Mpne 2015 conference material

Conference materials

THE RISK OF NOT TAKING RISKS IN MELANOMA

MPNE 2015 ADVISORY BOARD SATURDAY- 25TH APRIL ‘THE RISK OF NOT TAKING RISKS IN MELANOMA’ Session 1- Risk 9.00- 10.30am 1.1 How much evidence and how much risk? Introduction to the conference Bettina Ryll, MPNE 1.2 The risk in Melanoma Stage IV Lori Murdoch, Melanoma Network UK and Stage IV Melanoma patient, UK 1.3 New hopes and new risks- the oncologist’s perspective on innovative medicines in Melanoma. Bart Neyns, University Hospital Brussels, Belgium 1.4 Who should decide which risk to take? Pan Pantziarka, The George Pantziarka TP53 Trust, UK

1.2 The Risk in Melanoma Stage IV- the patient perspective Lori Murdoch, Melanoma Network UK founder, patient advocate and Stage IV Melanoma patient, UK

‘I am a 59 year old mother of three beautiful, healthy, happy, successful children and a retired solicitor and university law lecturer. I paint seascapes and vibrant abstracts and I am a passionate sailor. I am the owner of a small black and white terrier who hates everyone save for her family and friends whom she totally adores. I am fortunate enough to live on a beautiful river where I keep my small yacht, Panache and I love to sail the south coast of England and meander up the many gorgeous rivers in my bilge keeler. I am also a stage IV melanoma patient with a life expectancy of a few months. Over the summer of 2013 and 2014 I sailed around the UK in an old leaky wooden yacht to raise awareness of mm and money for local charities. I recently set up Melanoma Network UK on Facebook to disseminate information about melanoma and I am a keen patient advocate.’ Watch Lori’s story

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Lori Murdock MPNE 2015

LORI MURDOCK BRUSSELS CONFERENCE 2015

The risk of not taking risks in melanoma treatment

For those of you that don't know me my name is Lori and I'm a mother of 3, a retired solicitor and law lecturer and I'm passionate about sailing and painting seascapes and colourful abstracts. I am a stage IV melanoma patient

My starting point on taking risks in my treatment plan is this: left unchallenged I know, 100%, that my melanoma will kill me, therefore all other decisions flow from this one reference point.

As my disease has progressed so my level of risk taking has increased-to the point where before treatment I understand that it could cause me harm or even, in an extreme reaction be fatal

But, I reason to myself, the treatment COULD cause me harm but I know 100% my melanoma will kill me….the benefit I receive outweighs the risk….

In July 2012 when I was given 9 months to live as a newly diagnosed stage IV patient I knew that if I didn’t take risks, I would die.

So, I know all about the risk of not taking risks in melanoma treatment.

In fact the very first trial I ever signed up to nearly killed me. At the time I was a stage III patient and it was post a groin node dissection. The trial was Avastin and although the potential side effects read like a horror story – they always do – I was feeling fit, healthy and hardy and thought that I would ‘probably be ok’.

As patients we are always given information prior to a trial of:-

• The type and extent of the treatment • The trial benefits and disadvantages


• Any significant risks or side effects

Well I had balanced up the benefits and disadvantages. A benefit was to hopefully ‘knock out’ – I’m sure that’s not a medical term! any odd melanoma cells still lurking around in my body and I’ll read you just a ‘taster’ of the

Side Effects of Avastin:

High blood pressure

Blood clots which may include:

Numbness or tingling in your fingers and toes or swelling, pain redness or warmth in arm or leg

Chest pains

Difficulty speaking or moving

changes in vision

Increased risk of bleeding or

Dry or flaky skin or inflamed skin and a change in skin colour.

So 10 months into the 12 month trial out of the blue I took to my bed early one night as I didn’t feel well. I was advised to regularly check my blood pressure which I did - my blood pressure was 277/147! That, my PC informed me was the stroke, heart attack level! Little wonder hypertension is referred to as the ‘silent killer!’.

I had to change the battery in my blood pressure monitor machine as I didn’t believe the reading! Unfortunately when I arrived in A & E the doctor confirmed that it was true and therefore I was off the trial. As a direct result of the trial I went from being a patient presenting with BP on the low side to having to control my BP with daily drugs to this day.

Patients are prepared to take risks on trials for a variety of reasons, for my part I sign up because

• I perceive some benefit – there must be a ‘carrot’ in there somewhere • I understand the risks but I am willing to accept them on the basis that the ‘perceived benefit’ may out weigh any potential risk


• I enter into a contract with a drug company to form a partnership – the drug companies cannot conduct clinical trials without patients – we are a vital part of what they do. They wouldn’t function without us.

• I enter into a contract as I want to effect change, I invest my time, my money, my energy and take the risks of damage to my health to further the cause – I want to see the novel drugs that look so promising in laboratories tried and tested and if of benefit, licensed and made available to patients.

• I invest time and effort because I want science to succeed in finding a cure for melanoma and I want to be engaged with that process. What is the reality of this relationship that I refer to as a ‘partnership’ between myself and the drug companies that I have engaged with and continue to engage with? Have I ever received any feedback from a drug company, no Have they ever made contact with me to inform me that the results of the trial that I have participated in has been published so I know where to find them, no The scientists and the trial designers need us brave souls that read the significant risks and go ahead anyway to test the efficacy and safety of drugs but then I find I am offered trials with my ‘carrot drug’, the one I have researched, waited patiently for to come along, read promising reports about, the drug I pray that I shall be allocated to, along side a drug known to be of none or little use. Not a fair exchange. If I'm willing to take the risks of clinical trials I want to engage with ethical trials. The reality is that we are distant, arm’s length, anonymous statistics even at the conclusion of the trial – I have no problem with that distance during the conduct of the trial, it is right and proper, but after the conclusion of the trial? No, I would prefer data, information, over anonymity every time. So I must search around the internet to find out the results of clinical trials I've participated in. I have endured the physical discomforts of a trial, the risks, effort and commitment and invested my own money travelling from one side of the country to the other yet received nothing at its conclusion. I want to see results published, positive or negative and transparency in reporting.


It was recently suggested that if part of the funding for a clinical trial was withheld until the research team had concluded and written to the patients that were involved on the trial things may change – unfortunately money does oil the wheels. If we continue to be anonymous statistics my view is that we will never see trial design change for our benefit and Bettina will never receive a YES to her question, would YOU go on this trial or want a member of your family to? Unfortunately for 30 years there were hardly any developments in the world of melanoma so trials must have been relatively thin on the ground. Now there are so many it’s hard to keep up. Clinical trials are now, for the most part, the way a melanoma patient is treated, yes they are clinical trials but we know access to them is vital if we want to stay alive. Someone here said last year that she thought all stage IV patients didn’t survive that long – well historically we don’t! I am alive because of the novel drugs. As the drug companies have slipped into this fast stream of novel drug production I think they have forgotten to update their attitude to the new breed of patients out there. We are better informed than at any time and if I am prepared and willing to take the risks of a clinical trial then as a vital part of the dynamic I would expect ethical trials, not be left praying I am allocated to the active drug arm.

In the UK my view is, if you are not prepared to take risks, if you are not prepared to travel to a specialist melanoma centre, if you are not prepared to give over time and effort to research clinical trials if licensed drugs are exhausted you will be out in the treatment wilderness. That's a heavy burden on sick patients.

