Oxford debate: this house believes that over engineered  clinical development has inhibited innovation

Panellists: Bettina Ryll (Founder of Melanoma Patient Network Europe) Martin Landray (University of Oxford),  Mike Ryan (Medidata Solution), Sam Wadsworth (Dimension Therapeutic) -session chair Jullianne Hull

Mike Ryan
innovation -new ideas
new implies taking risks
regulatory authorities are seeing that as a risk
scientific advices -helpful but time consuming

Martin Landray
To engineer- a methodological approach to integrate elements
there is prudence in engineering in the context of CT
-is quality of clinical design, involving all stakeholders including pts and public
a critical thinking
we should stop to do things that we suppose others are expecting from us
over engineering is not the problem, but forget engineering is the problem
CTs (clinical trials) -have to integrate a critical human element,
each element can be subject of engineering
we live in imperfect world
we do need systems to review errors
''I have heard from Pharma that the new technology are inducing undetermined risks '' so better to not go for new technologies..
but..engineering is the necessity for innovation

Sam Wadsworth
looking to 20 years clinical trials experience
how we engineer clinical trials now
the number of CTs has increased
but the number of new drug approved has decreased
we are asking pts (patients) to take procedures which are not necessary (?!)
Pts and doctors are finding impossible to run CTs
Interactions with specific IT tools within CTs is difficult for doctors/investigators (!)


Bettina Ryll
Not true-the above assertion confounds symptoms with the cause
Innovation in health improves clinical efficacy, cost effectiveness, pharmacovigilance,
Innovation is there to bring timely access to the good drugs to the patients.

Innovation has to be accessible in the right time and for all! ..
Clinical trials with a bad design  -from the day they start everybody knows that half of our people would die on inferior comparators: this has to stop and we have to ask ourself for what and for whom we are doing this, what are our real goals.
Innovation has to be sustainable


Regulators comments
The most problems come not for engineering the trials but from designing bad protocols
We have to ask yourself if what we do is meaningful for the research -engineering just for engineering is not the way to go

Statistician view -poor quality of clinical trials in phase II compromises in fact the entire protocol design -should really learn from phase II in order to design properly phase III


''Just think!...'' (Martin Landray)

IMI2 project ADAPT SMART

Friday, 14.00- 15.30

Session to give an update on ADAPT SMART is an enabling platform for the coordination of MAPPS (Medicines Adaptive Pathways to Patients ) previously called Adaptive LicensingMPA

http://adaptsmart.eu

Definition

MAPPS are a concept that, based on scientific innovation, procide timely access to specific medicines, with a potential to address unmet need(s) in a specific, well-defined patient populations in a sustainable way.

ADAPT SMART is a support tool to MAPPS.

Ad Schuurman- Dutch payer

Very interesting to listen to a payer's perspective on MAPPS and the specific issues a payer faces. Volume control

Adaptive show-stoppers

- prevent decline in quality of evidence
- cost control
- want to restrict MAPPS to special cases:

• patients who cannot wait
• deteriorate irreversibly or die
• urgent public health protection
• major improvement expected

realistic exit strategy.

Start-ups with regulatory and industry- small biotech companies potential to develop treatments - Session 0104

How can idea from academia can be better translated to novel treatment options

Important to give a chance to thesmall companies- they are the ones developing new compounds/drugs that are later bought by Big Pharma.

Small companies challenges (finances and innovation)
New treatments paradigms

Andreas Schmidt CEO AYOXXA Biosystems Germany (35 people)
interest in huge topics
medical decision based on proteomics
company interested in genomics and proteomics
ambition to base clinical trials on proteomics
access to clinical samples
to identify which patients are going to respond (biomarkers)

Sam Wadsworth, Dimension Therapeutic
2013 -company was funded
partnership with big companies (e g. Bayer)
partnership with academics
partnership is bringing money and/or validation
clinical trials- small trials (phase I, II)
gene therapy -challenge for a small companies, few receive positive recommendation by EMA
focus on one topic is better

Melanie Carr, EMA -European Medicine Agency
why is important to support small companies
90% -commercialised by big pharma
no product commercialised by academia
but the true is that less than half health technologies are coming  from big companies
incentives
Innovation Task Force -early guidance how companies can be embarked in development programs
Difficult to comply with EU regulations
Plan Management Risks has to be included in the projects of small companies

Dr. . Kalkbrenner,  Boehringer Ingelheim
Company Bayer -life science companies -pharma component
Grants4Apps, funding and supporting small companies (?)

