Bridging the gap between the bench and the bed:

A Report from Fighting Blindness

Radisson Blu Hotel, Golden Lane, Dublin 8

10th November 2016

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Contents:

1. Background………………………..................................................3 2. Facilitated Discussion...........................................................4 3. Closing Remarks.................................................................11 Appendix 1 ............................................................................12

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1. Background

A recent workshop saw clinicians, patients and representatives from groups with a special interest in eye care come together to share their different perspectives and discuss the relationship between researchers and the regulator.

The workshop, which was titled ‘Consideration of Regulatory Requirements at all Stages of Research’, was hosted by Fighting Blindness and took place in the Radisson Blu Hotel, Dublin. The attendees heard from national and international experts in their respective fields and testimonies from patients who shed light on the realities of living with a sight-limiting illness.

The workshop was held as a satellite event to the annual Retina Conference.

The meeting was chaired by Prof Brendan Buckley, Chief Medical Officer of ICON, and member of the Medical and Scientific Advisory Board with Fighting Blindness.

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2. Roundtable Discussion

Prof Buckley began by pointing out that this workshop has run for a number of years: “These workshops help to clear the path in bringing the bench to humans,” he told the attendees. “There is a long-perceived problem that primary researchers tend to become hesitant as their ideas become more developed and become potentially applicable as therapy. There tends to be a certain amount of ‘fear and loathing’ when it comes to regulators and the barriers that may appear to stand in people’s way in making the step to clinical trials.”

He explained that the main purpose of the meeting was to discuss such issues and to remove such perceived obstacles. He also noted that the meeting included individuals with considerable experience in the regulatory sphere, including Dr Jayne Crowe of the Health Products Regulatory Authority (HPRA).

“One of the discussions in recent years has been around what are appropriate end-points in clinical trials of treatments for retinal degenerations and other forms of sight loss,” explained Prof Buckley. “Until very recently, with the notable exception of the macular degenerations there have not been many studies presented to regulators that are likely to give rise to very effective treatments. Regulators do not know much more than we do about what end-points are appropriate and we have a great opportunity to ‘make a market’ on this, so to speak, to collaborate with regulators and to influence regulator’s positions when they come to assess clinical trial protocols and eventually assess safety and efficacy.”

He called on the people at the meeting to share their experience in this regard in an effort to “bridge the gap between the bench and the bed”.

“There was a long-perceived problem that primary researchers tend to become hesitant as their ideas become more developed and

become applicable as a therapy.”

- Prof Brendan Buckley, Chief Medical Officer, ICON Plc.

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Dr David Gamm of Wisconsin, US, spoke about his stem cell work and interaction with the FDA and his experience in working with ex vivo cell therapy. “What got me excited was the semblance of a cell where we could actually replace a cell within the eye, but also actually one that had a great deal of the functional and structural characteristics that one would need,” he told the workshop.

He spoke about how at the time, he was initially uncertain of the practical considerations in working with industry and stated: “If you wait until you have all your ‘T’s crossed and ‘I’s dotted, you are never going to get there. If you get 20 people into a room, you might get nowhere because everyone will have two or three issues where they say, ‘we need to see this before we move forward’.”

‘Helpful’

Another attendee, Prof Robin Ali from University College London, shared his experience on a number of levels with the regulator in the UK and said he found them to be “extremely helpful”.

“I have gone from a position of being very nervous in dealing with regulators many years ago, to now regarding them as an ally. I have often used my interactions with the regulator to bring common sense to our own institutions, who tend to be far more risk-averse than the regulatory body… I have often found that the best way to deal with a clinical trials unit and ethics bodies is to go right to the top - to go to the competent authority and pass that down,” he told the meeting.

“That’s what I would advise - when your own local risk-averse office is telling you something that seems crazy, you will find that the regulator has a lot of experience and wisdom and is there to help. They tend to be very sensible; they often see what can go wrong and in discussions, I have often found that we are actually much more cautious than they are. The regulator is often much more flexible than most researchers would imagine at the outset.”

He advised the attendees to have conversations with the regulator early in the research process, as this will inform researchers:

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“It’s not about waiting a long time to amass data, because you could be gathering the wrong

data and the regulator might inform you on things you haven’t thought about and ask some

very fundamental questions.”

- Prof Robin Ali, Professor of Human Molecular Genetics, University College London

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Expertise

Dr Anne Cody of the Health Research Board (HRB) told the attendees that there are people within the regulatory bodies who have expertise in the design of clinical trials, including safety aspects and methodology.

“In terms of funding, we used to fund more basic research but we have been emphasising more and more that we want to take investigators with us and bring things forward, because there is nobody else in Ireland really funding that,” she said, explaining that the HRB initiated this policy change approximately six years ago.