I want oncologists to allow me to take risks, if I feel, having looked at the situation that's what I need to do. Being terminally ill focuses the mind. Im fortunate enough to be surrounded by an amazing team of doctors and I'm very grateful to them and the scientists that have developed the fantastic drugs that have been keeping me alive. Where possible I do try to give back. I recently had a bronchoscopy during my first bout of pneumonitis and I agreed to have samples taken from my lungs to further research, it should be a case of give and take…..although it was a very unpleasant experience!!!

At the conclusion of the Avastin trial I was diagnosed as stage IV so the trial for me had failed. Next treatment was dacarbazine followed by ipilimumab or Yervoy, which despite the significant risks and side effects explained to me I tolerated well.


Some side affect of Yervoy are:

Colitis

Hepatitis

Inflammation of the skin

Inflammation of the nerves that can lead to paralysis

Inflammation of the hormone glands esp the pituitary, adrenal and thyroid glands

Just for a taste. You need to be brave to enter clinical trials.

As they were read out I saw my children's faces turn pale!

What I did experience was tiredness, hay fever type symptoms in the morning and evening and rashes but nothing compared to some patients I know who have experienced some of the more serious side effects, and they are not uncommon.

I did experience some success as a result of yervoy but it was short-lived and I experienced a lean period when for 12 months I could not secure another clinical trial. This agonizing period of my life has been documented in a video called ‘Patient on trial - what clinical trial participation really is like’ made by the wonderful film maker Alexandra Sorgenight so do find it on the MPNE website if you haven't seen it.

In August of last year I began Keytruda as part of Merck’s Open Access Programme. As I had very few side effects on Yervoy I was horribly optimistic that this widely considered less toxic immunotherapy would be a ‘walk in the park’. How wrong I was!

Some of the risks include:

Lung problems - pneumonitis


Colitis

Hepatitis

Hormone gland problems

Kidney problems

Problems in other organs

The first scan after 3 IVs appeared nothing short of a miracle. Looking at the screen and searching for tumours that I knew were there previously but had since almost disappeared was like a dream come true.

Then a bolt out the blue, I had pneumonitis, level 2 - level 3 and you are off the trial - off the programme altogether.

I was warned that more treatment could trigger a more serious attack and could even be fatal. Fortunately to date my pneumonitis has remained at level 1 or 2 and has responded well to steroids – hence the fat, plate face! But each time I have had pneumonitis the treatment has been suspended until it has receded and in the interim I have experienced progression as a result.

Also I believe the steroids are compromising the treatment as I have never had a marked response as I did after the first 3 IVs and I have remained on some steroids as a prophylactic. It is clear now that Keytruda is no longer working for me but it is controlling growth to some extent so I am continuing with treatment while I research more options. Always, always a balancing act…..

Where do I go from here?

There is in my view a direct correlation between the stage of your cancer and the level of risk you are willing to accept.

It’s like I am playing a game of chess with melanoma, a game I can assure you I never wanted to play, a game with dire consequences. I can see now how every decision I have made throughout my treatment has contributed to where I am placed on the board.


Every time I make a decision I am reluctant to take my hand off my chess piece in case it’s the wrong one. I look around hoping for clues, melanoma is always one step ahead. You need to be very brave to play this game.

I can see ‘check mate’ up ahead at times, then I recover myself slightly. It’s never me who’s winning ultimately.

I am mentally pretty strong, I can stay calm when it's force 8 but my melanoma storm is testing.

My pool of options is drying up so I must take higher risks.

My options are:

• Removal of left kidney on 18 May. My kidney contains the only accessible tumours for Til treatment and press on with Til treatment. • Remove kidney on 18 May and have cells stored and try radiotherapy to 3 tumours left behind sternum, but there is a risk of radiation pneumonitis and damage to lungs and surrounding area • Research phase 1 or 2 clinical trials as back up

I'm scared for sure, but I will still make the decisions and move forward, I will take the risks because checkmate moves ever closer.

Not easy decisions to make, but they never are easy decisions. While I am still relatively well I feel it’s time to make a bold decision.

Yes, high stakes but potentially high gain and if I do nothing? 100% certainty of checkmate.

There is currently no funding for Til treatment in the UK. My house is on the market to find the 70k required to finance the procedure on a private patient basis. This makes me angry, not just for me but for the door slammed in other melanoma patients faces…hopefully in time this may change.

In the interim I am assessing my next move, I still have my hand on my chess piece but I know the next high risk decision will need to be made…and onward towards TIL treatment.

1.3 New hopes and new risks- the oncologist’s perspective on innovative medicines in Melanoma. Bart Neyns, University Hospital Brussels, Belgium

Bart has set-up and conducted as a lead clinical investigator twelve academia sponsored clinical trials in the domain of melanoma (immunotherapy and targeted therapies), glioblastoma (anti-VEGFR and anti-EGFR targeted therapies) and colorectal cancer (hepatic arterial infusion of chemotherapy). He is an author on over 100 scientific publications in peer review journals and has contributed substantially to pivotal industry sponsored clinical studies. Currently his main focus is on the development of autologous dendritic cell therapy for advanced melanoma and targeted therapy for glioblastoma. Training: 1992 graduated from Med School, Free University of Brussels – 2001 PhD in the molecular biology of ovarian cancer and the potential of gene therapy using a recombinant AAV-vector - 2002 head of clinical oncology-2007 Clinical Professor Current position: Head of Clinical Oncology UZ Brussels

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'THE RISK OF NOT TAKING RISKS IN MELANOMA‘ New hopes and new risks- the medical oncologist’s perspective on innovative

medicines in Melanoma

Bart Neyns MD PhD Afdelingshoofd Medische Oncologie Universitair Ziekenhuis Brussel Brussels, Belgium [email protected]

Disclosures

•  Personal financial compensation – BMS, GSK (Novartis), Cryostorage, Roche

•  Research funding (UZ Brussel) – Pfizer, Roche, GSK (Novartis), Merck-Serono

Personal Perspective •  Medical Oncologist

–  University Hospital (UZ Brussel, 1000 beds)

–  Head of Division (melanoma, glioblastoma)

•  Experience –  UZ Brussel sponsored early

clinical trial program on autologous DC therapy for advanced melanoma (>150 pts treated over 13 years)

–  Pharma comp sponsored clinical trials and compassionate use/medical need programs

Randomized Trials on Cytotoxic Therapy and Cytokine Therapy for Advanced Melanoma Prior to 2010

No randomized trial for the treatment of advanced melanoma demonstrated to improve overall

survival before 2010

Tsao H et al, N Engl J Med

2004

Scientific Breakthroughs leading to Improved Melanoma Therapy

Remarkable progress is made since 2010 !

1y OS % 3y OS

Before 2010 50% <15%

2010-2014 60-70% 25-30%

2015-? 70-80% ?

Issues •  How to justify the necessity for phase III RCT in

order to approve new innovative high-activity drugs and is overall survival the legitimate endpoint?

–  E.g. BRAF-inhibitors •  How to shorten the delay in access to

innovative “best in class” life-saving innovative treatments as first options for therapy?

–  E.g. anti-PD1blocking mAb •  Medical-need and compassionate use

programs –  Can we get more out of these?

Pivotal Clinical Trials with Vemurafenib and Dabrafenib

'THE RISK OF NOT TAKING RISKS IN MELANOMA'

Are we figh)ng the war on melanoma the way world war I was fought?

BRIM-3: progression free survival (PFS)

Chapman PB et al. N Eng J Med 2011; 364 (26):

2507-16 Sosman J et al. N Eng J Med

2012;366:707-714.