Adaptive Pathways and conditional approval

Thursday, 16.00

Francois Houyez

Valid point
differences in compassionate usage programs between countries effectively create disparity in access across Europe, even between countries with similarly efficient healthcare systems. Francois mentioned 4 years- but need to verify in which setting.


Advantages

Disadvantages

Tomas Salmonson

Comment-
conditional earlier approval can make it difficult to recruit for the registration trials. And I wonder why that is!!! Guess the trial design is not attractive for patients? 

Susan Forda

comparison between US and EU approvals of innovative therapies-

for indications that let to special pathways for both sides.

US has more fast access designations than the EU

US takes less time to approval than EU

BUT less post-marketing studies in the EU than in the US. 


And- faster approval does not lead to more withdrawls
So far, no withdrawl after accelerated approval/ conditional approval. In the US, none on break-through and one withdrawl for a priority review!



Niklas Hedberg, TLV

used a great analogy of a stream to describe how new therapies come down after a damm (the regulators) and how the downstream tries to cope.


Hans-Georg Eichler

Use of real-world data in the Adaptive Pathways pilots

and again the very valid point that IF registries, they need to have the right quality

Discussion
interesting enough, this is an adaptive pathway discussion and the first comment goes directly to drug prices. Niklas made the point that there is the worry that adaptive licensing effectively out-sources part of the development cost to society (instead of the company paying for it). 
Very valid point by Tomas Salmonson- what is the point if we approve drugs for a wide indication (like HepC) but then only give them to a few patients because of price? That makes no sense from a public health perspective!

Niklas, TLV, suggestion to discuss conditions with a consortium of different Pharma working in that space to discuss the specific challenges and needs way before a single products hits the market.

Why involve patients in Rare Disease Research

The Genetic Alliance

Patient voice

Reasoning 
Rare disease condition
understand the condition
define the question
plan the strategy
recruit the volunteers
validate the outcomes
help secure implementation

we move in a era of full  scientific advances
with  advance of personalised medicine-small and careful defined populations are much more likely to get benefits from the drug that  is administered

Clinical data is based on number-are important-but what that numbers means in real life?
Numerical changes have impact of quality of life for pts* and their families

we have NO interest in poor quality science
Involvement in judging research proposal
is this a relevant question for us?
working with James Lind Alliance-involvement of pts pushed-up the quality of research

How pts can help?

Research Priority Settings
Donors -have interest to see where the money goes
Registries
Recruitment
Realism -tangible deliverable related to our experience, to things that matter t us
Sustainability
Results -Eurogentest-what patients want to know, but not what clinicians think is the ought to go

Citizen jury
Close relationship with the pts and their families

About EUPATI- expertise is needed; skills to have to conversation with regulators, clinicians, payers..etc.

''We are not experts in everything but neither are you!''
We can tell you what is important for us, but not how to use the statistical tools -this is the job you are paid to do..

pts*-patients

Innovative ways of involving patients in RD

The industry view 

Tony Hoos, Amgen

We all serve patients& society (?)

Patient -consumer/Peer
Patient involvement consideration

strategic document
strategic purpose
R-D. Life cycle (R_D, Life cycle management)

Where there opportunities for patients involvement
insert slide (red)
meaningful pts involvement -which stages

enhance pts access
embrace pts centric healthcare
facilitate coordination  and integration of pts data -un-bias info
acquire and develop talent
do we have the right talent to interact with pts organisation?

evolution of pts engagement
number of pts involved increased
FDA strategic priorities

Shall HTA depend on RCT (randomised controlled trilas) or RWD (real world data) or both?

Thursday, 14.00- 15.30

Chris Chinn, Head of Real World Investigations, Sanofi and GetReal 



outcome- comparator- patients- intervention

Outcomes are affected by patient behaviour, physician behaviour and the healthcare system and not all of these can be measured in a clinical trial.

Current- 

RCT to inform clinical effectiveness
Observational study for budget impact

Now
integrate both data sets using network meta analysis (NESTA involved in this- worth checking out!)


