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REAL-WORLD STUDY

PLANNING:

A SYSTEMATIC APPROACH

Finding the unexplored value of your

product.

Ingress White Paper No. 1

by Thomas Wilke

Document details:

By: [Prof. Dr. Thomas Wilke]

Date: [October-2016]

Version: [2]

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1 BACKGROUND

The value proposition/target product profile (TPP) of a pharmaceutical product is generally

based on its efficacy/safety profile as shown in clinical studies. Also, both market approval and

reimbursement discussions/decisions are based on clinical evidence. However, health

authorities as well as prescribers/insurers are increasingly aware of the fact that the real-

world-effectiveness/safety profile of a treatment may differ from its efficacy/safety profile as

shown in clinical studies. So, real-world evidence (RWE) data are getting more important for

reimbursement discussions:

Products may have benefits/disadvantages that cannot be shown in clinical studies (e.g.,

adherence/persistence benefits).

Patients in real life may differ from patients included in clinical studies.

There may also be patient subgroups that benefit more/benefit less from the new

treatment, which have not been addressed in clinical trials.

Physicians’ behavior in real life may differ from that in clinical studies.

RWE data may be the basis for pay for performance contracts between pharmaceutical

companies and health insurers and/or health authorities. Here, health authorities may

use provisional reimbursement systems, which require additional real-life data to be

collected and evaluated after a pre-defined period of time.

Also, health insurers are increasingly interested in the real-life resource use/costs

associated with treatments. Given tight financial constraints these institutions are

facing, they are willing to pay only higher “real-world prices” for new treatments if these

are associated with a higher “real-world benefit”.

The main purpose of RWE studies is to collect data about the real-world treatment of patients

and the real-world effectiveness/safety profile of specific treatments. However, many

pharmaceutical companies are still unsure about the following:

When should a company start to develop a design for a RWE study/a RWE study

strategy?

Which scientific/other requirements exist?

Which data should be used, what should be the primary/secondary endpoints, what are

the right analyses, which study design is the most appropriate one?

Will agencies, physicians and other stakeholders accept the data derived from RWE

studies?

This white paper discusses these questions in very general terms. In separate Ingress-white

papers, specific RWE study designs like medical chart reviews, claims data analyses,

prospective observational studies, patient surveys or pragmatic trials will be discussed.

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2 REAL WORLD EVIDENCE STUDIES –

DEFINITION AND STUDY TYPES

A RWE study is a scientific study analyzing the treatment of patients/patient groups or whole

populations in a real-world environment.1 So, three elements constitute a RWE study:

It is a scientific study which is based on a scientific study protocol (regularly reviewed by

a scientific steering committee as well as an ethical board), a peer-reviewed publication

of results irrespective of their conclusion, and a discussion of results in an independent

scientific steering committee. Furthermore, it is based on known guidelines for scientific

RWE studies.2

It analyzes specific patients, patient groups/subgroups or the whole population.

It analyzes patients in a real-world treatment environment meaning that

number/strength of study site/patient inclusion/exclusion criteria as well as influence of

the study protocol on physicians/patients and their behavior will be minimized.

Ingress health developed a systematic classification of RWE studies which is shown in Figure 1.

It does not show all theoretical study design options but only the ones most frequently used in

recent scientific practice. Moreover, please note that different study designs can be combined

with each other; in these cases, we talk about “hybrid” studies.

1 Sometimes, the term “HEOR studies (health economic outcomes research studies)” is also used. However, RWE studies may address purely clinical outcomes so that we prefer the term “RWE studies”. 2 See for example, www.strobe-statement.org, or ISPOR-guidelines for observational studies: www.ispor.org.

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Figure 1: RWE studies in health care: a systematic overview

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3 PLANNING OF RWE STUDIES IN THE INDUSTRY

RWE data can support a product’s value proposition in different ways:

In more epidemiological terms, they may describe current patient characteristics

(including subgroups), the current disease burden (in clinical and health-economic terms)

or the current treatment of patients including currently unmet needs. These data are

collected by explorative RWE studies. Explorative RWE data should be available at the

date of market approval; nevertheless, these data should also be based on a product’s

value proposition/TPP. So, for example, an existing medical unmet need proved by a

RWE study should ideally be associated with a positive benefit a new product might have.