BREAK-‐3: 3-‐year landmark overall survival (OS) update

An>-‐PD1 mAb are currently not made available for first-‐line therapy

•  The evidence is there, the clock is >cking ... lives are lost •  Worse situa+on = experiencing the added

value of a new drug in prospec)ve trials and having no access therea=er

•  Compassionate Use/Medical Need –  Conflicts with commercial interests –  Conducted by pharma

–  No prospec>ve data collec>on allowed –  Lost opportunity for collec>on of real life data

–  New regula>on needed? •  Early condi>onal reimbursement •  Facilitate/encourage programs with prospec>ve collec>on of “real life data” coordinated by “non-‐for-‐profit organisa>ons” (e.g. academic centers, EORTC)

THE RISK OF NOT TAKING RISKS IN MELANOMA •  2015: progress in the treatment for advanced melanoma is s>ll made by

sacrificing lives (e.g. BRAF-‐inhibitors, an> PD-‐1 mAb) –  Do we sufficiently balance the risk of doing harm (PFS, HRQOL, OS) with the need of

demonstra>ng a gain in OS?

•  A higher level of civiliza>on will be reached when progress is made without the need to sacrifice lives

–  Technological improvements to assess endpoints different from OS

•  Should pa>ents/rela>ves be compensated for harm done in phase III trials with OS as the primary endpoint? –  Third party claiming compensa@on when a

phase III trial demonstrates an an@cipated gain in PFS/OS

[email protected]

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1.4 Who should decide which risk to take? Pan Pantziarka, The George Pantziarka TP53 Trust, UK

Pan, PhD, is a research scientist working for the Anticancer Fund, Belgium. He is joint co-ordinator of the Repurposing Drugs in Oncology project, an international collaboration between the Anticancer Fund and the US not-for-profit organisation GlobalCures. Pan is also the co-founder and chairman of the George Pantziarka TP53 Trust, a not-for-profit organisation supporting families with Li Fraumeni Syndrome and related conditions. In addition to research on drug repurposing and cancer policy, Dr Pantziarka is active in research on Li Fraumeni Syndrome. Current position: Head of Oncology, Haematology and Diagnostics in the Human Medicines Evaluation Division.

The Risk Of NOT Taking Risks In Melanoma 24th-‐ 26th April 2015

Who should decide which risk to take?

1 Pan Pantziarka

My Background

•  Pa6ent advocate and co-‐founder of the George Pantziarka TP53 Trust (www.tp53.org.uk) – suppor6ng families with Li Fraumeni Syndrome

•  Scien6st working with the An6cancer Fund (www.an6cancerfund.org) – primarily looking at drug repurposing in oncology

•  Trustee of Star Throwers – a UK charity suppor6ng late-‐stage cancer pa6ents

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July 28 1993 – April 25 2011

Risk Strategies

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Higher Risk

Lower Risk

Time

Pay-‐off – healthy pension fund

Risk Strategy – pension planning

Adap6ve strategy

AppeEte for Risk

•  Appe6te for risk -‐ how much of a gambler are you? –  Subjec6ve factors – some people are naturally cau6ous, others are inclined to take bigger chances

–  Context-‐dependent – someone might be a risk-‐taker in sports, but not in finance

–  Time-‐dependent – we learn from experience (we hope!)

•  A cancer diagnosis is a context changer! –  A person’s view of risk will naturally change – especially in a disease with a poor prognosis such as metasta6c melanoma

–  The 6me-‐line and pay-‐off will change radically

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Capacity for Risk

•  In finance this is the degree to which you can afford to take risks –  If you only have $10k can you really afford to lose it in a gamble, regardless of your appe6te for risk?

–  In effect this is the ‘what if it goes wrong?’ or ‘what can you afford to lose?’ ques6on

•  Capacity for risk changes over 6me and context –  You might take greater risks when you can afford to lose more

–  You may discover strategies which can increase your capacity for risk

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Capacity for Risk -‐ Cancer

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Time

Disease Burden

Capacity to benefit from new

interven6ons Scenario -‐ Disease progresses and

standard treatments fail

What does this mean for a paEent?

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Higher Risk

Lower Risk

Time (Disease Burden)

As disease progresses and treatments fail there is o"en a greater willingness to consider

riskier approaches


interven6ons Pay-‐off: Cure

What does this mean for the clinician?

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Higher Risk

Lower Risk


interven6ons

As disease progresses and treatments fail there is some'mes a greater willingness to consider riskier approaches

Changes to stable

disease or quality of life

Disease Burden (Time)

Adap6ve strategy

A more raEonal strategy?

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interven6ons

Take bigger risks when the capacity to benefit is greatest – fall back to lower risks to preserve

quality of life

Higher Risk

Lower Risk

Pay-‐off: Changes over 6me

Disease Burden (Time)

Who should decide on the risk strategy?

•  Pa6ents have the most invested in the ‘pay-‐off’ •  They know what risks they are willing to take •  Clinicians know what the capacity to benefit from these risks are

•  Together there can be a dialogue – using this type of framework – to define the best strategy to meet the pay-‐off the pa6ent decides on

•  Pa6ents need to accept responsibility for the decisions •  Clinicians need to be honest with their pa6ents •  Together they can work in partnership that benefits all

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QuesEons/Comments

Email: [email protected]

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George’s story: ‘For the love of George’ by Irene Kappes

hip://newparadigmpublishing.co.uk/for-‐the-‐love-‐of-‐george/

MPNE 2015 ADVISORY BOARD SATURDAY- 25TH APRIL ‘THE RISK OF NOT TAKING RISKS IN MELANOMA’ Session 2- No risk, no innovation 11.00- 12.30am 2.1 Innovative medicines and risk. Michel Goldman, Free University Brussels, previous IMI director, Belgium 2.2 Risk / benefit assessment- the regulatory perspective. Jorge Camarero, Spanish Agency of Medicines and Medical Devices, Spain 2.3 Innovation and risk- the industry perspective. Brendan Barnes, EFPIA, Belgium 2.4 BIG data and innovation. Nathalie Kayadjanian, Science Europe, Belgium

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2.1 Innovative medicines and risk. Michel Goldman, Free University Brussels, previous IMI director, Belgium Michel was the Executive Director of the Innovative Medicines Initiative (IMI) from 2009 to 2014. With a budget of 2 billions € provided jointly by the European Federation of Pharmaceutical Industries and Associations and the European Commission, he launched and monitored 59 public-private consortia in areas of major importance, including cancer. Professor of Immunology at the Université Libre de Bruxelles, Belgium, Michel Goldman was previously the Head of the Department of immunology-hematology-transfusion at the Hôpital Erasme (Brussels) and the Director of the ULB Institute for Medical Immunology. He currently builds interdisciplinary research and education programs on collaborative innovation in medicine. Michel Goldman’s scientific achievements resulted in more than 400 articles in peer-reviewed journals and he was recognised as ISI Highly Cited Scientist in 2006 by the Thomson Institute for Scientific Information. In 2000 he received the Joseph Maisin Prize, a major award for clinical sciences delivered by the Fonds National de la Recherche Scientifique (Belgium) and he held in 2001 the Spinoza chair at the University of Amsterdam, the Netherlands. In 2007, Michel Goldman was awarded the degree of Doctor Honoris Causa of the Université Lille II, France.

Current position: Professor of Immunology Université Libre de Bruxelles

Michel Goldman

Managing risk in therapeutic innovation:

A critical role for public-private partnerships

The declining productivity of the pharmaceutical industry

Scanell et al. Nature Rev Drug Disc 2012, 11:191-‐200

How to address the innovation conundrum ?

