceptable formulation

Describe the process used at Pfizer during formulation

development to assess taste and acceptability
Case study example showing the need

Acceptability current landscape

Where are the gaps?
How are we addressing acceptability testing as a consortium?

Accelerating Paediatric Formulation Development

- through smart design and predictive science
Co-funded by Innovate UK

Ambition: to establish an industry standard

framework and suite of tools to develop safe
and efficacious paediatric dosage forms

UCL

Aston
Univ.

1
2

Bham

Univ.

Bath
Univ.

APS

Developing in vitro tools taste prediction

GSK

BMS

Developing in silico & in vitro tools clinical exposure

Selection of `novel formulation technologies

Acceptability in children understanding and

defining methodology

Manufacture of formulations for use by different

workstreams

Validation and exploitation of proposed paediatric

strategy

AZ

Pfizer

Juniper
Pcals

Defining Acceptability and Regulatory View

The PDCO FWG

recommend that
acceptability, including
palatability testing will
be performed during
clinical trials in target
patients population

Number of Challenges in Establishing Whether

a Formulation is Acceptable

No regulatory direction on
assessing palatability
Science based
evidence required!
Limited access to children.
Broad age range. Reliant
on adult data-relevant?

A number of different
formulation approaches

Lack of predictive in vitro

tools reliant on in vivo
studies

No standardised
methodology or scales

Assessment of Taste/Acceptability in Industry/Pfizer Approach varies - no standard practice

Study Variables

Prior knowledge from adult clinical studies

Medical need / Disease area

Taste study

Acceptability

-API vs surrogate cpd

-Dosage form

-Untrained vs trained

-Untrained (patients)

-Adult vs child (patient)

-Child

-Assessment method
hedonic scale vs VAS
vs open questions

-Assessment method
hedonic scale vs other
methods

-Bespoke taste study

vs add on to PK
study

-Add on to clinical
study?

Market - current lead

Availability of data for similar compounds

Clinical study or not

Local country requirements

Safety considerations

-Single dose vs
bitterness threshold
study

Factors influencing what we do

for taste/acceptability testing

Overview - Process Used for Taste Assessment

at Pfizer/Industry

Identifying taste
issues

Overcoming
taste issues

Judging
success

FOCUS ON API

FOCUS ON FORMULATION
Taste studies

FOCUS ON ACCEPTABILITY
in the patient

1. Identifying Taste Issues

Reliance on adult data
In vitro systems not used

Prior Knowledge patient feedback from

adult PK study
Taste data questionnaire maybe
included in adult PK study
Bespoke adult taste study

API
Characterisation
-to understand
taste

Untrained and trained panelists have been

used

Relevant taste attributes identified using drug

dissolved in water or simple buffer

May include evaluations of solutions at different

concentrations e.g. bitterness threshold study

Taste issues known -conduct studies with

specific concentration(s)

Studies include evaluation of aftertaste typically

out to 30 minutes

2. Overcoming Taste Issues

Reliance on adult data

Formulation
Development

Formulations progressed to adult taste studies to aid

formulation selection
e.g. selection sweeteners, flavours etc or taste
masking technology.

Include comparator
Marketed compound
In house

Also consider:Use of a surrogate system (for the API)

API key attributes characterised by sensory experts

Paediatric formulation
experience with
solutions, suspensions
and recently
multiparticulates

3. Judging Success of a Formulation

Different approaches used:

Children

Questionnaires given as secondary end point

in an adult PK study

Use adult data to judge whether formulation is

likely to be acceptable.

Acceptability

Examples of where compliance has been the

only endpoint for determining acceptability in
paediatrics

Paediatric PK Studies

VAS scales used in adults

Patient journals/clinical feedback

Inclusion of questionnaire
Open questions
Hedonic scale no standard

Consumer studies (target patient

population)

Limited and focussed questions

Need to be conducted earlier?

Snapshot of Taste Testing in Paediatrics

What varies? - Current and recent experience
Project API/Surrogate

Inclusion of
Bitterness
comparator? Threshold
study?

Untrained Methodology Methodology

or trained used to judge used to judge
taste in adults acceptability
In children

API

Yes

No

Untrained VAS -categoric NoneTrained

compliance

API
No
Surrogate cpd(s)

No

Trained

API
No
Surrogate cpd(s)

No

Untrained
Trained

4
5

API and
Yes
Surrogate Cpd(s)
Project halted
-

API

Yes

VAS continuous

Hedonic 3pt
with text and
open
questions
Hedonic with
text

No

None

None

No

Hedonic 5 pt

Trained

Not defined

Case Study Cpd A illustrates the need for

improving understanding of acceptability

Formulation
development

Acceptability

Primary formulation approach

Surrogate system used in taste/palatability studies (trained experts) during development of a taste
masked solution formulation to aid in excipients selection /formulation development
Secondary formulation approach
Microsphere formulation developed taste neutral - reverse enteric coat.