In more product-related terms, data derived from comparative RWE studies prove that

there exists a RWE benefit of a specific drug. Typically, these types of studies only start

after market approval of a drug; exceptions may be possible in terms of pragmatic trials.

Because of the importance of RWE data for a product’s value proposition/TPP, but also

because some RWE studies need a substantial amount of time to be planned/conducted (from

6–9 months to several years), an early and systematic planning of a product-specific RWE study

strategy is of critical importance. It needs to be noted that, 2–3 years ahead of market

approval, the value proposition/TPP of a product may still be uncertain because of unknown

Phase 2/3 trial results. However, in these cases, the RWE strategy development should be

based on value proposition/TPP scenarios. In most cases, planning/conducting the RWE study

needs to start before rather than after the availability of final clinical study results.

The decision for/against a specific RWE study design depends on several factors; the following

are the most important:

Which outcomes/endpoints need to be analyzed?

Who are the main stakeholders that would be interested in the RWE data?

Is the planned study a more explorative RWE study (main purposes: collection of

epidemiological data, analysis of the treatment of patients and identification of unmet

medical needs) or a comparative study (main purpose: assessment of the real-world

additional benefit of a product)?

What time/budget-related constraints exist?

What is the required sample size?

What kind of biases could exist?

What is the potential benefit of the study; what are the risks? Risks may specifically exist

if a comparative RWE study has been planned despite ongoing Phase II/IIII trials; here,

RWE results may differ from Phase II/III trials.

Figure 2 describes, in ideal terms, the RWE planning process for a specific health care product.

Based on a product’s value proposition/TPP, different RWE study options (epidemiological

studies, explorative RWE studies, RWE studies comparing different treatments) need to be

evaluated. The first RWE study strategy for a product should be formulated 2–3 years before

market approval; afterwards, it should be updated on a yearly basis.

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Figure 2: Development of a RWE study strategy for a health-care product

4 SUMMARY AND CHECKLIST

RWE data derived from different types of RWE studies will play an important part in the value

proposition/TPP of future health-care products. Reimbursement agencies as well as payers are

increasingly aware of the fact that “real money” should only be paid if there is a “real-world

benefit” from a product.

Consequently, pharmaceutical companies as well as producers of other health-care products

(such as medical devices) should develop product-specific RWE study strategies as early as

possible. These may be related to pre-approval collection of epidemiological data or

explorative RWE data to show unmet medical needs, but also to post-approval comparative

RWE data proving the additional real-world benefit of the own product. Ingress health, based

on a long-year experience of RWE studies and based on access to RWE databases in many

major European countries, can support you in this process.

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Checklist: Planning of a RWE study3

Checklist point General study

planning

Shows high

scientific

quality – high

probability

that results

can be

published

Shows limited

scientific

quality – high

probability

that results

cannot be

published

1. Do you know the value proposition of

your product?

No –

please develop

the value

proposition/TPP;

if clinical data are

not available yet,

define TPP

scenarios

Yes –

continue with

planning process

2. Based on the value proposition and,

additionally, a possible general need for

epidemiological/general RWE data, did

you define the outcomes/endpoints you

are interested in? Are these

outcomes/endpoints well acknowledged

in the scientific community and do they

matter for patients?

No –

please revise your

outcome/endpoin

t planning.

Yes –

continue with the

planning process.

3. Do you know the main stakeholders

who have an interest in the RWE data

(agencies, insurers, patients,

physicians/clinical community, others)?

No –

please define top

1/2/3

stakeholders,

because different

stakeholders have

different

requirements

with regards to

RWE studies.

Yes –

continue with

planning process.

3 Based on Ingress-Health experience and www-strobe-statement.org.

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4. Did you do a thorough/systematic

literature review with regards to your

area of interest?

Yes No

5. Did you develop an a-priori study

protocol which has been discussed in a

peer-review by internal/external

experts?

Yes No

6. Did you register your study at public

sites like clinicaltrials.gov?

Yes No

7. Will the results (irrespective of their

“direction”) be published?

