Geriatric RegulationCan we do without?

A critical review

Evi Charitou

1 November 2018

Presentation Outline

2

Introduction

Paediatric Regulation – lessons learned

EMA’s Geriatric Medication Strategy

Geriatric drug development – a critical analysis

Conclusions

An ageing population

3

Source: Eurostat

With the increase of the aging population, new age groups are being formed:

• Elderly (65-74Y)

• Very elderly (>75Y)

An ageing population in need of medication

4

Diseases either specific to the elderly (e.g. Alzheimer’s) or with higher

incidence with increasing age (e.g. Heart disease)

More patients with multimorbidity Polypharmacy

Source: Moriarty et al., BMJ open 2015

Elderly reported to consume nearly one-third of all medications (Source: Avorn, Health Affairs (Millwood) 1995)

Drug development not in line with geriatric

representation

5

Source: Talarico et al (FDA), Journal of clinical oncology 2004

Analysis has shown that in several cases elderly are under-represented in CTs,

including diseases affecting mainly geriatric patients

Cancer

Geriatric population: special considerations

6

Different Pharmacokinetics (PK)

Frailty

Multimorbidity Co-medication (polypharmacy)

Difficulty in self-administration

Adherence to the prescription

Medication errors

Heterogeneity,

no linear age - health status relationship

7

Dedicated studies / studies with adequate representation required to address:

• dose adjustments

• new AEs

• drug-drug interactions

• ease of use

ICH E7 (Studies in support of special populations: Geriatrics)

• guidance on minimum inclusion of geriatric patients in CTs

• type of studies to ensure the safe use

However, ICH E7

• only a general recommendation (at least 100 elderly included in the CTs)

• not adapted to each disease & disease representation

Geriatric population: special considerations Drug developers

Challenges with geriatric patients inclusion in CTs

8

Difficulties with

• Patient recruitment

• Patient retention

Due to

• Logistics

• Fear of potential AEs /

misunderstanding of potential benefits

• Physicians facing ethical dilemmas

• Strict inclusion / exclusion criteria

9

Very heterogeneous population

How do you define the age groups for this population?

• Not a linear correlation between age and health issues

• Frailty to define groups? Geriatric research & active discussion on a

uniform definition of frailty

In February 2018 EMA published a reflection paper on how to characterise

the baseline frailty status of older patients enrolled in clinical trials other than

by their age

Challenges with geriatric patients inclusion in CTs

10

How to address the balance between adequate

research in the geriatric population and the

safe/efficient use of medicine by this population?

Look into recent knowledge gained from another

“special group” of patients: Children

Parallels geriatric & paediatric population

11

Children

CT-“ignored population”

Heterogenous group across ages

Medication might require special

pharmaceutical development

Optimal dose might be different

than the one for adults

Ethical issues associated with

CTs

Elderly

CT-“ignored population”

Heterogenous group across ages

Medication might require special

pharmaceutical development

Optimal dose might be different

that the one for young(er) adults

Ethical issues in CTs

Paediatric Regulation (PR) / Lessons learned

12

PR was introduced in 2007

Establishment of the Paediatric Committee (PDCO) determine the studies that

companies must carry out on children as part of paediatric investigation plans (PIPs)

Set out a number of incentives, to ensure compliance with agreed PIPs

Positive impact

• Increase in medicines developed for children

• Increase in development of paediatric formulations

• Increase in information on the efficacy/safety of medication for children

10 year evaluation

13

However,

Challenges

• Development of paediatric medication follows the one for adults

• Mismatch between adult disease burden and medical need in children

• For some indications very difficult to recruit children, resulting in delays / non-

compliance issues

• Difficulty to recruit neonates/premature

• The additive burden of the paediatric requirements may influence development

priorities

Paediatric Regulation (PR) / Lessons learned

Could we have achieved the same without

the PR?

