Clinical trials insight: cardiovascular disease

In the latest in a series of interviews with INC Research clinical trial specialists, pharmaphorum talks to Sally Osmond, therapeutic business unit head for the company's Cardiovascular & Endocrinology group.

What are the biggest challenges in planning cardiovascular trials today?

The biggest challenge is access to the patients - in particular, access to the right sub-groups of patients. A few years ago we used to conduct mega trials which encompassed all kinds of patients, but today trials are much more specific. That means finding sub-groups of patients, and that is much harder.

You have to educate everybody along the way, the physicians, patients and people who are executing the trial, so that they understand that we're not fishing in a great big pool. Access to the patients themselves is difficult; I still regularly meet patients who say: "I wish I could be in a clinical trial", but there is no point of entry for them. Their doctor doesn't do clinical trials. So even if a patient is motivated to find the trial themselves, it is still not an easy thing to execute.

Another factor is that many patients are very well informed these days, and know what medicines are currently available. So they say to their doctor "I'm on this medication, and I think you should give me that new one, I see it is on the approved list". That allows them to be picky. The expansion of trials into the rarer geographies of the world was partly driven by the fact that a comprehensive healthcare system, and modern medicines, were not available to ordinary patients in those countries. But standards are improving in those countries, and that tends to take patients out of that pool for clinical research.

"It's good to see patients empowered... the challenge is how to best link those patients to potential trials"

Another factor is the ageing of the world's population. This is affecting the patient profile in terms of diseases. We've got a whole generation now moving into their 80s, and it is just becoming clear what sort of challenges that will create in medicine. One example of that is the co-morbidities patients now have, which can complicate trials.

Does that mean that people in their 70s or 80s are eligible for trials whereas 10 years ago they wouldn't have been?

I haven't personally seen it - the majority of protocols have an age limit of 65. One reason for that is that participating in a clinical trial can be quite intensive. It can require multiple hospital or doctor visits, and a lot of procedures such as fasting before blood tests. So, the concern is about the patient's ability to comply with protocol; if there's any reason for lack of compliance then you could put your trial at risk.

What impact is the empowered patient having on trials?

It is good to see patients empowered, understanding their illness and wanting to push the boundaries of medicine. The challenge in clinical trials is how best to link patients to the right trial. Some people suggest that we can create open databases to allow patients to say I've been diagnosed with X, Y or Z and volunteer to enroll on a clinical trial that suits them.

But I think there is still a long way to go before we get there. Each pharmaceutical company has its own intellectual property to protect, so I'm not sure the industry is ready for an open market where you put all the trials out there. That's totally alien to what we're accustomed to, but perhaps it's something we'll have to consider in future.

What other developments have made an impact on the trial process?

The biggest impact I see is the ever increasing requirements of the regulatory agencies for more data. That means sponsors are trying to collect more data than they've ever collected before – the idea being: 'We'd better collect this data because somebody might want it in the future'. This creates increasing complexity. We have electronic diaries, we have patient reminder tools - what 10 years ago would have been a 30-minute session between a CRA and the investigator can now take half a day. My opinion is that all these processes are clouding the protocol. In my opinion, the protocol should ask clear, limited questions and then the data collected should be specifically designed to answer those questions. If protocols are becoming more complex, responsibility lies partly with regulators but also partly with sponsors. We need to revisit this 'everything and the kitchen sink' approach to trial design, which is increasingly common.

That is fascinating because your colleague Nick Kenny had a very similar insight in oncology – so clearly it's a problem that is common across therapy areas. What can be done to rationalise that process?

Pharma really can and should take the lead. Research shows that the data we collect and analyse has multiplied by a factor of thousands in recent years. Pharmaceutical companies have to go to the regulators and ask, 'What is it you absolutely want to see the trial achieve?' That, as opposed to giving them data on all the things they've ever requested.

How are market access challenges impacting trials? For instance the data demands of Health Technology Assessment (HTA) organisations such as NICE?

Market access challenges do affect trials, because we've seen a serious diminishment of 'me-too' drugs. This brings us back to the issue of informed patients. If a Google search has told them that drug 'A' is ten times better than drug 'B' you would be a very brave practitioner to start writing a prescription with 'B' written on it!

Because payers have tightened up their requirements, you are trying to prove your drug is more effective than existing treatments. But in terms of trial design, this is only a secondary pressure compared to the problem I just mentioned of collecting too much data.

