Clinical Research - Improving access to myeloma drugs

Improving access to myeloma drugs

Eric Low looks at the problems with current clinical research into myeloma in the UK and explains how the new Myeloma Clinical Trial Network will encourage more clinically relevant studies

Each year nearly 4,000 people in the UK are diagnosed with myeloma, a rare cancer of the plasma cells. For these sufferers there are many promising new developments on the horizon, including next generation proteasome inhibitors, next generation immunomodulatory agents, and classes of drugs that target the chromatin pathway. Yet despite current progress in myeloma research and treatment, the difficulties in setting up clinical trials in the UK, and in translating the benefits from clinical trials into NHS practice, have proven a stumbling block.

The national clinical trial databases reveal there are only around 10 Phase I or II trials for myeloma in the UK, compared with approximately 250 that are recruiting or soon to recruit in the US. The clinical trial impetus in recent years has generally been led by the pharmaceutical industry, where international licensing trials have been able to accumulate the necessary critical mass of patients. But while some patients have benefitted from participating in these international trials, they represent the minority of myeloma patients in the UK.

For example, just a tiny minority of UK myeloma patients (less than 50 out of the several thousand relapsed myeloma patients in the UK) took part in an international licensing trial for lenalidomide – only the second drug to be developed and licensed specifically for myeloma. Other patients in the UK had to wait several years – many until Autumn 2009 – for NICE to approve it for use on the NHS – and it has still not been approved by the Scottish Medicines Consortium, which means patients in Scotland have only patchy access to the drug.

Moreover, commercially led clinical trials in the UK do not adequately reflect standard UK clinical practice, and often fail to answer the most relevant or critical clinical questions. There is therefore a need not only to conduct more clinically relevant studies in the UK, but also to conduct studies that complement a registration study and give an indication of the likely lifetime use of the drug in the clinic. The Myeloma Clinical Trial Network, which launched in October, aims to do just that.

The heart of the Network

The Network is a key component of the Myeloma UK research strategy, which is designed to systematically address the critical challenges slowing down research, development and access to new effective myeloma drugs in the UK. Eight lead trial sites have been recruited to conduct a prioritised portfolio of early phase trials of novel myeloma drugs in the UK. These are:

St Bartholomew’s Hospital, London
University Hospital, Birmingham
Christie’s Hospital, Manchester
King’s College Hospital, London
St James’s University Hospital, Leeds
Nottingham University Hospitals
Royal Marsden Hospital, London
University College Hospital, London

These centres – recruited following a peer reviewed application process – have well-maintained links to other collaborating sites across the country, so patients around the UK will have equal opportunity to participate in the trials – something that has not been possible until now.

Not surprisingly, patient recruitment is currently difficult in myeloma, both because of a lack of trials and because those trials that are conducted tend to be focused in individual geographic areas. Under the Network, trials will be prioritised and available to all qualifying patients in centres across the country. This prioritisation will have the added benefit of allowing patients to be recruiting to a strategic, non-competing portfolio of trials, so making the whole recruitment process easier.

Moreover, a central aim of the Network is to overcome the current problems of bureaucracy and funding which stifle the desire of researchers, doctors and industry to set up and undertake clinical trials of novel myeloma drugs in the UK. A national coordinating office will therefore be based at the University of Leeds to relieve much of the administrative burden.

The office will have six to eight core staff – trial coordinators, trial managers, data processors, statisticians and clinical trial associates – who will manage the trials and coordinate them throughout their design, risk assessment, regulatory issues, trial logistics and feasibility at a practical level, including obtaining ethical, regulatory and NHS approvals. It will ensure the trials run smoothly in each centre, manage pharmacovigilance, and provide quality assurance and analysis of the trial data on behalf of all the trial sites. Myeloma UK will fund these roles, as well as provide funds for a research nurse and trial coordinator at each centre, investing more than £3 million over five years in the Network.

A coordinated approach

The objective of the Network is to ensure that all available resources are used to the maximum benefit of patients. Until now, NHS-led clinical trials have tended to be undertaken in isolation of each other and independently of a structured and coordinated approach, which is a problem when resources and eligible patients are scarce.

At the same time, pharma’s commercially led, straightforward ‘A versus B’ outcomes trials – designed to satisfy the licensing process – are becoming increasingly irrelevant to complex diseases such as myeloma, as tailored treatment combinations of several synergistic drugs define much of its management. The international APEX licensing trial looking at Velcade monotherapy vs dexamethasone is a good example of a commercial trial that has not provided answers to the critical questions. This ‘A vs B’ trial was designed to prove the efficacy and safety of Velcade. However, in reality Velcade would not be used as a monotherapy as it is more effective in synergy with other drugs, and what the myeloma community needs to know is the most effective synergy for optimal outcomes. The clear advantage of the Velcade arm in the APEX trial resulted in the trial being stopped and all patients crossed over to the Velcade arm. Not only did this not answer the critical question, but it caused problems in the robustness of the data, which in turn created difficulties in the NICE appraisal process.

Indeed Professor Sir Michael Rawlins, Chairman of NICE, recently said that Phase III licensing trials are not the only gold standard of evidence. International pharmaceutical-led Phase III trials often do not adequately reflect standard UK clinical practice as they are designed for an international market and therefore cannot use the UK standard clinical practice as the comparator. Nor can these trials aim to answer every country’s priority research questions: if they were to do this they would limit their market. But this can cause problems at the approval stage when new drugs are assessed for the added value they would offer the NHS compared to the current standard of care. Too often, this is not factored into the trial design, and the result is a more difficult appraisal process of new drugs. The Novartis/NICE pilot in 2007 has set the scene for earlier discussions between NICE and industry and we hope that companies involved in future Phase III trials for myeloma drugs will see the benefit in this. However, it is still an issue that the NHS is a small player in the international market, and therefore the international licensing trial data will tend to present a stumbling block.

Research communities need to think more holistically about the process from laboratory to the NHS clinic; to reassess the type of data trials generate; and to ensure the anticipated clinical use of a treatment is factored into the research at the outset. But paradoxically, those trials that do aim to answer the most relevant questions to improve patient outcomes – normally NHS trials – face the most problems in securing funding and getting off the ground because of the inherent problems of bureaucracy, funding and resources.

This is where the Network comes into play. The priority of the Network will be to research new, novel small molecules in very early phases of clinical development, such as next generation proteasome inhibitors, IMids, HSP90i, chromatin and monoclonal antibodies, and find effective new drug combinations for currently available products.

By answering priority questions through an early phase trial portfolio, the key gaps in the evidence base can be addressed and the knowledge used to set the standard within current NHS practice. Additionally, the outcomes will help supplement and inform later stage licensing trials of the most promising new drugs. Each research question will be trial specific.

The pharmaceutical industry will be a key player in the success of the Network; but as a partner, not as the driving force. The Network will facilitate collaboration between the experts in the pharmaceutical industry and the NHS to conceive, design and together deliver a portfolio of relevant and prioritised trials of novel myeloma drugs. Trials will be designed and prioritised on the basis of clinical need; however, the Network will also provide a platform from which NHS researchers can engage with industry and attract commercial opportunity.

With all the key players on board the Network offers benefits to all parties, but most importantly to the 14,000 myeloma patients in the UK. Patient benefit is both the driving motivation for the Network and will be the measure of its success.

Eric Low is Chief Executive of Myeloma UK