Improving the Access to Immuno-Oncology in Europe ... · formulary restrictions (44%) and lack of...

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Improving the Access to Immuno-Oncology in Europe: Barriers and Potential Solutions

Date: 31st Jan., 2017


Executive summary


Oncologists from

17EU countries

responded to

the survey

89% believed

I-O therapies

are

very important

<50% oncologists were highly

familiar with I-O and

hence only <45% prescribed them

~78% oncologists

positive about

role of combination

I-O therapies

Flexible reimbursement guidelines or cost-effectiveness decision parameters (83%) Less stringent regulatory review process (56%) Defining target population (44.4%) Clinical practice guidelines (38.9%) Training HCPs (27.8%)

Solutions

suggested to

improve access to

I-O therapies

2

>77% encountered

challenges in

prescribing

I-O therapies

83%faced challenges in

selecting

the right patient

population

100% support

early access

programs

for I-O

~39% strongly believed that

uniformity and

stratification of HTA will

improve access


Background

4© phamax AG, 2017- All Rights Reserved4

Cancer is a major healthcare concern in Europe demanding advanced treatment strategies

2.45 million 1.23 million 126 billion 75 billion

New cancercases

per year1

Deaths per year1

Euros in

total cost1

Eurosin

indirect cost1


Growing trend of the global I-O market

• I-O therapies are gaining a strong

foothold in the cancer treatment paradigm

over conventional cancer treatment due to

the following advantages3,4:

− Active immunity

− Sustained response

− Applicability in multiple indications

− Favorable adverse effect profile

• 78% of the new oncology medicines launched

between 2010 and 2014 were available within

the greater EU by 20155

Expected rise in the global I-O market (USD billion)2

34

14

1.4

2014 2019 2024


The I-O arena is expecting several drug approvals, even for second and third indications

2015: Pembrolizumab for melanoma8

2015:Nivolumab

for melanoma and NSCLC7

Atezolizumab (Approved by FDA

in March 2016, Under review by

EMA)9

2016:Nivolumab

for RCC (Extended approval)7

Ipilimumab for melanoma6

Phase IPhase IIPhase III

Registered Under investigation

Avelumab9

Tremelimumab9

Pidilizumab9

Durvalumab9


The survey objectives

7

Survey objectives

• Limited and disproportionate access to I-O therapies across Europe despite demonstrated efficacy and safety in clinical trials5,10

• A survey was conducted to explore the status of I-O therapies in European countries to understand the key hurdles that limit access and to develop solutions to overcome the same

Assess the clinical practice patterns of oncologists in prescribing or recommending I-O therapies

Understand the barriers faced by oncologists in using I-O therapies

To assess the oncologists’ awareness on the status of I-O therapies in the European countries

Encourage oncologists to propose solutions and recommendations to improve access to I-O therapies in Europe

Assess the causes of disparities in accessing cancer therapy across Europe


Methodology


• Both quantitative and qualitative data were collected

• Individual responses and cumulative analysis reports were

generated in Microsoft Excel

4Data collection

• Extensive literature search in databases such as MedLINE,

Google Scholar and various regulatory, government, and

healthcare websites to identify key topics

• Questionnaire consisted of three sections and 13 questions

overall

1Questionnaire

• Oncologists across the EU: Oncology practitioners involved in

policy shaping activities or associated with leading oncology

societies

• Dendron11 – A scientific platform by focus scientific research

center (FSRC) where stakeholders from different fields interact,

portray their activities, share knowledge and best practices

• Survey sent to 206 oncologists

2Participants

• Emails and LinkedIn

• Questionnaire was made available on a website

(www.esurveyspro.com)

• Duration: three weeks between May – June 2016

3Communication and survey platform

9

Methodology


Results


• Inequities in cancer care has led to more demands from the EEC10,13

• Only 1/3rd of the former Eastern Bloc countries have access to at least one of the new

targeted I-O5

• The Czech Republic launched a mass cancer screening program focused on the increased demand

of drugs due to the increased burden of cancer14

• Response rate: 9%

• 18 participants from Albania (AL), Austria (AT), Bosnia and

Herzegovina (BA), Croatia (HR), Czech Republic (CZ), Denmark (DK),

Italy (IT), Lithuania (LT), Poland (PL), Kosovo (RS), Portugal (PT),

Romania (RO), Slovak Republic (SK), Slovenia (SI), Switzerland

(CH), Ukraine (UA), and United Kingdom (UK)

• Most responses (66.7%) were from the emerging European

countries (EEC)12

• Most oncologists have a clinical experience of >5years and are

associated with various universities across Europe

Findings from the survey

Evidence from secondary research

11

Survey results

Developed European Countries

Emerging European Countries


PART 1: Experience with I-O therapies

The questions in this part were mainly on the basic scientific knowledge on the mechanism of action of I-O therapies, recent developments in this space, clinical experience with I-O therapies and challenges with I-O access