Ø  Strengthening basic research

Ø  Harnessing the informatics revolution

Ø  Moving regulatory science forward

Ø  Revising clinical trial designs

American Economic Review 2013 103: 406-‐411

Can Financial Engineering Cure Cancer?"

By DAVID E. FAGNAN, JOSE MARIA FERNANDEZ, ANDREW W. LO, & ROGER STEIN

Innovative trial designs: Enablors of therapeutic advances

Randomized registry trials Pragmatic trials: •  Provide real-world evidence based on patient-reported outcomes Adaptive trials

•  Modifications in the course of the trial according to collected information ("real-time learning")

•  Facilitates assessment of combination therapies

Ø  Harnessing the informatics revolution

Ø  Revising clinical trial designs

Ø  Moving regulatory science forward

Ø  Ensuring patient access to new therapies

April 20, 2015

§  5 companies (AstraZeneca, J&J, Eli Lilly, Lündbeck, Pfizer) §  34 clinical trials testing second generation anti-pyschotics §  11,670 patients §  Budget €25 Million

Rabinowitz J et al., J Clin Psychiat 2014, 75: e308-‐316

The power of data sharing

Drug-‐placebo differences already significant: §  aVer 4 vs.6 wks observaXon §  with 40% less paXents when appropriate gender balance, symptoms and disease dura;on are selected

Promoting responsible data sharing §  AdopXon of standards for clinical invesXgaXons

§  BioinformaXc tools and pla_orms

New Engl J Med 2014, 370:2063

Nature Medicine 18:341, 2012

EDUCATION IS KEY !

N Engl J Med 2014, 371:794

“Medicine is a science of uncertainty and an art of probability.”

-  Sir William Osler

Thank you

[email protected]

@MichelGoldman

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2.2 Risk / benefit assessment- the regulatory perspective. Jorge Camarero, Spanish Agency of Medicines and Medical Devices, Spain

Jorge has more than ten years of experience as regulatory clinical assessor in oncology and is Head of Oncology Area in the Spanish Medicines Agency (AEMPS) and Member of Oncology Working Party (EMA). Current position: Head of Oncology, Spanish Medicines Agency (AEMPS)

Risk / benefit assessment The regulatory perspec8ve.

Jorge Camarero MPNE 2015 Annual conference 24-‐26 April. Brussels

“A very brief summary”

DISCLAIMER The views expressed in this conference are the personal views of the author and may not be understood or quoted as being made on behalf of or reflec8ng the posi8on of the Spanish Medicines Agency, European Medicines Agency or one of its commiJees or working par8es.

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Efficacy Safety

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•  What do you understand by benefit?

1.   “Cure”

2.   “Incremental progress”

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Overall survival

Time to Tumor progression

Progression free survival

Response rate Dura8on of response

Quality of Life

Rate of responders

Event free survival

Disease free survival

Time to treatment failure

Progression free survival 2

•  Simple and easy (no blinded studies)

•  No bias

•  Directed linked to benefit

Advantages

Disadvantages

•  Larger studies

•  Crossover and 2nd therapies effected

•  All deaths

Overall Survival

•  SD included

•  Short follow up

•  No affected by Crossover

Advantages

Disadvantages

•  Randomised studies

•  Assessment bias (8ming)

•  Double-‐blind or IRC

•  Linked to OS?

Progression Free Survival

•  Single arm studies

•  An8-‐tumour ac8vity

•  Small studies

Advantages

Disadvantages

•  Pa8ent selec8on

•  Dura8on?

•  No SD TTP

•  Final Benefit?

Response rate (ORR)

Points to consider when it comes to evalua8ng data

•  Overall design (comparator, endpoints, etc)

•  Sta8s8cal issues (reliability of results)

•  Relevance of results (clinical relevance)

•  Robustness of data (subgroup analyses)

•  Uncertain8es (biomarkers, etc)

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What about safety?

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Key aspects to be considered within the safety profile

•  Adverse Events (AEs)

•  Severity of Adverse events

•  Drug-‐related AEs

•  Deaths

•  Discon8nua8ons

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Important premise to take into account

Cancer is a life threatening condi8on!!!!!

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The Benefit risk assessment within the assessment report

Sec8on 5 of overview Benefit risk assessment

•  Beneficial effects

-‐  Uncertain8es in the knowledge about the beneficial effects

•  Risks

-‐  Uncertainty in the knowledge about the unfavourable effects

•  Importance of favourable and unfavourable effects

•  Discussion on the benefit-‐risk assessment

•  Conclusions

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…”The purpose of this sec0on (Importance of favourable and unfavourable effects, Benefit-‐risk balance) is to describe if the favourable effects, with their uncertain0es, outweigh the unfavourable effects, with their uncertain0es”. …

Guidance document on the content of the Rapporteur day 80 criLcal assessment report (hNp://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004800.pdf)

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So, in the end, all the informa8on could be summarized on how of important benefits are and if these posi8ve results overcome the risks

But, …

How much evidence?

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Depends on:

•  Unmet medical need?

•  Available alterna8ves

•  Outstanding effects

•  Rare disease

Not always two confirmatory trials are needed!

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Type of authorisation

100

Adequate Data

Time

+ve CHMP opinion

“normal” MA

+ve CHMP opinion

ExcepLonal Circumstances

CondiLonal MA

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“New opinions are always suspected, and usually opposed, without any other reason but because they are not already common”

John Locke

Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) Calle Campezo 1 • Edificio 8 • E-‐28022 Madrid • España/Spain Tel: (+34) 918225152 Fax: (+34) 918225161 [email protected] www.aemps.gob.es

Thank you!

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2.3 Innovation and risk- the industry perspective. Brendan Barnes, EFPIA, Belgium Brendan joined EFPIA in 2002 to work on the alignment of national laws in new member states during the enlargement of 2004. Subsequently, he has been involved in EFPIA’s work on multilateral trade and intellectual property issues, including the EU’s legislation on product diversion and compulsory licensing and on issues relating to access to medicines. More recently, he has been involved in the development of new business models in the areas of neglected disease and infection. He previously worked in the pharmaceutical industry for 11 years, in a range of roles including Finance, Strategic Planning and Public Affairs, among other things coordinating work on the Montreal Protocol phase-out of CFC’s. In the course of his career he has also worked in a number of other industries in a range of finance roles. He has degrees in Psychology and Business. A UK national, he is married with two children. Current position: Director IP and Global Health at EFPIA

Innovation and risk- the industry perspective

MPNE conference

24th April 2015

TITLE OF THE POWERPOINT 1

“The potential of losing something of value” (in relation to innovation)

Þ The industry exists to use science to deliver benefits to patients (the value)

Þ  Innovation is complex, lengthy, expensive and uncertain Þ  Innovation is regulated to protect the wider public interest Þ  Innovation is lost when

Þ The potential of science is not recognised Þ Those needs that would generate most value are not articulated

and/or supported Þ Opportunities to address complexity, duration, cost and uncertainty

in the innovation process are not taken


Issues (and responses)

Þ  The potential of science is not recognised Þ  Improved coordination (eg: joint programming) Þ  Strategic investments to overcome bottlenecks Þ  Collaboration structures (eg: IMI)

Þ  Those needs that would generate most value are not articulated and/or supported Þ  WHO priority needs report Þ  Effective planning for new technology adoption Þ  Patient input


The Innovation Process


All of the above taking place within a macro-level context of priority needs and the opportunities arising through the evolution of science

What are the issues?