“We are trying to instill the question of, ‘what will you need as you move on and what will the regulator want to see?’ There is no point in doing a huge battery of lab tests, funded by the Irish taxpayer, which might lead to a great result but that hasn’t been documented properly and will need to be done all over again.”

She emphasised that it is “extremely important” to have agreed end-points and to gather high-level evidence beyond one trial, for example.

Prof Buckley reminded the meeting that clinical trials were experiments, the same in principle as the bench experiments with which researchers were daily familiar. It is often helpful to remember that. “There is sometimes a sense that clinical trials should be able to ‘demonstrate something’. That misconception has grown because sometimes, researchers are talking to those in the wrong levels in industry who want you to demonstrate their preconceptions.”

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He suggested that researchers should ask themselves the question “Do I know enough about this treatment to perform the first experiment in man? Am I ready now?? This means, am I prepared to do this experiment; do I know enough to formulate the hypothesis correctly; do I know enough to set up the end-points; can I write a protocol; and can I back it up in evidence in an investigator brochure that sets out all that is known about the safety and efficacy in animals and other model systems? If the answer to all of that is “Yes”, then you are ready to have that first early discussion with the Regulator.

“Do I know enough about this treatment to perform the first experiment in man?”

- Prof Brendan Buckley, Chief Medical Officer, ICON Plc.

Dr Bart Leroy, who conducts most of his work in the Ophthalmo-Genetic Unit in Ghent, Belgium, raised the question that anatomical end-points are often not easily accepted by regulators. “Sometimes that is frustrating because if you look at an OCT of a retina and you can say something about the anatomical aspect of one cell layer, that sometimes helps to evaluate whether you are doing something right or wrong,” he said. “The regulator is there to protect the public and society, which is ultimately what we are here to do too, so it’s easy to collaborate if you get onto the same level.”

It was observed by one attendee that “there is some movement” among regulators in terms of acceptance of anatomical aspects, but Prof Robin Ali pointed out that “it’s all about having validated end-points”. He also observed that the emergence of serial imaging is helping researchers to reach such validated end-points.

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Supportive

Dr Jayne Crowe, Director of Human Products Authorisation and Registration at the Health Products Regulatory Authority (HPRA), explained that her organisation is “totally supportive” of research in Ireland.

“We have a really vibrant life sciences industry in Ireland, with the presence of nine out of the 10 large pharmaceutical companies here… there was a big downturn in the number of clinical trials being conducted in Europe and from our own statistics, here in Ireland in 2014, we approved only 80 clinical trials. The figures in the UK are not much better but for us, that was quite a drop in the number of trials.

“But I’m very pleased to report that in 2015, we approved 108 trials. That’s fantastic and it looks as if we are going to be on target for this year also. We also approved 10 clinical investigations into devices.”

She told the meeting that earlier this year, the HPRA introduced its new strategic plan for 2016-2020 and shared two of strategic goals of the plan, which she said fit perfectly with the workshop’s discussions.

“The first goal is to have better-informed users,” said Dr Crowe. “We know as a regulator that we have to reach out to everyone who is involved and wants to be involved in research, because the title of our conversation this afternoon is relevant - if people don’t know what the regulatory requirements are, it makes it very difficult in all areas of research. We have started to reach out — we are part of the Young Scientist of the Year initiative, we are getting involved with early-stage researchers and academia, and we are reaching out to tell people who we are and that we want them to come and talk to us,” she explained.

Advice

“We want to give advice and we’re reaching out to industry and to patients and the public in general. At the moment, we are very much involved with Derek Mitchell and IPPOSI - we are very much aware of the EUPATI initiative and we are working with Derek to try to continue this initiative at a national level in Ireland.”

Dr Crowe outlined the second strategic initiative to attendees: “This is about supporting innovation and it takes me right back to things like horizon scanning. I can let you know that the HPRA is launching an Innovation Office in the very near future. We also have national scientific advice process in place. We are heavily committed to the European Medicines Agency and we are represented in all of the committees.

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“To answer some of your questions, I would say that we very much want you to come and talk to us at any stage of your research development. We will give you the best advice that we can. Regarding some of the comments today, we are very happy to discuss end-points with you because there is no point in doing a trial and then considering end-points and finding that they are not effective.”

She continued: “One message that I would like to give you is that the HPRA is very open and wants to talk with you at any stage of [research] development. We will point you in the right direction — from our Innovation Office, we will give scientific advice… we have been heavily committed to the EMA scientific advice process for many years but we now have a dedicated service at the HPRA also.

One attendee stated that they were involved in a device trial in 2015 and found the HPRA “very accommodating, very straightforward and very helpful”.

“In terms of clinical trials, we will give you good advice on design and protocols, developments, end-points — anything to do with the trial, really. We are very willing and want to do business with you.”