• There was a lag between the advancing I-O field and knowledge among

oncologists in the EU-5 and Greece in a survey15,16

− Only 35% oncologists from Europe interviewed in a survey were

well-informed on I-O

− There was a disparity in knowledge on I-O, irrespective of economic and

scientific development, policy making, education and general population health

• As per another survey, 76% of oncologists wanted to be trained or educated on cancer

immunotherapy4

• Overall, 44% of the oncologists were highly familiar

• All oncologists in the DEC were moderate to extremely familiar

• In the EEC, 33% oncologists were only slightly familiar



13

Q1. How familiar are you with the concept of I-O therapies?

33.3%

66.6%

50.0%

16.6%

33.3%

Extremely familiar

Moderately familiar

Slighty familiar

Figure 3: Knowledge about I-O




• The overall attitude towards I-O therapies was largely positive amongst various

HCPs17

− Oncologists: 48% positive

− Surgeons: 65% positive

− Nurses: 77% positive

• The overall optimism in I-O therapies is also shown by the number of new therapies getting

approved3,6,7,8

− Three I-O therapies currently approved in Europe: Ipilimumab (2011) for advanced melanoma,

Nivolumab (2015) for advanced melanoma, NSCLC, Pembrolizumab (2015) for advanced melanoma

and seeking expanded approvals

89% believe I-O is very important



14

Q2.Compared to other oncology therapy measures (chemotherapy, radiation therapy, and surgery), what is the importance of I-O therapies in improving the outcomes of patients with cancer?

Immuno-modulatory

mAbs

Activation or stimulation of

receptors expressed on the

surface of immune effector cells like tumor necrosis

factor

Inhibitors of cytotoxic T

lymphocyte-associated protein

4 (CTLA-4) receptors or their

ligands

Inhibitors of programmed cell

death 1 (PD-1) receptors or their

ligands

Actagainst factors

released in the tumor environment that

diminish the immune system ability, (e.g.

transforming growth factor β1)


• Common barriers in recommending/prescribing cancer immuno-therapies:

cost and reimbursement issues (58%), past failures in clinical trials (45%), access/

formulary restrictions (44%) and lack of long-term safety/efficacy data (40%)4,10,16-23,

• The Institute for Clinical Immuno-Oncology (ICLIO) educates clinicians and patients

about the clinical implications and benefits of I-O in day to day practice24

• The ESMO has developed clinical practice guidelines to facilitate the adaptation of I-O in

clinical practice25

Positive trend towards recommendation of I-O therapies,

however, not many prescribe them in clinical practice



15

Q3. Please indicate your clinical experience in recommending and/or prescribing following classes of I-O therapies

44.4% 44.4%

16.7%

38.9%44.4%

16.7%22.2%

50.0%

27.8%

Recommended andPrescribed

Recommended but did notprescribe

Neither recommended norprescribed

Clinical experience with I-O therapies

PD-1/PD-L1 inhibitors (nivolumab and pembrolizumab)

CTLA-4 inhibitors (lpilimumab)

Combination of PD-1 inhibitor and CTLA-4 inhibitor


• Increased familiarity with I-O therapies does not necessarily increase prescribing

− Nearly 68% of oncologists in a survey showed interest in immunotherapy;

however, only 24% had direct experience with them4

• Practice gaps might be due to the availability of I-O therapies in the country and

understanding the attributes of I-O therapies (e.g. mechanism of action, clinical efficacy and

treatment response)26

• Out of the 14 oncologists extremely or moderately familiar with

I-O therapies:

− 8 prescribed PD1/PD-L1 inhibitors (4 in DEC and 4 in EEC)

− 7 prescribed CTLA-4 inhibitors (4 in DEC and 3 in EEC)

− Only 4 prescribed combination therapies (2 in DEC and 2 in EEC)



16

Q3. Please indicate your clinical experience in recommending and/or prescribing following classes of I-O therapies

28%

36%

36%

50%

36%

14%

57%36%

7%

Recommended and prescribed

Recommended but did not prescribe

Neither Recommended nor prescribed

A) Experience with PD1/PD-L1 inhibitors B) Experience with CTLA-4 inhibitors

C) Experience with combination I-O


• Varied clinical response in trials depending on the status of the biomarker

(E.g. No clear survival benefit for pembrolizumab in the subset of patients with

EGFR mutation even in the presence of higher proportion score for PD-L127,28

• Although efficacious, these drugs are not affordable to all patients

− >50 HTA agencies exist in Europe, leading to unequal evaluation criteria and disparity in

reimbursement decisions23,29

• Oncologists need to be more aware on AEs for checkpoint inhibitors which have distinct side effects

compared to conventional chemotherapy and may occur at different time intervals30