14

According to EMA’s 10-year report,

• “The PR has led to successful changes in the development and authorisation

process of medicines and brought about a major increase in awareness of

paediatric needs in regulatory interactions.”

• “The EU PR contains a system of obligations and rewards which has proven

to be effective in stimulating paediatric development of medicines.”

However, the challenges associated with the PR has made EMA

reluctant into supporting a GR as well

EMA’s geriatric strategy

15 Source: EMA Geriatric medicines strategy

For the geriatric medicine, EMA has introduced a different approach based on

existing tools (February 2011)

EMA’s geriatric strategyGoals

16

Medicines used by geriatric patients must

be of high quality, and appropriately

researched and evaluated for use in

this population.

Improve the availability of

information on the use of medicines for

older people

Informed

prescription

Evidence based

medicine

Source: EMA Geriatric medicines strategy

To address the needs of the elderly during the

development, approval and use of medicines.

EMA’s geriatric strategy Tools

17 Source: EMA Geriatric medicines strategy

Medicines Evaluation

• Peer Review comments

• Updated AR template

(+RMP template)

Medicines Development

• Scientific Advice (and Innovation Task Force)

• Identification of validated tools (e.g. to assess

frailty)

• Guideline drafting and revision

Product Information & EPAR

• SmPC/PL and EPAR to reflect data

appropriately

CHMP Advisory

Group on Geriatrics

Interaction with

stakeholders

Geriatric Strategy

Geriatric drug development in the

light of EMA’s geriatric strategy; a

critical analysis

18

19

• Assessment of 42 medication approved by CP (Article 8.3 submissions)

Methodology

• Medication approved >2013 vs <2011

• 12 Therapeutic areas chosen:

• Typical geriatric: Alzheimer’s,

Parkinson’s

• Not typical geriatric: Diabetes type II,

Hypertension, Congestive Heart Failure ,

Rheumatoid Arthritis, Glaucoma, COPD,

Lung Cancer, Colorectal Cancer, Breast

Cancer, Prostate Cancer, Osteoporosis –

Menopause associated conditions

Therapeutic Area

# med

<2011

# med

>2013

COPD 1 1

CHF 2 1

Glaucoma 2 2

Hypertension 2 2

RA 3 3

Type II Diabetes 2 2

Osteoporosis /

Menopause-

associated 1 2

Breast cancer 1 2

Colorectal cancer 1 1

Lung cancer 2 2

Prostate cancer 1 1

Parkinson’s 2 3

Alzheimer’s 1 0Excluded from

further analysis

Total 20 22

• Excluded Alzheimer’s because no

medication intended to treat approved after

EMA’s geriatric strategy came to place

(*only 2 diagnostic agents)

20

Methodology

• Collect information from:

• Appropriate SmPC sections

• EPAR

• Research questions:

1. Is elderly representation in CTs connected to epidemiology of disease in

this population?

2. Is adequate information provided on safety in older population

(multimorbidity, polypharmacy, AEs)?

3. Are special measures taken for the ease of medicine administration by

the elderly patients?

-1,5

-1

-0,5

0

0,5

1

1,5

<2011 >2013

Elderly representation in CTs / Disease area

COPD Glaucoma Hypertension CHF

Type II Diabetes RA Lung cancer Colorectal cancer

Breast cancer Prostate cancer Parkinson

Research Question 1:

Elderly representation in CTs

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Under-representation

Balanced representation

Compare % of population >65Y with disease and % of total patients included in CTs >65Y

Score 1: balanced representation (%elderly included ≥ %elderly affected)

-1: under-representation of the elderly population (%elderly included < %elderly affected)

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Research Question 2:

Safety elderly

Specific ADRs identified in geriatric patients

ADRs more often reported in geriatric patients

Related to

• PK changes (altered distribution, renal / liver failure)

• Multimorbidity

• Polypharmacy

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Safety Elderly

4.2 Posology

Dosing information for elderly in 42

medications studied.