Yes No

8. Did you choose the best-possible

study design to derive outcome data in

the most possibly representative way?

Yes No

9. Will the study sample be

representative?

Yes No

(mainly panels

and small

sample sizes)

10. Did you define inclusion/exclusion

criteria for study centers/patients? Did

you do realistic sample size planning?

Did you plan for data gaps/lost to-follow

up patients?

Yes No

11. Are you going to use validated data

collection instruments/questionnaires?

If not, did you plan for a pre-testing and

a validation?

Yes No

12. Did you describe all

descriptive/endpoint variables in the

study protocol? Are the descriptive

variables sufficient for a detailed

sociodemographic/clinical

characterization of the study patients?

Yes No

13. Did you describe the planned

statistical analyses in the study

protocol? Are these analyses

sufficient/scientifically accepted?

Yes No

14. Did you describe the different forms

of bias in your study protocol? Did you

plan for specific measures to minimize

or, at least, to describe the bias

Yes No

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(randomized/consecutive inclusion,

non-responder analyses, scenario

analyses etc.)?

15. Did you plan to ask for an ethical

vote?

Yes No

16. Will the study be steered by a

scientific steering committee, which

may consist of members of the financing

company, the institution conducting the

study and independent experts?

Yes No

17. Will the study be conducted by an

institution which has experience/a

track-record in these kind of studies?

Yes No

5 AUTHOR

PROFESSOR THOMAS WILKE – INGRESS HEALTH PARTNER

Thomas has 14 years of experience in leading/conducting

German/international real-world evidence studies. He published several

papers about the topic of treatment-adherence and persistence. He has

a wealth of experience with respect to the German market, chart

reviews, prospective studies and patient reported outcomes. Thomas

has an above-average access to German claims data and has a well-

known reputation for conducting claims data analyses in Germany.

Thomas holds a PhD degree in Economics from the University of

Duisburg, Germany, and a Diploma degree in Economics from the

University of Duisburg. From 2001–2004 Thomas worked for the Boston Consulting Group.

Since 2004, he has worked as a professor at the University of Applied Sciences Wismar.

Furthermore, he is the head of an institute in health economics and has published in many

international journals.

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6 INGRESS HEALTH WHITE PAPERS

No.1: Thomas Wilke (2016): RWE study planning: a systematic approach

No. 2: Thomas Wilke (2016): Planning and conducting of claims data analyses: the

example of German claims data studies

No. 3: Thomas Wilke (2016): Planning and conducting pragmatic trials

No. 4: Sabrina Mueller/Thomas Wilke (2016): Treatment adherence/persistence studies:

measurement of adherence/persistence

No. 5: Sabrina Mueller/Thomas Wilke (2016): Treatment adherence/persistence studies:

measurement of causes of non-adherence

No. 6: Sabrina Mueller/Thomas Wilke (2016): Treatment adherence/persistence studies:

evaluation of the effectiveness of adherence interventions

No. 7: Bart Heeg and Maarten Postma (2016): Real world effectiveness, cost-

effectiveness and reimbursement

7 INGRESS HEALTH – OUR VISION

YOUR LANDMARK IN

HEOR SERVICES

We strongly believe that the future of health technology reimbursement in the EU will be based on

provisional reimbursement, corresponding outcomes based managed entry schemes and health

economic evaluations. This belief is based on trends in digitalization of patient outcomes in clinical

practice, the increasing number of drugs approved with conditional market authorization by EMA

and an increase in outcomes based managed entry schemes in the EU.

This shift from reimbursement to conditional reimbursement requires a change of mind-set in

industry as in the past when developing RWE studies manufacturers often did not (need to) consider

the health economic perspective. We also strongly believe that a lot of products are underutilized

because clinical trials did not show their value in terms of, e.g., reduced side effects, improved quality

of life and/or compliance.

Therefore, Ingress health, with its combined and integrated health economic and real-world evidence

expertise and passion for the field, will be successful in optimizing your products` pre- and post-

marketing value proposition.

For more information, please visit www.ingress-health.com

Evidence

Synthesis

Health

Economic

Modelling

Strategic

Market Access

& Health Policy

Communication

INGRESS HEALTH – OUR SERVICES

RWE Studies