• Conventional methods to determine MTD in clinical trials have failed to determine appropriate dosagef or I-O

drugs mandating the development of novel methods to determine the effective doses31,32

• Delayed response or pseudoprogression are specific attributes of I-O therapies that limit compliance33,34

• All oncologists from DEC and about 66% from the EEC faced

challenges

• The top three challenges were: Selecting the right patient

population (83.3%), Cost/reimbursement of the drug (50%), AE profile

of the drug (44.4%)



17

Q4. Have you experienced any barriers in recommending/prescribing I-O therapies to your patients?Q5. Please assign ranking based on the challenges that you face while recommending/prescribing I-O therapies to your patients?

77.8%

22.2%

Yes

No

Faced any challenges?

22.2%22.2%

44.4%50.0%

83.3%

Challenges with I-O therapies

Delayed response

Dosing or duration of treatment

Side-effect profile

Cost/Reimbursement

Target patient population


• Combination therapy of nivolumab + ipilimumab showed tumor reduction of

80%, and more among 53% patients with advanced melanoma35

• AEs related to combination therapy were similar in experience with monotherapy and

were reversible35

• Various I-O combinations are being investigated

− mAbs + small molecules

− mAbs + vaccines

− I-O + radiotherapy/other chemotherapy36

• Complications of combination therapy: Cumulative toxicities, extensive collaboration between pharma companies for

development and research and difficult regulatory review37,38

~78% oncologists were positive that combination therapy could

perhaps improve outcome and prolong patients’ lives



18

Q6. What do you think will be the role of combination therapy (i.e. combining two or more I-O products with different mechanisms of action?

22.2%

77.8%

Some what improve outcomeand prolong patients' lives

Will improve outcomes andprolong patients' lives

significantly

Role of combination therapy


PART 2: Status of I-O therapies in respondent’s country

This part included questions on the status of reimbursement of I-O therapies in

the respective countries and the role of the various government and public

organizations and the pharmaceutical industry in controlling the access to I-O


• Disparities in pricing and reimbursement decisions for oncology drugs across

the EU member states is widely known10

− Till 2015, while >25 innovative cancer drugs were covered under

reimbursement in Netherlands, Italy and Switzerland; the EEC such as Czech Republic

and Poland reimbursed <5 of these drugs39

− One example is Jakavi (ruxolitinib), which is reimbursed in the northern and central European

countries but not in the eastern European countries40

• Reimbursement status of I-O therapies:

− Not reimbursed in 6 countries in EEC: Romania, Slovak Republic,

Albania, Ukraine, Kosovo and Bosnia and Herzegovina

− Not reimbursed in 1 country in DEC: Portugal

− Not available in Lithuania

− Reimbursed completely or partially in DEC



20

Q7. What is the reimbursement status of I-O therapies in your country?

Reimbursement status of I-O therapies

8.3%

50.0%

25.0%

16.6% 16.6%

33.3%

50.0%

I-O therapies notavailable in the

country

Not reimbursedPartially reimbursedCompletelyreimbursed




Q8. Who plays a major role in improving access of oncology drugs in your country?

Partnership between WHO and European Society for Medical Oncology (ESMO) since 2002 driving efforts from all sectors to improve cancer care 47

BMS launched compassionate use program for Nivolumab in Ireland. It benefits 200 patients with advanced lung cancer and is free for these patients for 30 days 45,46

NICE reviews all new cancer drugs and changes in indications for existing drugs in the UK NICE negotiated with BMS to reduce the pricing for Ipilimumab 43,44

The ESMO Patient Advocates Working Group (PAWG) and Lung Cancer Europe educates HCPs and improves access 41,42

Payers

(33.3%)

Advocacy groups

(11.1%)

Examples of initiatives by variousauthorities/organizations

Organizations and bodiesinfluencing access

Pharmaceutical companies

(38.8%)

Government

(77.7%)


Part 3: Future recommendations to improve access to I-O therapies

This part included questions on suggestions from experts to improve access to I-O


• Flexible reimbursement, funds and risk sharing agreements decrease cost burden19,48-50

− Special innovation funds in Italy, CDF in UK for research and development− Ipilimumab was approved by NICE following price discounts by BMS

• Identification of target population can be easier with predictive biomarkers and companion diagnostics− Pembrolizumab was approved with companion diagnostics to determine responders

based on PD-1 expression20,21,28

• Revisions in clinical trial methods will generate credible evidence and ease the adaptation of these drugs in clinical practice− Determine biologically efficacious doses instead of MTD51

− Assess response through irRC52

• Many organizations are continuously working to educate HCPs− CIC and CIMT are working towards educating and improving clarity on I-O15

− The ECPC has also developed a framework on awareness to improve access53

Most important suggestions were the improvisation in

reimbursement guidelines or cost-effectiveness decision

parameters (83%) followed by less stringent regulatory review

process (56%) and defining target population (44.4%)



23

Q9. In your country, what could be done to improve access toI-O therapies?