Nominated paediatric formulation was first used in an adult relative bioavailibility study in which
taste/palatability was built in as a secondary endpoint (untrained).
Questions on overall acceptability, acceptability of taste, amount of sweetness, bitterness,
burning tingling.
Adult data average scores were in the middle not good but not bad enough to not proceed?
Taste issue found with solution formulation in paediatric patients solution formulation not
acceptable
Microsphere paediatric studies adult VAS scale, children hedonic questionnaire.

Reformulation

API taste
characterisation

Taste issue identified in initial clinical paediatric study.

Bespoke taste study in trained expert sensory panelists . A surrogate system was identified
Three surrogate cpmpounds (reproducing negative taste attributes) were then identified to represent
compound
Throatburn known not to be well mimiced by surrogate system

Work of the Innovate UK Paediatrics Consortium

Existing landscape on acceptability testing

41 literature reports on taste testing in paediatric populations
Controls often not included
Sample population ranged from 10-769 with a mean of 112.6
and a median of 46
Age of participants ranged from 0-18 years with a mean of 7
years and a median of 7.5 years
Data also being gathered from industry - AZ, BMS, Glaxo and
Pfizer

Range of Scales Used in Assessing

Acceptability of Medicines
Reference

Image used

Comments

(Chen et al., 1996)

Used in children aged 48-59 months to assess

taste of UHT milk

(Powers et al., 2000,

POWERS, 1996)

Gender specific scales used in children aged 4- 8

years to assess palatability of antibiotic
suspensions

(Angelilli et al., 2000,

Freedman et al., 2010,
Hames et al., 2008,
Dagnone et al., 2002,
Smith et al., 2013)

Assess palatability of antimicrobial agents in

children aged 5-8 years

(Zaman et al., 2013)

The Smileyometer instrument used to measure

product experience and product liking for foods.
Used in children aged 5 and up

http://www.doctoryum.
org/wpcontent/uploads/2011/
02/yumscale.pdf

The Yum scale measures how much children like

or dislike the food.

(Verrotti et al., 2012)

Assess taste of modified release granules of

valproate in children with a mean age of 6.7 years

(Thompson et al.,
2015)

Proposed Best practice scale for assessing

palatability of paediatric medicines

(Ranmal et al 2015)

Created to assess the "willingness to take"

capsules

Many scales
based on food
sensory analysis
or pain ratings

Within companies
not necessarily
standardised on a
scale

What is Acceptable?
VAS Scales
Literature reports on what is acceptable are
varied not always clear what score was
regarded as acceptable

Hedonic Scales

Using VAS and hedonic scales acceptable

definitions are shown as green,
unacceptable as red (purple = excellent
palatability)

Other measures include:

70% of population agreeing that the product
was equally or more acceptable to their child
than other medicines

Studies Planned to Assess Acceptability in Children

1. Develop methodology

2. Evaluate acceptability of:

Triangulate data using

hedonic, VAS and observation
of children to evaluate a good
measure of acceptability

(a) The palatability of a range

of liquid medicines

Observation of facial
expression and behaviours

(b) The acceptability of

multiparticulate dosage forms
in children
no data in children looking at
size and amount of
multiparticulates that would be
acceptable

Summary

Approaches to acceptability testing are varied

No standardised methodology for acceptability testing

Limited data in literature
Limited (no) regulatory guidance
Need more scientific evidence

Within companies approach varies

Need for better tools
In vitro tools lacking / not predictive
Adult data understand limitations
Improve understanding of how to assess acceptability in children.
What is the best methodology to use

Overview of consortium plans to address some of the gaps with acceptability testing

Define best approach to judge acceptability in children

Obtain data on acceptability for multiparticulates

Aknowledgements
Paediatric Innovate UK consortium members
Industrial Partners

Anita Jackson (Project manager

Academic Partners

Hannah Batchelor (University of

Birmingham)

Punam Mistry (University of

Birmingham)

Nicoletta Fotaki (University of

Bath)

Catherine Tuleu (UCL)

Abeer Ahmed (UCL)

Afzal Mohammed (Aston)

Priory Pharma Consulting Ltd)

[Marcel De Matas (AZ)]

Richard Storey (AZ and APS)

Alastair Coupe (Project Leader Pfizer)

Joanne Bennett (Pfizer)

Peter Timmins (BMS)

John Jones (BMS)

Terry Ernest (Glaxo)

Andrew Parker (Juniper Pharmaceuticals)