Title: NIBSC Regulatory Science Research Unit
Funder: Department of Health and Social Care

Abstract: Introduction Biologics are hugely important from both a public health and an economic perspective, encompassing well established vaccines delivered to virtually every child in the world, through life saving blood and tissue derived products to innovative and very high value monoclonal therapeutics for cancer and inflammatory disease. In addition, the revolution in genomics analysis, coupled with major advances in understanding of molecular and cell biology, has stimulated the development of a very wide range of potential new biological medicines and technologies, often highly complex, that if proven to be both safe and effective, could have a major impact on human health over the next 20 years, particularly within an aging population. NIBSC is on the verge of joining the Medicines Healthcare Regulatory Agency. The enlarged Agency has two fundamental goals: • Ensuring existing medicines remain safe and effective • Supporting the safe and effective development of new medicines The rising importance of biological medicines, to the point where they now dominate both the list of top selling drugs as well as the future pharmaceutical pipeline, underlines the importance of maintaining this scientific strength in the UK. The MHRA, in formulating its new Corporate Plan, has identified clearly the need to focus on biologics, and has fully recognised the benefits of maintaining and building on NIBSC’s existing research capability in order to deal with inevitable challenges ahead and to further its objectives both nationally and internationally. Achieving these goals for biological medicines is, and will remain, a major challenge. Their complexity is such that they present significant risks as well as opportunities. Managing these risks effectively, while at the same time supporting the development of novel products to meet important clinical needs, requires a deep scientific understanding of what they are, and how they work. This in turn requires specialised research, termed here Regulatory Science Research, targeted at key problems. Research at NIBSC NIBSC’s central mission is standardisation and control of biological medicines. Its expertise, capability and facilities are unique, and it enjoys a very high reputation as the global leader in international standardisation of biologics. NIBSC’s statutory functions include carrying out research related to its core aims1. The Institute has a very successful history of regulatory science research stretching back over many years, evidenced by peer review, publication output (an average of 100 scientific publications per year) and an impressive track record in winning external research funding (currently £2.5m per annum). Over the past 30 years, the Institute has forged unique ties with the Biologics Industry and established strong and dynamic links with academics with pertinent scientific or technical expertise. Its senior scientists are expected to maintain an active research programme alongside their core standardisation and control duties. As well as addressing important research questions related to the NIBSC mission, this helps build the breadth of scientific expertise and influence that allows the Institute to provide evidence-based advice to shape policy, maintain its position as the global leader in its field, and to respond effectively to challenges relating to biological medicines as they occur. Examples of such challenges in recent years have been serious unexpected adverse events following clinical trials, concerns over vaccine safety and quality, product contamination issues, and blood product safety. Merger with the MHRA offers an excellent opportunity to strengthen further the regulatory science research programme at NIBSC, ensuring that it is as closely aligned as possible with the challenges of product development and that its outputs feed into the development of robust, evidence based regulation. It is crucial, especially in the area of innovation, that regulation, while managing risk effectively, is as ‘light touch’ as possible and supports new product development. NIBSC’s scientific understanding of the issues, the MHRA’s broad expertise in regulation, and the leading international position that both organisations hold, puts the combined organisation in a unique position to lead the way in developing better regulation. We anticipate that this will also help make the UK a more attractive environment in which to develop biological medicines in support of the Government’s Life Science Agenda2, which specifically highlights the role that effective regulation has to play. Until 2009, core funding for research was embedded in the total Grant in Aid provided to the Institute by the Department of Health. Following merger with the HPA, projects classified as research needed to be identified separately and the associated resources, consisting entirely of existing permanent NIBSC staff time and internal laboratory costs, were administered through NIHR. This arrangement will cease on merger with MHRA. The proposal put forward here is to establish a Regulatory Science Research Unit (RSRU) within NIBSC, funded by DH, to maintain this core research capability and to focus on key research priorities. The intention is that these research activities will be supplemented through drawing in additional research funding from national and international sources. The Unit will therefore provide a solid platform for senior scientific staff to maintain their involvement in research and to build their scientific expertise and international profile through: • developing programmes