Þ Evaluation as a continuum Þ Supporting the more precise understanding of which

patients will benefit that is now emerging Þ De-risking of the investment decision Þ Efficiency of the regulatory process (duplication) Þ Mitigating attrition Þ  International alignment Þ  Integration of patient views of benefit-risk across the

process


Patient Involvement at EMA

Þ Management Board Þ PCWP – recommendations to EMA and its scientific

committees Þ Workshop participation Þ Product-specific activities

Þ EMA scientific committees COMP, PDCO,CAT, PRAC Þ SAWP –protocol assistance/scientific advice Þ Scientific advisory committees

Þ Pilot project on CHMP participation Þ External consultations


Looking forward………

Þ Consensus on the need for patients to play a larger role Þ Closer patient involvement in Innovation process will

require reflection on governance of relationships between the groups involved

Þ  Industry investment in working with patient groups needs to paralleled by a receptivity on the part of regulators and payers towards the outputs

Þ Moving beyond “representativeness” requires consensus on how patient preferences should be elicited and how they should be input to the broader regulatory process


IMI

Þ PROTECT – looking at limitations of current methods in pharmacoepidemiology and pharmacoviglance

Þ New methods of data collection from consumers Þ Testing methodologies and software solutions Þ Assessing methods to improve patient understanding

Þ  IMI 2 Þ  An understanding of when patient involvement in benefit-risk

evaluation is most valuable: Þ An understanding of how patient involvement in benefit-risk

evaluation can best be performed: Þ Experience with applying methodology to collect patient

preferences with respect to benefit-risk


EFPIA Brussels Office

Leopold Plaza Building Rue du Trône 108 B-1050 Brussels - Belgium Tel: +32 (0)2 626 25 55 www.efpia.eu

EFPIA Brussels Office

Leopold Plaza Building Rue du Trône 108 B-1050 Brussels - Belgium Tel: +32 (0)2 626 25 55 www.efpia.eu

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2.4 BIG data and innovation. Nathalie Kayadjanian, Science Europe, Belgium

Nathalie, Ph.D is the senior scientific officer of the Medical Sciences committee of Science Europe. She is an expert in translational biomedical research with extensive R&D experience in academia, biotech, and the pharmaceutical industry in Europe and in the USA. For the past several years, Nathalie has occupied top management positions in patient-driven non-profit organizations as associate science director of the French Association against myopathies (AFM) and associate director of biomedical research of the Amyotrophic Lateral Sclerosis Association (ALSA) in the US where she developed and implemented strategies to accelerate the development of innovative therapies for neurodegenerative and rare diseases. She is currently working with the Medical Sciences committee of Science Europe to develop science-based policies to advance biomedical R&D at a pan-European level. She received her Ph.D in Neuroscience from the University Pierre and Marie Curie in Paris and did a postdoctoral training at the Salk Institute in the US.

Current position: Senior scientific officer Medical Sciences committee of Science Europe

Workshop: How to transform Big Data into

Better Health?

Envisioning a Health Big Data ecosystem for advancing

biomedical research and improving health outcomes in Europe

Erice Nov 24-25

SCIENCE EUROPE 24 Nov 2014

SCIENCE EUROPE I 2

THE CONTEXT

SCIENCE EUROPE I 3 EU faces Big health challenges

•  Complex diseases

multi-factorial, multi-systemic

•  Complex health challenges aging, non-communicable disorders…

•  Inefficient & unsustainable R&D model

high attrition rate, lengthy & costly

•  Transitioning from “diagnose and treat” to “predict

and prevent” Ø Big challenges requires Big science Requires a Big Science approach

SCIENCE EUROPE I 4

FROM BIG DATA TO BIG SCIENCE

SCIENCE EUROPE I 5

Big Data = multi-dimensional & heterogeneous health-related data

Big Data

Exposome

Social network

Clinical phenotypes

Microbiome

Epigenome

Metabolome

Proteome

Genome

Other type of data

(imaging…)

Individual subjects

B I G DA T A

“Human Health Information System”

SCIENCE EUROPE I 6

The conceptual framework

Public health Clinical Decision (Personalised Medicine) Fundamental mechanisms

Data Integration

National Research Council. Toward precision medicine: Building a Knowledge Network for Biomedical Research and a new taxonomy of disease. Washington DC: The National Academies Press, 2011

B I G DA T A

Knowledge

Data interconnectedness

Data Interpretation Exposome Social network Clinical phenotypes Microbiome Epigenome Metabolome Proteome Genome Other type of data (imaging…) Individual subjects

Data Interpretation

SCIENCE EUROPE I 7

Organisational model

Knowledge

B I G DA T A

Creating a Health Big Data Ecosystem

Human resources

Funding models

Data sharing

Exposome Social network Clinical phenotypes Microbiome Epigenome Metabolome Proteome Genome Other type of data (imaging…) Individual subjects

Infrastructure

SCIENCE EUROPE I 8

CHALLENGES & RECOMMENDATIONS: 1.  Data integration 2.  Data interpretation 3.  Data-sharing ecosystem

SCIENCE EUROPE I 9

Public Health records Population risk management Epidemiological studies

Administrative data

Risk management…

Clinical data

Patient data

Health self-monitoring data Wellness Social networks…

Electronic Health records

Medical records

Patient registries

BIOBANKS

Omics data Epigenomics Genomics Proteomics Metabolomics Lipidomics…

Data Integration


Data fragmentation, heterogeneity, availability, handling, privacy

1. Data Integration: challenges

Clinical trials

Imaging data

MRI DTI…

Biological data

INFORMATION COMMONS

SCIENCE EUROPE I 10


1. Data Integration: Recommendations

1.  Integrate –omics data with higher levels of complexity (e.g. lifestyle, environment)

2.  Leverage existing national centralised databases (e.g. Scotland, Denmark)

3.  Leverage undergoing pilot projects initiative based on disease areas (e.g. HBP, U-BIOPRED, EMIF)

4.  Develop best practices to improve data accuracy (e.g. data reproducibility)

SCIENCE EUROPE I 11 2. Data interpretation: Challenges


Lack of concepts and theory to derive relevant knowledge from data Spurious correlations Investigator-based approach

Exposome Social network Clinical phenotypes Microbiome Epigenome Metabolome Proteome Genome Other type of data (imaging…) Individual subjects

SCIENCE EUROPE I 12 2. Data interpretation: Recommendations


1.  Develop an integrated approach to biology (i.e. system biology)

2.  Implement best research practices to increase proportion of true research findings

3.  Foster multi-disciplinary and collaborative expert networks

SCIENCE EUROPE I 13

Knowledge

B I G DA T A

3. A Data-Sharing Ecosystem: Challenges

Infrastructure

Human Resources


Funding models


SCIENCE EUROPE I 14

The current organisational model

Funding

Public Industry Death Valley

The biomedical R&D chain value: linear & in silos Inefficient: long, fragmented & disconnected

Stakeholders/ Organisations Academia CROs/Biotechs Regulatory agencies

Industry Clinicians

Patients

Basic Research

I II III IV

Clinical Development Preclinical

Development

SCIENCE EUROPE I 15

The current organisational model

Funding

Public Industry Death Valley

The DATA chain value: linear & in silos Inefficient: long, fragmented & disconnected

