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International Clinical Trials

Early Action

This year’s conference – one of my favourites in the clinical trial calendar – was attended by some 80 delegates and, in a change from normal, was co-located alongside the Central and Core Laboratories Conference.

The plenary session which opened the conference was introduced by Dr Allan Houston, formerly Senior Vice President of Astellas, who discussed innovative thinking in designing leaner, fitter Phase 1 and Phase 2a studies. He asked the question: what needs to change?

Dr Houston drew a comparison between innovation and invention, and noted that in the 20th and 21st centuries, the increase in gross domestic product per person is decreasing. He wondered if the innovation needed to fuel an increase is failing.

He also discussed how Phase 1 has changed from 1986, when safety and toxicity were the basic objectives of studies, to the more modern concept of ‘quick win, fast fail’, with the mechanism of action being investigated at the earliest stage possible. He noted that regulatory innovation is being driven by the Food and Drug Administration (FDA), rather than the European Medicines Agency, but also remarked that there are no shortcuts.

Future Development

The second plenary lecture was delivered by Neil Smith, Director of Regulatory Affairs, Chorus, Lilly Research in the US. He made the first of many references in the conference to the development crisis which is producing fewer new medical entities at an ever-increasing cost. His Chorus organisation is very lean, with some 40 people who, over its ten-year history, have looked in detail at over 40 new compounds, 30 per cent of which are biologics.

Of particular relevance is that 95 per cent of the work carried out by Chorus is outsourced. Dr Smith also referred to the fast fail technique and noted that the company was trying to get to proof of concept, and did so some 50 per cent faster than the industry norm.

The next speaker was Larry Lesko, a much-respected retired director from the FDA, who is now a Professor at the University of Florida. He gave a US regulatory update, and discussed how regulators write guidelines and help to develop models. He reviewed how user fees help communications and noted an increasing trend, at least in the US, to ask for more Phase 1 and 2a post-marketing studies.

Lesko commented that the FDA has considerable interest in why drugs fail, and he then discussed some of the key differences in values and judgment between the US and Europe. According to Lesko, the FDA now expects DNA to be collected from all patients in clinical trials and for this to have an impact on drug development in the future. He was very bullish about the use of modelling and simulation, but thought that Phase 3 was not likely to change in the near future.

Venture Capital

Following on, Francesco de Rubertis of Index Ventures gave an interesting presentation on how this venture capital fund assists companies in drug development. Unusually, the fund has a strategic partnership with two pharmaceutical companies: GSK and Johnson & Johnson. Currently, Index has 35 investments that are managed by its team of 16 drug development experts. The company is very realistic about potential failures, and so far over 70 per cent of the projects it has started have stopped for one reason or another. Because the company has such financial muscle – eight funds totalling over $2 billion – it can tolerate failures better than smaller funds.

The plenary session finished with a panel discussion which examined the evolving relationships between pharmaceutical, biotech, contract research organisations and venture capitalists, with representatives from all of these types of company.

Application of Science

The conference then split into two streams. One covered strategy and mechanics, which discussed sourcing models, sponsor vendor relationships, and patient recruitment. The other, which I attended, explored the application of science in early phase studies, knowledge-based strategies, pharmacology, safety and biomarkers.

Massimo Bani, Head of Clinical Pharmacology at UCB Pharma in Belgium, highlighted the use of positron emission tomography (PET) scanning in the development of drugs for anxiety. In addition, Yvonne McGrath, Head of Development at Immunocore, an emerging biotech company no longer funded by venture capitalists, discussed how her company has evolved and is now developing cell-based therapies in the cancer field. Its approach was contrasted with that of its sister company, adaptimmune, which is also developing cell-based therapies for cancer.

Hot Topics

The role of a good manufacturing practice (GMP) pharmacy in speeding up Phase 1 studies can often be overlooked, as was illustrated by Willem Jan Drijfhout, Executive Vice President of Early Development Services at PRA in the Netherlands. He explained how a GMP pharmacy on-site can save signifi cant amounts of time and money compared with the production of drug doses outside of the company.

Another hot topic today is adaptive designs in clinical trials, and Michelle Combs, a Vice President at Celerion, spoke about how single and multiple ascending dose studies can be carried out concurrently. She went on to describe how special arms can be added during these studies to address food, special patient groups, different formulations, smoking and the elderly.