of laboratory research related to NIBSC-MHRA goals • establishing links with appropriate academic experts in fields of research that support the programme • opening up new areas of through generation of preliminary data • preparing applications for grant and other additional funding that builds on the preliminary data generated as above • directing externally funded projects and managing the additional scientists recruited to perform this research. It should be emphasised, however, that the RSRU is not intended to be the only focus of research at NIBSC. All senior scientific staff at NIBSC will still be expected to be active in research and to seek external research funding to pursue research goals. Over time it is expected that priorities will change and that new projects, and other members of NIBSC staff will become associated with the RSRU. It is critical that research capability at NIBSC is maintained. Government funding for the organisation has dwindled steadily over the last 30 years, and NIBSC’s work is now largely funded by selling standards and control services. This trend is set to continue, placing ever more pressure on staff to focus on revenue generation at the expense of scientific research. We anticipate that the RSRU will provide an important bulwark against these pressures, while delivering research that has real impact in the field. Interactions with Policymakers We have outlined above how this research will inform the development of regulatory policy both nationally and in Europe through MHRA. NIBSC scientists also contribute directly to over 80 bodies in the UK and abroad, and their influence is substantial. These include key national committees such as JCVI3, JPAC, SPI, European bodies such as EMA and EDQM, and many other international organisations. Of the latter, WHO is without doubt the most important. NIBSC’s work on standardisation and control is a core component WHO’s Biological Standardisation programme, one of its oldest normative functions. This is highly influential in developing the regulatory framework for biologics internationally. With the rise of biologics production in India, China, Korea and other countries, this is a very important and growing area of influence. Key Research Themes for the Next 5 years The field of biological medicines is extremely broad, encompassing well established classes of products such as vaccines, immunoglobulins and blood derived products, monoclonal antibodies and protein based therapeutics produced by recombinant technology, through to highly complex novel cell-based and gene medicines. The challenges these medicines throw up are extremely varied, and so the potential areas of for research are myriad. Careful research prioritisation is therefore essential (see section 7). A recent review of the field of biological medicines by NIBSC, in conjunction with the MHRA, highlighted the following priority areas for research. • Ensuring existing biological medicines remain safe and effective Confidence in a continued supply of high quality safe vaccines is absolutely vital for national and international public health. This is by no means assured, however, as the global landscape for vaccine supply and uptake evolves. There is now a heavy reliance on a small number of manufacturers supplying the developed world, and this, together with the development of increasingly complex combination products, makes ensuring resilience of supply ever more difficult. New vaccine producers are coming on stream, especially from India and Far East, but their products have as yet limited safety and efficacy history. It is vital that we have robust tools in place for rapid and thorough assessment of vaccines to manage these challenges. The continued presence of a very active anti-vaccine lobby with access to receptive media coverage means that any genuine quality issues would likely have a major impact on vaccine uptake in general and a highly detrimental effect on public health. A further specific vaccine research need is to support the rapid deployment of safe and effective influenza vaccines. Pandemic influenza remains near the very top of the global risk register, and there is intense pressure to reduce as far as possible the time needed to develop and supply tailored vaccines. Potency testing is a critical step in the process and improved methods could both speed and ‘de-risk’ the process. Protein based biotherapeutic medicines have been enormously successful and products such as cytokines, growth factors and monoclonal antibodies now rank amongst the most lucrative pharmaceuticals on the market,. They are mostly produced by recombinant DNA techniques and can be extremely expensive. Patents covering the earliest recombinant products to be developed are now nearing expiry and so it is not surprising that a raft of so called “biosimilar” products are now being developed by manufacturers around the world and put forward for licensure. These promise considerable savings to purchasers, but the key question is whether they really do have the same efficacy and safety profile. It is often said that biologics are defined not so much by what they are but by the process through which they are produced. The move toward such biosimilar products, while attractive in many ways, needs to be managed carefully. Biosimilars require a full quality dossier, and somewhat abbreviated preclinical and clinical dossiers (although considerably larger programmes than for chemical generics), including usually large head to head clinical studies against the reference product. The key to the licensing process is comparability – in terms of quality, safety and efficacy – and so there