Age groups defined as “eldelry” or more

specifically per age

(> 65Y or 65-74Y / >75Y / >85Y)

Co-morbidities (renal/liver failure)

Dosing information for patients with renal/liver

failure in 42 medications studied.

In some cases, close to these morbidities, other,

relevant disease was also studied

Other disease:

diabetes/obesity/CV disease/ hypertension

9

8

2

0

1

5

8 8

1

00

1

2

3

4

5

6

7

8

9

10

Elderly >65Y 65-74Y / >75 >85Y NO info

# o

f m

edic

atio

n

SmPC Section 4.2

<2011 >2013

4

11

5

22

15

5

1

0

2

4

6

8

10

12

14

16

Renal failure Hepatic&renalfailure

No studies &other diesease

# o

f m

edic

atit

ion

Studies on multimorbidity

<2011 >2013

16

4

19

3

0

4

8

12

16

20

D-D Interaction studies NO D-D interaction studies

# o

f m

edic

atio

n

SmPC Section 4.5

<2011 >2013

24

Safety Elderly

4.5 Interaction with other medicinal products 4.4 Special warnings & precautions

7

13

3

19

0

4

8

12

16

20

Info on eldelry NO Info on elderly

# o

f m

edic

atio

n

SmPC Section 4.4

<2011 >2013

25

Safety Elderly

4.8 Undesirable events

6

14

2

20

0

5

10

15

20

25

Info on elderly NO info on elderly

# o

f m

edic

atio

n

SmPC Section 4.8

<2011 >2013

26

Difficulty to self-administer (related to frailty, other health issues)

Specifically for solid oral dosage forms, about 1/3 of older patients have exhibited

problems with swallowing (Source: Stegemann, Int.J.Pharm 2012)

In August 2017 EMA published for a six-month public consultation a reflection

paper on how medicine developers can better address the needs of older people,

for example by considering appropriate routes of administration and dosage forms,

dosing frequency, excipients, container closure systems, devices and technologies,

and user instructions in the product information

Research Question 3:

Geriatric formulation

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Geriatric formulation

No specific geriatric formulation developed in any of the products reviewed

Only in the case of solid tablets, in some cases there was a provision for patients

with difficulties swallowing the tablets

2

4 4

3

5

3

0

1

2

3

4

5

6

Tablet can becrushed, dispersed

etc

Tablet must be takenintact

No info

# o

f m

edic

atio

n

Provision if tablet cannot be swallowed

<2011 >2013

Alternative approaches, other than CTs

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Population Pharmacokinetics (PopPK)

• Collect few PK samples from many patients in CT mathematical models to analyse data

• 24 out of the 42 medication studied had used PopPK, to assess the PK in elderly

(11/20 <2011 and 13/22 >2013)

Pharmacokinetics/Pharmacodynamics (PK/PD) Modelling

• Effect intensity time course in response to a drug dose

• 9 out of the 42 medication studied had used PK/PD Modelling

(4/20 <2011 and 5/22 >2013)

Research into other alternative approaches, ongoing

EMA’s Geriatric Strategy based on the strengthening of existing tools

In the 5 years since the introduction of the Strategy not much change

can be observed in geriatric drug development

In the majority of cases the relevant age groups are under-

represented

Not more research in the safe use of medicine by the elderly

No research in pharmaceutical development for the frail

Summary

Conclusion

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Not an impact of EMA’s strategy

• In most cases, drug developers perform the minimum required

studies in geriatric patients to simply comply with ICH E7

• Not many innovative solutions appeared, to support geriatric drug

development

LIMITATIONS of the analysis

• EMA’s geriatric strategy is in place for 5 years

• Direct comparison on data from <2011 and >2013 is based on a small sample size

Recommendations

31

Drug developers need to intensify their efforts to meet

the goals of EMA’s Geriatric Strategy:

• by using more tools out of EMA’s toolbox

• by thinking along with the regulators into meeting the elderly needs

to avoid the introduction of a Geriatric Regulation…

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