Meanwhile, Dennis Dean from Vertex, Senior Vice President of Exploratory Development, outlined his company’s approach to cystic fibrosis. He noted that Big Pharma is now becoming increasingly interested in orphan drugs, partially under pressure from patient groups, and how new designs are required in these areas. Cystic fi brosis is not a single genetic disease but multiple diseases, with current treatment evolving to improve the life expectancy of patients.

In the last lecture of this stream on the first day, Don Nichols, Vice President of Pharmatherapeutics Research at Pfizer in the US, discussed the use of modelling and human systems biology to discover and validate targets. He referred to the rising cost of drug development but noted that failure, particularly in Phase 2, is the greatest cost of all.

The two streams then recombined into a discussion on the future structure of the pharmaceutical industry and how that could impact on exploratory drug development. However, this turned out to be a somewhat rambling debate on the relationships between venture capitalists and emerging biotech companies, which gave rather more heat than light.

Biomarker Update

Day two of the conference offered an even wider choice of three streams: one addressing sourcing models, a second looking at science in early phases, and the third on how to choose the optimal location for early phase studies.

Again, I attended the stream on science, which started with a discussion of how biomarkers can optimise drug development in the respiratory area. Lindsey Cass, Head of Clinical Development at RespiVert UK, examined how to identify and validate biomarkers in respiratory medicine. In a case study on the use of biomarkers in central nervous system (CNS) studies, Paolo Bettica of Italpharmaco went over much of the same ground that had been covered in a presentation the previous day on the use of PET scanning in anxiety and other CNS studies.

Carol Astbury, Head of Early Development and Global Project Leader at Almirall Spain, also looked at biomarkers in respiratory studies. She noted that for chronic obstructive pulmonary disease and asthma, there may be multiple targets that are available for validation, but in all cases models are very difficult to validate.

Manuel Meyer, a Professor of Cardiovascular Proteomics at King’s College London, covered the use of biomarkers in cardiovascular disease. One of his frustrations seemed to be that biomarkers may predict statistically cardiovascular events in a large population, but do not predict on an individual scale. He felt that there would be some future in looking at micro-ribonucleic acid fragments which are very stable.

Complex Studies

Robert Lins of SGS showed how his company in Belgium is developing a special facility, wherein healthy volunteers and patients may be inoculated with viruses. He noted that there was little guidance on how these complex studies, which measure cytokines, respiratory functions, mucus and sputum, among others, might be carried out. The audience was surprised at the willingness of asthma patients to be inoculated with viruses, but Lins said that recruitment into his studies was not a problem.

Thorough QT studies with healthy volunteer panels exceeding 100 can incur costs well into the millions of dollars. Marek Malik from St George’s Hospital, University of London, discussed how smaller Nearly Thorough QT studies can in many cases replace Thorough studies. He noted that a consortium was now producing a white paper for guidance in this area.

Dose Regimens

Ronald Smulders, a Senior Medical Director at Astellas, talked about establishing dose regimens in first-in-man studies. He reviewed the different approaches between regulatory bodies in defining the starting dose. The first step he uses is to do a thorough risk assessment based on toxicology in animals – a complex task which must eventually choose the smallest dose using all relevant data. Having determined the minimum anticipated biological level, he felt that if this level was well below the predicted no effect of adverse event level, then doses could be aggressively escalated if no adverse effects were noted. John Connell, Vice President, Pharmacodynamics at Icon UK, discussed the early use of clinical pharmacodynamic models in healthy volunteers. He said some indication of efficacy can be developed, but warned that many animal models or models in the healthy do not predict human efficacy accurately.

Driving Regulation

The closing plenary session was devoted to the role of regulators in driving early phase trial developments. David Jefferies from Eisai gave an overview of the proposed new European Regulation for clinical trials and how it differs from the current European Directive. He noted that, going forward, regulations covering clinical trials in devices, in vitro diagnostics and pharmaceuticals will become identical. Industry, he felt, was relatively happy with the timelines and structure of the planned new regime, but until the final details are available it will not endorse it wholeheartedly.

True to form, this event did not disappoint. Unusually, many of the speakers gave real-life case study examples of their experiences. Audience participation was, by the standards of many conferences, good. Anybody interested in Phase 1 and Phase 2a studies will have felt that the two days was time very well spent.

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