Methods to improve access

27.8%27.8%

38.9%44.4%

55.6%

83.3%

Preclinical and clinical

evidence

TrainingHCPs

Clinical practice

guidelines

Defining target

population

Flexible regulatory

review

Flexible reimbursement


• More than 50 HTA agencies exist in Europe leading to inconsistencies in the evaluation criteria and disparity in access to oncology drugs23

− Differences in reimbursement decisions (from 2002-2004) on cancer drugs in Europe: England rejected reimbursement in 21.52% cases, Sweden and France rejected only 3-4%. Germany had 1% non-favorable opinions and Spain and Netherlands had none39

− Trastuzumab (Herceptin) is available widely in many countries, but it requires29

preapproval or is available to patients at out-of-pocket costs in some European countries − NICE rejected reimbursement of Imbruvica (ibrutinib) contradictory to the decision by other EU

countries such as Greece54

• Personalizing reimbursement schemes and developing precision medicines catering to a group of responders could be advantageous. E.g. Herceptin treatment coverage in UK applied only to patients showing higher degree of HER2 staining and responding better19

Seven out of the 18 (~39%) strongly believed that uniformity in

the HTA process across Europe and its further stratification will

improve access



24

Q10. Do you believe that uniformity in Health Technology Assessment (HTA) model across European region and stratification of HTA (e.g. based on those who respond compared to those who do not) will help improve the access to I-O therapies across European region?

Will uniformity and stratification of HTA improve access to I-O?

38.9%

61.1%

Strongly believe

Somewhat believe


• Early access or compassionate use programs have improved access in

Europe55

• Nivolumab was approved on compassionate grounds in Ireland. This program

benefits 200 patients who get it free for 30 days44,56

• Compassionate access programs for oncology drugs existing in Austria, Estonia, Greece,

Hungary, Italy, Lithuania, Portugal, and Spain etc. have shown positive outcomes45

All the oncologists supported early access programs for

I-O therapies



25

Q11. Should early access be provided to new I-O therapies?

Opinion on early access provision for new I-O therapies

100%

Yes


Findings from survey Evidence from secondary research

26

Q12. In your view, what efforts could be taken by the following stakeholders to improve the access to I-O therapies in your country?

• Improved reimbursement guidelines, negotiated prices of these

drugs and improved research funding are a priority for many

researchers19,48-50

• Literature suggests the lack of education and awareness on I-O.

More training and education programs should be conducted as

per HCPs4,15,16

• Developing guidelines and recommendations for target

populations, dose regimen, clinical evaluation and managing

side-effects in addition to appropriate dissemination of clinical

trial data will help better clinical adaptation20,21,30,51,52

• Early access programs and fast tracking the review process will

bring these drugs sooner to the market44,45,55,56

• Strategic planning like the framework developed by the ECPC

will help in healthcare reforms and suitable actions53


High cost and lagging reimbursement standards are the most common barriers hindering the patient access to these drugs

27

Q13. Share your experience with I-O therapies

Oncologists believe that these drugs will help reduce the burden of cancer

More funding and development of biomarkers will facilitate access

Some of the oncologists in the EEC only experienced the drugs in clinical trial settings


Conclusion


Strengths and Limitations of the survey

LimitationsStrengths

• Responses from oncologists from 17 of the 28 EU

countries with varied economical and development

status

• Five or more years of clinical experience of

the participating oncologist, indicating their expertise

• Collection of qualitative responses - suggestions and

recommendations

• Response rate of ~10%

• Only one response from each country (except Poland)

• Results not analysed to assess the statistical significance


Conclusion


Conclusion

Reasons cited by oncologists:• High price • Lack of awareness and education about the target population, dose, duration, efficacy, and safety profiles of these drug • Disparities across Europe delaying the uniform use in clinical practice

Despite the survey respondents believing that I-O may transform the standard of care in oncology, not many of them had used these therapies in clinical practice

Solutions suggested by the oncologists: • Education, awareness and appropriate dissemination of clinical trial data • Clear treatment policies • Improvisation in reimbursement guidelines

The gaps should be addressed by reducing the economic and disease burden across the various member states in Europe


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