What role can real world data play in this?

There are two questions which clinical trials are designed to answer: does my drug work and is my drug safe? But with the new technology and with the real world databases that we can now access, quite a lot of the 'environmental' questions or the statistical questions could be quickly and easily answered.

There is so much that you can do with real world trials and real world data. For example the data now available through UK databases is remarkable; you ask the right questions when you've got millions of patients' data available to you to do the analysis on it. It becomes very powerful very quickly.

How is technology affecting the way trials are conducted?

Technology, used properly, should make collecting data easier, and make us less worried about the validity of that data. It should help us predict which sites will do well and the enrolment of patents, including potential dropouts. That means the technology has to be constant, reliable and simple for the users - patients, investigators or nurses. Unfortunately, we are not there yet. When you introduce a complicated tool into an investigator's, or a nurse's, hands, inevitably things will sometimes go wrong. What is the most common problem the IT help desk has to deal with? It is always the same: 'I've forgotten my password.' That is such a simple problem, but it means you can't even start work, so it causes huge delays and inefficiencies.

"Stem cell therapy will play a role in the future of cardiovascular medicine"

In terms of so-called 'disruptive technology' or innovation, is there anything which could change the whole model of cardiovascular healthcare? What about, for instance, regenerative therapy such as stem cell therapy for heart failure?

We are seeing a big increase in stem cell studies coming through now; these are often very academically driven. Specialised companies are taking those on, but they face a very complex technical challenge, in terms of ensuring consistent quality and procedures in the cell harvestings, the regenerations and the re-planting of the cells.

I think that's where people like us come in, because we can apply rigour, train and work with those experts. If you can't get that technical challenge right, your trial will be a failure. What's worse, it will suggest that your technology is a failure, when in fact it could just be human error in the production process.

So regenerative medicine isn't mature either in practice or technology?

No, but I am convinced it is going to develop, because we have seen some of the technical challenges overcome, such as the consistency of the cell preparation. Many of the necessary ethical questions have also been discussed and now have legal frameworks, so that has also been tackled.

The rationale as you have described it, in terms of identifying the disease mechanism precisely, has been used in cancer. Is that emerging now in the cardiovascular field?

When you look at the sub-indications within cardiovascular disease, so many of those haven't really been targeted yet. Yes, the broad categories have been dealt with, but I suspect that there is a whole group of indications that are being managed and copied, rather than being treated. When people start to take that deep dive, they will find more opportunities, and stem cell therapy is certainly going to be part of those developments.

Do you have any thoughts about new classes of cardiovascular drugs in the pipeline? There is a buzz about cardiovascular medicine at the moment, with the PCSK9 class, and the new heart failure drug LCZ696, among others. What will be the most exciting development areas?

There are some interesting things coming through trials, and some massively interesting molecules in the lab. The truth is that there are billions of people on the planet and many of those people have, or will one day have, a cardiovascular event or illness – much more so than any other condition. So the patient pool is enormous and there is still a huge demand for cardiovascular drugs that can be easily administered, that are cheap to manufacture and make a real difference to either life expectancy or life quality. So every week we see something novel. I certainly think we'll see cardiovascular medicine produce quite a few exciting drugs in the next decade or so.

"A novel mechanism of action can engage and excite not only the scientific world, but also your patients"

What is your best advice for pharma companies looking to enter the field for a specific drug?

The first piece of advice is be novel, be new; there is no point replicating research. So a novel mechanism of action can engage not only the scientific world, but also your patients, so that you create interest and excitement. The second piece of advice is 'less haste, more speed'; time and time again I see companies jumping into their clinical trial process before they obtain enough real data in their animal models. So they start before they've answered all the questions. Then quite often they have to stop again. They get asked by regulatory authorities to stop, go back and re-think. So sometimes in their anxiety to get into the clinical trials, companies haven't done enough work in the early phases of development.

About the author:

Sally Osmond has been the therapeutic business unit head for the Cardiovascular & Endocrinology group in INC Research since July 2011. Prior to this appointment she held executive roles in various large international CROs and has been responsible for the delivery of cardiovascular and endocrinology projects both at the rare disease level and for global mega trials involving many patients and geographical regions. Sally started her career in medical bio sciences and has fellowships in immunology and bio chemistry.

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