TWiCS- run a randomised trial within an observational cohort, using the registry as a whole as control. group in Manchester, failed to capture name


Discussion-

In the end, patients make personal risk- benefit assessments: are the benefits of the drug out-weighing the risks? That then affects the effectiveness of the treatment.

So in my mind, we would have to worry less about the gap between effectiveness (drug in the real world) and efficacy (drug in a clinical trial) if we paid more to those personal-risk assessments EARLY ON.

PAES- Post-Authorisation Efficacy Studies - applying RCT standards to RWD

Giovanni Tafuri, EMA


uncertainties about drug efficacy stem from:

• (sub-)populations studies
• endpoints
• long term use of a product
• co-treatment with other products
• real life usage
• change in the understanding of a disease or a drug
• change in scientific factors for previous efficacy 

choice of study design depends on the need and can include:

• randomised trials
• non-randomised trials
• explanatory trials
• pragmatic trials
• observational trials

Data sources-

1. can be collected for the purpose: clinical trials

2. analyze existing data- e.g. registries, electronic Health records



Importance to agree on a design prior to starting and the place of real world data during the life cycle of the product: worth noting the registries.

The PARENT joint action patient registry initiative: purpose to reduce duplication between registries. Worth looking up!


And important- who sets the standards for the registries?


Comment of Guido Rasi, EMA- we need to define what real world data means. 

Conducting HTA using RWD (real world data)

Francois Meyer, HAS

Achievements of EUnetHTA

1. Database EVIDENT - HTA bodies can find out what others have collected

2.

3. position papers on research recommendations

• how to best formulate research recommendations
• how to decide on the appropriate study design to answer those questions

4. core protocol pilot for AEG (additional evidence generation)

first pilot of a joint HTA process

would be worth looking this up- and see whether we agree or not

Discussion

Comment from Chris Chin
When to set up a registry? At launch of a product is too late- one should start earlier, so that there is a good quality registry in place at launch and one can focus on answering questions!

Luca Pani, AIFA
differential MEA in place in Italy with the existing registry - a different MEA (management entry agreement) for every indication of the same drug
but
it has been a major investment for the healthcare system to have a registry of this granularity and quality standards but he thinks it has paid of!

What are the challenges of conducting pragmatic trials (PCTs)?

Iris Goetz

Global Health Outcomes

Eli Lilly, UK

Get REAL PRoject 
IMI Work Package WP3 

Focus on randomisation

RCT in real world !

Aim

consequences of design

consequences of design choice

key activities

ensure feasibility while keeping validity

literature review

practical solutions

toolbox

stakeholders interviews

Definition of pragmatic trials -various- 

mainly  trials comparing different health interventions -effectiveness

Comparing RCT (randomised clinical trials) with PCT (pragmatic clinical trials)

Which design criteria important in designing a PCT?

Comparison of Treatments Arms -questions to be answered

Baseline-do we need wash-out period?

link hospital data with the GP data

How well can the pre-launch study design provide information on the relative effectiveness of a new medicine 

François Mayer

HAS France 

Assessment model of drugs in (HTA) -

study conducted in France

SMR- service medical rendu 

Drug eligibility reimbursement

Added therapeutic benefit 

5 ASMR levels model

major

important 

minor

no improvement 

post launch of observational studies

OS results are considered 

comparable

un-interpretable

not comparable

Reassessment SMR/ASMR

Clinical effectiveness

Safety

Quality of life 

Improvement of is quite rare post launch! 

Many cases when results do not confirm what was observed during RCTs!

Real World Evidence in Drug Development

Chris Chinn -Sanofi 

Acceptability of real world evidence
R-D decision anticipate the HTA decision

phase 3 optimise
phase 3b supplement
conditional licensing
conditional access
phase IV
''commit'

Would we accept the uncertain for a period of time while waiting for the study to complete?

R-D decision
to what extend  generate the study plan generate data for effectiveness?
the concern of pharma/producer of health technology : will the study be accepted by regulators and HTA agencies?

IMI Get real Work Packages
acceptability
understading the efficacy-effectiveness gap
clinical design barriers
best practices-predictive models
practical feasibility

Questions asked at workshop of Pragmatic Design of Clinical Trials

Get Real deliverables

Raising acceptability

The needs of the payers shape the evidence for market access

Thursday, 11.00- 12.30

How Companies fit all evidence requirements into one development plan

How all evidence requirements (regulators, HTA, payers) fits into one development plan for one product- first talk. So this decides what type of clinical trials we get to see!