Stakeholders/ Organisations Academia CROs/Biotechs Regulatory agencies

Industry Clinicians

Patients

Basic Research

I II III IV

Clinical Development Preclinical

Development

SCIENCE EUROPE I 16

Preclinical Development

Clinical

Developm

ent

INFRASTRUCTURE

FUNDING Human resources

Social Sciences

Mathematics

A data-sharing organisational model

SCIENCE EUROPE I 17

Preclinical Development

Clinical

Developm

ent

INFRASTRUCTURE

FUNDING Human resources

Social Sciences

Mathematics

A patient-centered model

SCIENCE EUROPE I 18

3. A Data-Sharing Ecosystem: Recommendations

1. INDIVIDUAL Develop pilot experiments to showcase evidence-based benefits of sharing data for researchers 2. SOCIETAL Develop transparency practices Develop patient/citizen-centered model (e.g. health data co-operatives) 3. ORGANISATIONAL Develop codes of conduct and research practices for data management quality control Develop funding mechanisms for collaborative research networks Develop reward and recognition mechanisms for data sharing activities by individual researchers 4. LEGAL Introduce an appropriate and supportive legal framework (e.g. Data Protection Regulation)

SCIENCE EUROPE I 19

Thank you

[email protected]

SCIENCE EUROPE I 20

SCIENCE EUROPE I 21

Science Europe

Brief overview

SCIENCE EUROPE I 22

Science Europe

"   Founded in October 2011

"   50 member organisations from 27 countries

"   Research funding and research performing

organisations

"   Represent approximately €30 billion per annum

"   Policy organisation – no funding schemes

Foster excellence in EU research and strengthen European Research Area

Collaboration

Think-Tank Advocacy

SCIENCE EUROPE I 23

Science Europe Structure

"   Cross-border Collaboration "   Open Access to

Publications "   Research Data "   Horizon 2020 "   Research Integrity "   Research Infrastructures "   Research Careers "   Ex-post Evaluation "   Gender and Diversity

Working Groups (MOs) "   Medical Sciences "   Life, Environmental and

Geo-sciences

"   Humanities

"   Social Sciences

"   Engineering Sciences

"   Physical, Chemical and Mathematical Sciences

Scientific Committees (Ind.)

Research and management policy Science-driven policy

SCIENCE EUROPE I 24

Activities

European

regulations

&

Consultatio

ns

MED Committee Activities

"   Data protection regulation "   Clinical trial regulation directive "   Animal use in research "   Embryonic stem cells "   Consultation “Health, demographic change and wellbeing”

Science Europe

"   ERA consultation "   Consultation “a la carte”

Strategy

"   Fostering the implementation of a health Big Data ecosystem in EU "   Moving forward personalised medicine in EU "   Improving ethical reviews of clinical research in EU "   Improving science quality through implementation of the 3Rs in EU "   Improving translational research in EU

SCIENCE EUROPE I 25

Data Protection Regulation How to transform Big Data into Better Health?:

Fostering the implementation of a health Big

Data ecosystem in EU

MPNE 2015 ADVISORY BOARD SATURDAY- 25TH APRIL ‘THE RISK OF NOT TAKING RISKS IN MELANOMA’ Session 3- Measuring and mitigating risk 14.00- 15.30am 3.1 The earlier, the better- learning in Early Access Programs Edna Venneker, mytomorrows, Netherlands 3.2 Concerns about risk when procedures accelerate- parallel scientific advice in Australia Andrew Bruce, Amgen, previously: Medicines Australia, Switzerland 3.3 Risk- is it a matter of time? Geert Bakker, Inspire2live, Netherlands 3.4 Incorporating patient risk/benefit assessment into regulatory decisions Francesco Pignatti, EMA, UK

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3.1 The earlier, the better- learning in Early Access Programs Edna Venneker, mytomorrows, Netherlands Edna obtained her medical doctor's degree in 1991 at the

University of Nijmegen in The Netherlands. She started her career as house officer cardiology at the Lucas hospital in Apeldoorn, NL. Hereafter she became responsible for the initiation, execution and reporting of phase II and III clinical trials studying new cardiovascular drugs and cardiovascular imaging agents at several academic institutions. In 1994 she joined Yamanouchi Europe Headquarters B.V. in Leiderdorp, NL, where she had the overall responsibility for the clinical development of new chemical entities and led the clinical development teams in the field of cardiology, oncology, dermatology and gynaecology. In 1998 she became Director Clinical Development with Pharming Group N.V. in Leiden, being responsible for the global clinical development of all new biological entities, among which orphan drugs for the treatment of congenital neuromuscular diseases. Besides her management tasks she has been responsible for setting up systems for CRO management, budgeting of clinical development and building infrastructure for clinical development including a quality management system. In 2000 she founded Afforce Healthcare, together with Margot Amoureus.

Current position:. Senior Partner, Clinical Development Consultant

Edna Venneker

What is it that we need to know -‐Regulatory perspec7ve-‐

� Positive risk/benefit assessment �  Is predominantly based on group means, not on individual patients

�  Limited data available at time of registration

What is it that we need to know -‐Mylotarg case-‐

June 21 (Bloomberg) -‐-‐ Pfizer Inc. will withdraw its blood cancer drug Mylotarg after 10 years on the U.S. market because studies didn’t prove it works and the treatment was linked to deaths from liver and lung complications. Mylotarg, for relapsed acute myeloid leukemia, is the first medicine to be pulled off the market that was cleared through the Food and Drug Administration’s accelerated approval program, the agency said today in a statement. Pfizer volunteered to halt sales after trial results raised safety concerns “and the drug failed to demonstrate clinical benefit,” the FDA said.

What is it that we need to know -‐Regulatory perspec7ve-‐

What is it that we need to know -‐cri7cally ill pa7ent-‐

� Critically ill patient �  Is there any chance, no matter how small, of benefitting from therapy

� How does treatment affect my quality of life Ø Completely different risk/benefit assessment

However � An undesirable outcome in an individual or in a small group of patients � Might have been avoided if the drug was investigated more thoroughly before putting certain patients at risk

� May result in killing a product due to safety concerns from which numerous patients might have benefitted if not killed early without sufficient data on which patients do benefit

The real ques7on is � How can we obtain data that serve both regulatory purposes as well as individual patients � How can we ensure that individual patients get a chance

� How can we ensure that data obtained in patients who (later) turn out to be not the right target group do not ultimately hamper the availability to patients who do benefit from treatment

� How can we ensure that we learn as much as possible from every patient treated

The real ques7on is �  Is it acceptable to give patients unlicensed medicines without learning from it. Either learning that: � We should not give a certain drug to certain patients �  That some patients may benefit from a certain drug

Data collec7on in early access programs (EAPs) � EAP: Medicines made available to patients for whom no other treatment option is available

� Data collection: rank order of clinical evidence �  Single case – case series – observational study – open, label study – randomized study -‐ randomized controlled study (RCT)

�  RCTs have highest level of evidence but other options of data collection are better than not collecting any data on unlicensed medicines

Data collec7on in early access programs A ‘non-‐interventional trial’ is defined in Article 2(c) of Directive 2001/20/EC as follows: “a study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data.”