- Dr Jayne Crowe, Health Products Regulatory Authority

Dr Dairine Dempsey of ICON added that it is time to initiate the “difficult discussion” between the regulator, researchers and patients as to what are clinically relevant end-points from patients’ points of view. “We have discussed gene therapies coming into play and the differences these can make for patients is something that we need to talk about as early as possible in the process.”

Another attendee posed the question of an ‘end-point’ vs ‘end-points’ and Dr Crowe encouraged researchers to approach the HPRA for advice in this regard. “We are realising that what we might think as a regulator to be a clinical end-point’ may not actually be a clinical end-point. For patients who are going to take prescribed medicines - and we have seen it several times — an end-point that we may not have considered can make a huge difference to a patient’s life.”

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Prof Buckley added: “There are precedents in other therapeutic areas for surrogate end-points to be acceptable at appropriate stages in clinical development of a therapy. However, ultimately the purpose of treatment is to make people see better and to achieve both a label for sight benefit as well as reimbursement, there will need to be clear clinical benefit demonstrated at the end.”

‘Informed partners’

Ms Catriona Dunne of Fighting Blindness explained the organisation’s initiative to make patients “informed partners” in the research and development process and told attendees that patient involvement is increasingly prominent in all stages of research. “If you are looking for scientific advice, a patient will be consulted at every protocol… we have spoken about the need to consult with regulators and researchers but no-one has actually emphasised the need to talk to patients and consult them in a meaningful way and not as a box-ticking exercise, and to really use EUTAPI.”

Dr Crowe concurred, adding that from the HPRA’s perspective:

“Patient input is totally invaluable.”

- Dr Jayne Crowe, Health Products Regulatory Authority

A representative of Novartis said from his company’s perspective, while there may be ‘end-points’, there “is certainly one crucial end-point — improvement in quality of life. Everything else is a surrogate end-point. Our focus is, how do you ask the right questions and how do you normalise patients’ mood, temperament and all the other factors that come into it when declaring whether or not a patient feels better as a result of treatment?

“That’s really where our challenge lies and if there is any help or collaboration around that, we are only too delighted to have it.”

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3. Closing Remarks

‘Go early’

Prof Buckley concluded the workshop by thanking all of those present for attending and summarised: “We have had a discussion that has really informed me enormously about this area. I will take a few things from this meeting but the really major headline is that you may be closer than you think to taking your research into humans. Also, you should go fearlessly and early to the regulator and you will be pleasantly surprised.

“There is the inevitable question of end-points, but we need to consider where we are in the experiment, whether we are at early exploratory phase, or whether we are trying to confirm what exploratory developments have shown us so far in terms of selecting our end-points,” Prof Buckley suggested.

“Surrogate end-points definitely have their place [in research], particularly early on, and will also probably reinforce the subjective elements that express what are important to patients. Patients are absolutely central to this process, because it is all about patients anyway. We are only bit-players in this, fundamentally, and every process that involves patients deeply in decision making will strongly benefit from doing so.”

A multi-stakeholder workshop entitled ‘Functional Vision versus Visual Function – Working Towards Integrating the Patient Perspective in Retinal Research’ is taking place in Washington DC on Nov 10, 2016. This meeting will provide a platform for discussions on current best practice in Patient Reported Outcome (PRO) and Patient Perspective Study (PPS) models for ophthalmology.

Prof Buckley continued: “I think we are short of validation in things that we are going to use to show efficacy. In many cases, we have to guess at the variance of measurements we are taking and that impairs our ability to take accurate power calculations. .

“We hope that the current meetings in Washington will be very informative on this — we expect that they won’t answer all of our questions, but we need to stay in close touch. There is a lot of work that can be readily done and even incorporated into routine clinical practice… some things can be done with a bit of thought and can advance the science just as much as working with rats, for example, because we are at the stage now where we need to know a lot more about humans and their eyes than we need to know about rats — this whole exercise is about treating blindness in humans.”

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Appendix 1: About Fighting Blindness

Fighting Blindness is an Irish patient-led charity funding and enabling world-leading

research into treatments and cures for blindness. The organisation was set up as a

support group in 1983 by families affected by sight loss and since then has invested

over €16.8 million in more than 90 research projects in Ireland.

We provide a professional counselling service to support people and families

affected by sight loss. Through education and advocacy Fighting Blindness works to

empower everyone in Ireland living with severe vision impairment.

Fighting Blindness is involved with rare, genetic, age-related and degenerative

conditions and represents the 224,000 adults and children in Ireland who are

affected by severe vision impairment.

Our vision is to cure blindness, support people living with sight loss and empower patients.

For more visit www.FightingBlindness.ie