Problem is: requirements for regulatory approval- EMA- are different from what HTA bodies (like NICE/ UK or ZIN/ NL) or payers ( like health insurers) want. 

It has happened that HTAs rejected regulatory assessment = no access despite drug is approved.

Marlene Gyldmark/ Roche is speaking how the company attempts to integrate how the generate evidence that fulfils BOTH regulatory AND HTA requirements. 
Personally, I would always assumed that this was done already...? Why would you want to risk to invest so much and then get stuck so late in the process? But then I'm sure there is something I missed- in any case, NOT good for patients either....

Trying to come up with ONE strategy to fulfil differing HTA requirements- referring to the HTA Core Model ® from EUnetHTA- so it is good to see that harmonisation efforts on the HTA side are showing effect! 

Interesting how to combine different types of evidence: clinical trials, real world data and modelling to have an integrated evidence plan. The challenge is integrating three different evidence needs from regulatory, HTA and medical

How will payers react to the future of Drug Development?

Steffen Thirstrup, UK

Health care systems are now the main customers for regulatory and HTA evaluation 

RWD has replaced clinical trials as the main source for evidence about effectiveness (and safety)

problem- regulators and HTA haven't developed methods how to use this RWD for evidence-generation

Development of early HTA advice: 
competition among reimbursement and payer agencies, so where to turn?
Hopefully, EUnetHTA will change some of that!!

SEED Consortium (14 EU HTA agencies, coordinated by HAS)- early dialogue processes- worth looking up

GetREAL 


Very nice summary slide on HTA collaboration :-) 

problem remains that health and finances are under national authority.

Interesting suggestion to have conditional reimbursement- something worth thinking about!

How can a joint regulatory-HTA scientific advice process help deliver the right evidence?

Jane Moseley, EMA

Interesting case study from joint advice: large company, small indication, unmet need-

original recommendation was a placebo-controlled study designed.

After multi-stakeholder discussion including EMA, 4 HTA bodies, clinicians, patients and the Pharma let to the adaptation of a different design.

Interview with Jane Moseley on the topic

- Very valid comments
- shared EMA-HTA advice is in patients' interest
- advice needs to happen EARLY to be efficient and guidelines are not sufficient

And yet another case where there is a willingness to alter trial design to a more patient-friendly design: no placebo as the indication was small with high unmet need 'to reduce patient suffering'. 

I can't get my head around that argument- in a large indication with high unmet need (where we can get the data), we insist in placebos. In a small indication with high unmet need (where we can't get the data), we are worried about the patient impact. 
That means that the suffering of a patient with in a small indication is worse than the one of a patient with a large indication. This makes no sense whatsoever!!!! 



Comment in the discussion-

we should not only discuss market entry but also market exit strategies

Opening Plenary Session INNovation- do you win by being IN?

Discussion about the Value of Innovation and impact on our society!


1. How global innovation 
will be financially sustained 
for future decades

Discussants

Mads Krogsgaard Thomson - Novo Nordisk
Sarah Garner- NICE

Mads makes the argument that YES- innovation is a long-lasting process and happens in waves and with newer therapies coming up in richer countries, previous waves spread to less wealthy countries so that over time, global society profits.

Sarah Garner is making a long list of very valid points - I will get her notes as it's too much to listen and type!!


2 .True cost of innovation

Karl Broich- president BfArM
Nicola Bedlington, EPF

Nicola makes the point that innovation has to be sustainable. Meaningful patient engagement requires educational resources for patients! 


3. Use of patient data for innovation, challenges and ethical dilemmas.

Ritva Halila, ministry of social affairs and health, Finland
Kemal Malik, head of innovation, Bayer 

Kemal on the role of patient in clinical development: 
'patient engagement seen as pre-marketing exercise' 
'lack of clear of evidence of patient engagement'
a key future trend will be to show real life outcomes

Regulatory Town Hall meeting

Wednesday, 5th April

A town hall meeting on the topic of the Network Strategy 2020. 

DIA2016

DIA Europe is taking place in Hamburg 6- 8th April 2016 and we have just arrived! 

Violeta and Bettina