Data collec7on in early access programs � Question is what is the usual manner: any drug authorized for use (only via official marketing authorization route or also via EAP)

� Why not learn what we can learn even if methodology is not optimal and even if numbers are small

Basics about observa7onal studies � Needs to follow routine medical practice � No extra ‘burden’ for patients allowed

� No additional diagnostic or monitoring procedures allowed

� No extra visits allowed à visit schedule not standardized

What can we collect �  Information about adverse events �  Information about effect on parameters which do not require procedures not part of routine medical practice, e.g. � Overall survival �  Global assessments �  But also information on blood biomarkers provided no extra venapuncture is required

Goal of observa7onal studies � Not sufficient for registration purposes but provides better data to a broader group of physicians

�  Some indication about safety and efficacy in patients who are not eligible for a clinical study

�  Sample size is likely not sufficient to draw firm conclusions about larger groups of patients

� But it will provide some information on whether some patients may benefit from it who otherwise might not have been treated with the product or only at a very late stage

Conclusion � EAPs should include (better) methods of data collection � May benefit future patients � Helps regulators to better judge risk/benefit in certain patients

�  Requires cooperation of regulators , pharmaceutical companies and patients

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3.3 Risk- is it a matter of time? Geert Bakker, Inspire2live, Netherlands

A Stage 4 Melanoma Patient and Patient Advocate and Life Coach. My focus at Inspire2Live is quality of life. My experience is that if you consciously examine what (else) you (would) want, you quite often accomplish it. My goal is to help people first to identify their situation and needs and then to stimulate and assist them in achieving their wants. Helping maximizing the quality of life as best as possible is what I want to contribute to. To do so gives me a lot of positive energy. Current position: Patient Advocate and Life Coach

Is it a matter of time A patient perspective

MPNE 25-04-2015

Geert Bakker – Patient Advocate

War on cancer

War on cancer

Is it a ma(er of -me?

War on cancer

Is it a ma.er of 0me?

Yes, Time to do it differently

War on cancer The war on cancer should go about

saving Human lives

War on cancer The war on cancer should go about

saving Human lives

Not a ba(le

Ba(le? Change business models, regula0ons,

structures and standards

Ba.le? Change business models, regula0ons,

structures and standards

Start with pa-ent involvement v  Academic ins0tu0ons v  Health care centres v  Industry v  Insurers v  Policy makers & regulators

Change business models, regula0ons, structures and standards

Start with pa-ent involvement v  Academic ins0tu0ons v  Health care centres v  Industry v  Insurers v  Policy makers & regulators

Working together on an equal basis


structures and standaards

Pa0ent involvement

Is it a ma(er of -me?


structures and standaards

Pa0ent involvement

Is it a ma.er of 0me?

Yes, it’s -me to break the barriers

Pa0ent is the one who decides on the balance of poten0al

benefits versus risks

Patient centric

• Make treatment individual

• Combine medicines •  Include Lifestyle & immune system

Patient centric

•  It’s about the potential curing the patient, not about medicines

•  It's about getting cancer under control

Patient centric

Is it a matter of time?

Patient centric


Yes, we are dying for good treatments

Share my data Big data

•  Share data •  Big data solutions •  Work together •  Beter data management •  Learn from each other, other hospitals,

other continent •  Lets learn best practise





Yes, start maximising learning opportunities

Start saving my life

Start war on drugs, by 1. Changing existing structures in the patients interest 2. Working together, on an equal basis (patients, industry, regulators, acedemics, health givers) Ø Better trial design, data management, combine drugs,

and cost effective Ø  To maximise patient centric learning opportunities

To get cancer under control And save human lives

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3.4 Incorporating patient risk/benefit assessment into regulatory decisions Francesco Pignatti, EMA, UK

Francesco graduated as medical doctor at the University of Rome La Sapienza. In 1995 he became research fellow at the EORTC Data Center, Brussels, Belgium, where he was involved in numerous activities including clinical trial design, conduct, analysis, and reporting. In 1997 he became Medical Advisor for the Gastrointestinal Tract Cancer Cooperative Group, and Brain Tumor Cooperative Group. In 1997 he obtained a Master of Science degree in Biostatistics from the University of Limbourg, Belgium. In 1999 he joined the European Medicines Agency (EMA) in London. Since 2009 he holds the position of Head of Oncology, Haematology and Diagnostics in the Human Medicines Evaluation Division.

Current position: Head of Oncology, Haematology and Diagnostics in the Human Medicines Evaluation Division, EMA

Disclaimer

§ The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to the European Medicines Agency.

§ These PowerPoint slides are copyright of the European Medicines Agency. Reproduction is permitted provided the source is acknowledged.

1 EMA/MPNE pilot study on eliciting patient values - work in progress

Contents

•  Background: Benefit-risk assessment

•  EMA initiatives involving patients

•  Revised framework of EMA interaction with patients

•  Feasibility study on eliciting patient values

•  Preliminary results: Questionnaires

•  Preliminary results: Decision conferencing

•  Conclusions and next steps


Benefit-Risk Assessment – Working Definition

The balance between benefits (and uncertainty) against risks (and uncertainty)

3

Benefits “Good things”; clinical efficacy

Risks “Bad things”; identified harms (toxicity) and potential harms

Uncertainty •  Measurable: Statistical uncertainty, measurement error,…

•  Things we could know but don’t, because, e.g., poor quality of the data, population not studied, …

EMA/MPNE pilot study on eliciting patient values - work in progress

PrOACT-URL adapted as B-R framework

•  Problem

•  Objectives

•  Alternatives

•  Consequences

•  Trade-offs

•  Uncertainty

•  Risk attitude

•  Linked decisions

4

J Hammond et al. (1999) Smart Choices: A Practical Guide to Making Better Decisions.


WP1: How do regulators decide? By…

Discussing Voting

5

No systematic elicitation of preferences.

5


EMA activities involving patients

Involvement as experts

•  CHMP

•  Scientific Advisory Groups

•  Scientific Advice Working Party

Involvement in benefit-risk assessment (pilot):

•  1-2 experts input sought during CHMP meeting


Revised framework of EMA interaction with patients •  In December 2014, the EMA Management Board adopted a revised

framework of EMA interaction with patients, consumers and their organisations to reach out to a wider audience;

•  One of the objectives of the framework is to facilitate participation of patients and consumers in benefit/risk evaluation;

•  Currently, a number of methodologies are available to elicit patient preferences. However, there is little regulatory experience with these methods.


Open issues A number of methodologies are available, from informal methods (expert opinions) to more formal methods (little experience so far)

•  Systematic or case-by-case

•  Whose values: Patients? Carers? Both?

•  Individual survey v. decision conferencing v. both?

•  How feasible in the context of a scientific assessment at EMA?

•  How informative for the assessment? Will it allow evidence-based decisions with impact, e.g., on the labelling

•  How informative for treatment decisions?


Feasibility study: Focus group and questionnaire •  Elicit values that can be

generalised to different drugs.

•  Online questionnaire v. decision conferencing.

•  Collaboration with Melanoma Patient Network Europe; Myeloma Patients Europe.

9

(More information: EMA Benefit-Risk Methodology project, Univ. Groningen ADDIS)


Results of all questionnaires combined (n=22)


Results of decision conferencing


How does this compare which the survey conducted at the EMA (n=73)?


Comparison across subgroups


How do the weights translate into preferences for specific treatments?


Rank acceptability indices for the two hypothetical treatments


Conclusions

•  Ongoing pilot to explore feasibility and usefulness of eliciting patient values to inform the benefit-risk decision

•  Preliminary learnings

•  It is possible to use “rapid methods” to elicit patient values •  Need to “validate” the approach on larger samples •  Need continue improving methodology/software

•  Next steps:

•  Assess regulatory usefulness of approach •  Complete pilot, get feedback, discuss, report •  Explore synergies with other programmes and stakeholders (IMI-

PROTECT; IMI-2 call in preparation)

16

Acknowledgments: N. Bere, L. Phillips, M. Mavris, I. Moulon, D. Postmus EMA/MPNE pilot study on eliciting patient values - work in progress

Contact me at [email protected] European Medicines Agency 30 Churchill Place • Canary Wharf • London E14 5EU • United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact

Further information

Follow us on @EMA_News

MPNE 2015 ADVISORY BOARD SATURDAY- 25TH APRIL ‘THE RISK OF NOT TAKING RISKS IN MELANOMA’ Session 4- Get Real! 16.15- 16.45 am 4.1 The Get Real project Sarah Garner, NICE, CASMI, UK

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4.1 The Get Real project Sarah Garner, NICE, CASMI, UK

Sarah, PhD, BPharm is a pharmacist specialising in the interface between Health Technology Assessment (HTA) and regulation. Sarah is the Associate Director for R&D at the UK's National Institute for Health and Care Excellence (NICE) and an honorary professor at UCL and Manchester University. At NICE her responsibilities include the planning and delivery of NICE’s R&D agenda relating to methodology and clinical research and the Citizens Council. She leads Work Package 1 of the GetReal project funded by the EU Innovative Medicines Initiative to develop policy proposals for the use of real-word data in pharmaceutical development, regulatory and HTA decision making.

Current position:. Associate Director for R&D, NICE

The research leading to these results has received support from the Innova6ve Medicines Ini6a6ve Joint Undertaking under grant agreement no [115303], resources of which are composed of financial contribu6on from the European Union’s Seventh Framework Programme (FP7/2007-‐2013) and EFPIA companies’ in kind contribu6on. www.imi.europa.eu

Get Real: The pa6ent experience of melanoma trials

Sarah Garner Gill Fairclough Amr Makady


•  Efficacy •  Pa6ent benefit and harm in

experimental and closely monitored research studies, normally RCTs.

•  Design minimises bias -‐ high internal validity

•  Generalisability ques6onable –  restricted entry criteria –  unrepresenta6ve se[ngs

•  Effec6veness •  Pa6ent benefit and harm when the

technology is actually applied in everyday prac6ce.

–  pragma6c clinical trials –  adap6ve clinical trials –  observa6onal studies –  Synthesis (network meta-‐analysis)

•  ISPOR: “evidence used for decision-‐making that is not collected in conven<onal randomized controlled trials (RCTs)”

•  “Messy” -‐ a lot of variability and biases



Evidence Hierarchy


The challenges of relying more on RWD

•  Culture change

•  Understanding of poten6al impact

•  Skill development and capacity

•  Concerns over confiden6ality

•  Ethical issues

•  Terminology

•  Methods

•  How to define best prac6ce –  Methods, Decision making –  Tools: Cri6cal appraisal etc.




WP1

Frameworks Processes Policies

WP2 Understanding the

efficacy-‐effec6veness gap

simula6on of trials to improve design

WP3 Overcoming

prac6cal barriers to the design of real-‐world studies

WP4 Iden6fying best

prac6ce and crea6ng new methods for

evidence synthesis and predic6ve modelling

Slide 8

•  Standardising terminology •  Interviews to understand

and the perspec6ves and policies of different stakeholders

•  Designing a framework for decision-‐making during development

Six Case studies using drugs that had difficulty at regula6on and HTA

•  360 degree reviews •  Re-‐designing development

pathways to include RWD •  Simula6on •  Ascertaining impact on

stakeholders


•  What can patient and carer experiences of clinical trials

for new melanoma treatments tell us about the issues

that might need to be considered in decisions about

whether it is possible to move towards real-world

studies?


What we are doing Survey – patient and carer experiences

Focus group – developing ideas

This podium session – agreeing themes

GetReal stakeholder workshop

Generating ideas and further research


Par6cipants •  Ques6onnaire (March 2015)

– 10 pa6ents and 8 carers – Stage 4 (14), Stage 3 (3), Stage 2 (1) – 4 experience of more than one trial – 11 experience of a trial for a NEW treatment – 5 considered trial par6cipa6on – 2 not considered

•  6 par6cipants in the focus group


Results •  Exploratory and highly qualita6ve •  Very small numbers of pa6ents all of whom are MPNE members

•  Can only iden6fy issues and common themes •  Need to find out whether this is typical of pa6ent experience

•  Need to capture the experience of other people involved for example clinicians.


Clinical trial is a treatment option

•  Access not possible without trial entry

•  “it was either that or go home to die”

•  “part of the strategy to survive”

•  “if you don’t go in a trial you are dead. That’s not a choice”


Compromising the treatment journey •  Patients had to fail a company’s first drug before they were allowed to enrol

in a trial for the second. But not available in some countries.

–  Previous ‘ipi failure’: “it doesn’t work so how long do I have to be on it before the box is ticked”. It could make you too ill to take another drug

•  Cross over as soon as not working - should be in best interests of the patient not the researcher

•  “Punished for participating in a trial” –  Researcher would not ‘unblind’ the patient even though treatment failed. Patient could

not proceed with further treatment

•  Harming the doctor-patient relationship –  “outcome depends on how hard you push” –  “you have this doubt all the time. Is this really the best for me?”


Eligibility criteria •  Previous treatments used as an exclusion criteria

–  Historical protocol stipulation –  Patients now living longer

•  “Pa6ents with many previous treatments are the survivors” .

•  “excluded because of a treatment you didn’t want to have but had no alterna6ve”

•  Age: “is it ok to let a 16 year old die?” •  Should not interfere with op6ons available


Choice and control is important •  Blinding and randomisation limit feelings of control

•  “a patient would never come up with the concept of a randomised controlled trial: it’s an alien concept”

•  Should be choice of treatment arm (and no placebo)

•  Trials should test genuine uncertainty

–  Helsinki declaration


Quality of life is a key goal •  Needs to be defined •  Excluded from most US trials but essential for

HTA •  Questionnaires are poorly designed and ask

the wrong questions. Ask the patients •  Side effects

–  If it’s not on the list it’s not a side effect – Experienced on a daily cycle – Not reported due to fear of treatment being taken

away


Patients as research partners •  There should be open and transparent dialogue with

patients

–  Feedback to patients during trial: did not happen

•  The data collected should be openly used to support the care of all patients- beyond the research team

•  Current situation completely erodes the doctor- patient relationship

•  Not give proper explanations- had to read clinician information

•  “Thank you? I dream of a thank you!”


Alternative trial designs

•  “a clinical trial should go about saving human lives rather than answer a scien6fic ques6on”

•  Treatment choice in a pa6ent’s care should not be affected by the design of the trial to produce the informa6on.

•  More uncertainty in evidence tolerated because the trials do not contain ‘pa6ents like me’ and therefore not good predictors

•  “cross-‐over should happen as soon as it’s the best thing for the pa6ent” •  “well the pa6ents are all going to die anyway so what’s the incen6ve to

improve the trial design” •  Conference presenta6on on survival curves: “unfortunately not enough

‘events’ have happened” •  Anecdotal informa6on valued highly •  “should use the experience of pa6ents who have been in trials to design

bejer ones:


What are the positive aspects of RCTs?

•  “There are none”.


Next steps

•  Presenta6on of results at GetReal stakeholder workshop

•  Experience Based Design: clinician focus group •  Look at whether experience comparable in other diseases

•  Develop proposals •  Report back to second GetReal stakeholder workshop •  Report •  MPNE conference next year?




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Thank you We thank our speakers for contributing to the success of this conference, their commitment to MPNE and for sharing their slides. Feel free to share but please acknowledge the rightful authors! Melanoma Patient Network Europe www.melanomapatientnetworkeu.org MPNE 2015 The risk of not taking risks in Melanoma. 24th- 26th April 2015, Brussels, Belgium

Documents

Mpne 2015 conference material