is a critical need for robust laboratory based methods to be able to demonstrate comparability. • Supporting the development of new biological medicines In the developed world, where the tools for controlling major infectious disease threats are well established, the development of treatments and preventative measures for non-infectious disease offers the greatest promise for continuing to improve public health. A class of medicine that has already had a major impact and is expected to continue growing in importance is immunotherapeutics – drugs which deliberately aim to manipulate the human immune system for clinical benefit. These drugs can be highly beneficial, but the exquisite balance and extreme power of the immune system is such that failure to understand completely their effect can lead to disastrous consequences, such as the serious adverse events that followed the trial of TGN1412 at Northwick Park hospital in 2006. Understanding better these negative and positive effects is an extremely important area for research. Of even wider potential significance, but much more complex and demanding from the perspective of standardisation and control are cell-based and gene-based medicines. Here the range of potential benefits is very wide indeed but the field is immature and there is as yet an incomplete understanding of how to ensure safety and consistency of effect. Practical laboratory methods are urgently needed to help develop a regulatory framework that can provide assurance of safety and efficacy while still allowing incremental development of the field. • Supporting the development of personalised medicines Rapid and inexpensive technology for sequencing genomes and characterising gene expression is creating the opportunity for stratifying the clinical effect of medicines according to the genetic makeup of the patient. Directing treatment based on genetic analysis offers the potential for benefit both in terms of safety and efficacy, but it is crucially dependent upon the accuracy and quality of genetic diagnostic information. Understanding and defining the principles that determine the quality of this diagnostic information is essential so that tests can be appropriately standardised and output data is reliable and comparable. This application does not include specific research proposals in this area, but it is intended that such proposals will be developed and initiated over the five year period, overseen by the proposed Scientific Advisory Committee (see Section 7). • Exploiting new technologies Recent technological developments have provided powerful new approaches for characterisation of complex biological medicines and these are already beginning to be used by both manufacturers and researchers. Next Generation Sequencing, for example, may be used to probe routinely live viral and bacterial vaccines with a precision hitherto impossible. The same technology also offers the opportunity to stratify medical treatments according to the genetic make-up of the patient. In addition developments in Proteomics now allow highly sophisticated analyses of peptide sequences in complex biological mixtures, facilitating better characterisation of innovative product classes and allowing post transcriptional regulation of gene expression to be evaluated with exquisite sensitivity. These technologies, however, have limitations, and it is essential that these are clearly understood and that the results are reliable. It is also crucial to make sure that results are interpreted appropriately. The recent ‘deep sequence’ analysis that revealed the presence of porcine circovirus in rotavirus vaccines illustrated the importance, from a regulatory science perspective, of keeping abreast of technology developments so that policy making can be based on a rational and balanced view of the scientific evidence. • Applying the principle of the 3R’s to biological medicines The complexity of biological medicines is such that their safety and potency profile can be determined only through measures of their key biological characteristics. Historically, many of these bioassays have been developed to use live animals. However, there is increasing pressure to move away from such tests under the Principle of the 3R’s (Reduction, Refinement or Replacement), most recently as a result of the recast of the EU Directive on the Use of Animals in Scientific Research. This is generally welcome, but there is some risk that introduction of poorly understood and validated non-animal tests in place of well tried and tested approaches could compromise patient safety. NIBSC has had a very successful 3Rs programme in place for many years, resulting in dramatic reductions in the use of animals, and so the new legislation presents an opportunity to further the programme, while ensuring that the highest possible standards of safety testing are maintained. Priority Project Areas Within each of these overarching themes, of course, there is a need to focus on particular research projects that meet practical needs and are likely to be most productive. Options have therefore been reviewed according to a set of criteria as follows: • Importance to public health • The specialist expertise that exists within NIBSC • The impact and likelihood of success • The ability to build on the internal research expertise and maximise its impact by working with external collaborators and bringing in additional research funding • Being prepared for biological products of the future On this basis a number of particular research topics have been identified and are put forward in detail in this proposal in Section 10.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE