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European Biopharmaceutical Review

In Harmony?

According to the EMA, at least 23 personalised medicines with safety or patient selection benefits based on genomic biomarkers have been authorised via the EU centralised procedure – significantly fewer than the 85 drug/companion diagnostic products estimated to be available in the US – while at least 26 orphan designations have been made for products based on a personalised medicine approach. Biopharmaceutical companies continue to increase their involvement within this field, and the number of trials has rapidly grown since the original trials of trastuzumab for breast cancer. While oncology has been at the leading edge of R&D, more recently, other therapeutic areas have seen patientspecific approaches, including cardiovascular, infectious and respiratory diseases (1).

According to McKinsey & Company, in the near term (three to five years), the next frontier of personalised medicine is likely to be in immune-related, paediatrics/pre-natal and infectious diseases. In the long term, central nervous system and cardiovascular diseases are considered to hold tremendous potential for this area, but research is still in the early stages of development (2). Experts also consider that conditions such as Alzheimer’s may be targeted once the individual mechanism of disease is more fully understood.

Furthermore, we are now starting to see the potential impact of personalised medicine on orphan research as we enter into post-genomic understanding of rare disease. For example, the EMA recently approved Vertex Pharmaceuticals’ Kalydeco (ivacaftor) for patients suffering from cystic fibrosis with a specific mutation – the first drug to address the underlying cause of cystic fibrosis, rather than the symptoms.

Catching Up

Personalised medicine products, such as (companion) diagnostics (CDx/Dx), are developed from a base of multi-layered research analysis referring to molecular and cellular processes, the purpose of which is to identify and understand the clinical relevance of biomarkers in relation to health and disease. There is a perception that the EU product regulatory framework is lagging behind the science: at present, there is no official definition for personalised medicine in the EU legislature, and the European Commission acknowledges that several challenges to its implementation exist – especially in the area of research – resulting in the need for a holistic approach (3).

Disease prevention and targeting of treatment requires R&D that delivers clinically viable combinations of new diagnostic technologies (such as assays, next-generation sequencing and imaging technologies) with new or better understood medicines. In order to allow the significant volume of research data generated from multiple layers of analysis to be translated into clinically meaningful information, the European Commission has also identified statistical methods and ways of analysing and managing big data as necessary.

Software tools will be essential in delivering relevant and useable clinical information to health professionals in clinics. In practice, this will entail development and use of diagnostic interpretation aids, clinical decision-making support, earlystage R&D analysis tools, and improved structuring and management of databases. Some of these data analysis tools and aids will be classed as clinical software. The approach to regulating this has already triggered significant member state debate, leading ultimately to non-legally-binding guidance in 2012 with the aim of promoting uniformity of practice and greater legal certainty for manufacturers (4).

Regulatory Demands

The challenge which personalised medicine presents to European regulatory authorities is how to encourage and facilitate high-quality, relevant research and innovation in the EU, at both pre-competitive and competitive stages across a variety of product development processes. At the same time, a high level of protection for patients and users must be ensured, particularly in relation to final products designated for the EU market and intended for use in combination. This is not a new challenge – the facilitation of the single internal market and a high level of patient/user protection have long been the twin legislative bases for EU regulation of healthcare products.

Personalised medicine can offer opportunities to regulators – with regard to patient safety, for example – as personalised medicine testing or investigation can provide additional, valuable safety-related data relevant to existing therapies, permitting these to be targeted more effectively in clinical practice. Personalised medicine technology is therefore likely to grow in importance as a tool in the operation of effective market surveillance and pharmacovigilance, and will increasingly feature in risk management planning and in post-market safety and efficacy studies.

The current EU healthcare products regulatory framework has developed based upon a silo approach, with the regulatory pathway for a final product depending largely on its qualification under one of the following sector-specific directives – pharmaceuticals, in vitro medical devices (IVDs) and medical devices. One practical consequence is that expertise in regulatory bodies is often located within separate agencies – for example, the EMA lacks competence and personnel to regulate CDx/Dx or medical devices, which are instead dealt with by national agencies and notified bodies. Additionally, personalised medicine demands a higher level of interaction across previously distinct regulatory pathways for medicines, CDx/Dx and clinical software/devices. However, the current European directives do not contemplate this type of holistic approach – nor does the guidance developed by the EMA’s Pharmacogenomics Working Group.


Biomarker identification is key for personalised medicine. Drug manufacturers use these to objectively stratify patient populations, demonstrate efficacy and identify safety issues, with the biomarker hypothesis being built into clinical trials from an early stage in order to test what, if any, clinical benefit the biomarker brings in terms of added benefit or patient safety. Regulatory authorities understandably require validation of the biomarkers relied upon by drug manufacturers. To permit biomarkers to be accepted on an accelerated basis, the EMA’s qualification process for drug development methodologies allows an early assessment and validation of the manufacturer’s proposed testing methodology (5). This offers manufacturers either confidential advice on biomarker development and validation, or a public opinion as to the acceptability of the methodology, and has been available since 2008.

The biomarker qualification process has been accompanied by a range of reflection and guidance papers (6-8). Currently, the EMA is consulting on a guideline on Good Genomics Biomarker Practices (GGBP), which will direct the development of acceptable clinical tools through guidance on the choice and use of genomics techniques to obtain a robust clinical genomic dataset, as well as on key scientific aspects for translation of biomarker data into clinical practice (9). GGBP is anticipated to become a reference for CDx/Dx once the proposed EU in vitro diagnostics regulation is adopted and comes into effect.

Medicines Development

With a view to reversing the reduction seen in the last 10 years with pharmaceutical clinical research in the EU, a new Clinical Trials Regulation was adopted in May 2014 to replace the existing 2001 directive (10). This could come into effect as early as 28 May 2016, although this is conditional upon significant IT infrastructure being developed and audited for successful functioning in the form of an EU web portal and database, to be operated by the EMA. The EU Clinical Trials Regulation is expected to facilitate crossborder and also academic (non-commercial) research and collaboration within the EU by:

  • Providing streamlined submissions and reporting via the single EU web portal, with a single assessment outcome for multi- and single-centre studies alike – possibly with single language submissions
  • Simplified reporting requirements
  • Increased transparency around recruitment of subjects for ongoing studies
  • Provision for co-sponsorship of trials – including some agreed division of liability
These legislative changes are expected to be important as the stratification and tailoring of personalised medicine means the authorisation of new medicinal products is likely to be based upon evaluation of smaller datasets, which is an inevitable consequence of therapies targeted at smaller patient populations. This is expected to necessitate larger numbers of trial sites recruiting participants across several member states.

Whether the EU Clinical Trials Regulation will succeed in reversing the decline of clinical research is likely to depend upon a variety of factors. Much will depend upon the successful building and operation of the EU web portal and database. The application process includes extremely tight, 10-12 day turnaround deadlines for responding to EU or national-level questions and answers, so sponsors will have to invest in significant upfront preparation before initiating applications – something collaborating co-sponsors may find challenging.

Additionally, the single outcome assessment does not preclude individual EU member states and their ethics committees refusing authorisation for a study. There are significant sensitivities among sponsors about public access to clinical study reports once the process has completed, in view of the decision not to treat these as commercially confidential information – triggering follow-on concerns about patient confidentiality and protection of intellectual property. Furthermore, the limited scope for dividing liability among co-sponsors is likely to be time-consuming to negotiate, and may not guarantee protection from all potential liabilities, discouraging collaboration.

Companion Diagnostics

On the CDx side, there are likely to be significant changes to the EU regulatory framework for supply of IVDs – of which CDx are a subset – with the adoption of an EU regulation (expected in 2015) to replace the existing 1998 directive. As with pharmaceutical clinical trials, the proposal is to minimise member state level divergence by opting for an EU regulation as the legislative instrument.

If current proposals are adopted, the IVD industry will have to swiftly adapt from the current regime – based upon light touch regulation largely in the form of manufacturer self-certification – to a significantly higher proportion of manufacturers requiring notified body certification or involvement before they can supply or use IVDs in the EU. Part of the proposed changes will be the introduction of a Global Harmonisation Task Force-style risk-based classification framework that will determine the regulatory pathway for individual IVDs. CDx are expected to fall within Class C or Class D, which are the two higher-risk classes.

The present EU IVD legislation includes a much-criticised exemption from Conformité Européenne (CE) marking for IVDs produced for in-house use by health institutions (so-called ‘home brew’). Such tests are characteristically produced and used by non-commercial (hospital) laboratories, which often apply lab standards rather than the specific technical ones followed by IVD manufacturers. This has raised some concerns about the adequacy of such testing, particularly in relation to the level of control exercised over labs’ supply chains. Manufacturers of CDx and personalised medicine therapeutics have particularly criticised the exemption on the grounds that it can adversely affect the quality of the testing and, therefore, patient outcomes.

In any event, the in-house exemption is unlikely to go when the EU IVD regulation is adopted. Although it may no longer be lawful to use exempt versions of the highest-risk class IVDs (Class Ds), the exemption appears likely to continue in relation to Class C CDx – subject to safety and quality-related conditions.

CDx are specifically defined in the proposals, which also designate a regulatory pathway that will likely include a consultation by the manufacturer’s notified body with the EMA, to assess the suitability of the CDx for the medicine concerned (although the European Parliament instead advocates verification by a EU reference lab of compliance against a common technical specification). This is a modest departure from the silo approach. Although there is nothing to indicate that this is more likely to lead to the EMA including references to specific CDx on the labels of medicine, it may promote drug label requirements for testing using a validated test – yet this may be done via an exempt test.

Changes of Note

Potentially, the most significant changes include the introduction of some form of additional scrutiny beyond pre-market conformity assessment, which will apply to novel IVDs or IVDs with significant clinical impact, possibly including CDx. This scrutiny will probably be performed by an Assessment Committee for Medical Devices, and has been criticised by notified bodies as likely to result in duplication and delay – raising substantial concerns for companies seeking to co-develop drugs and CDx.

Secondly, the new legislation may significantly increase the clinical evidence requirements for IVDs – and, therefore, also for CDx. Clinical performance studies may be a requirement for the majority of CDx, and post-market clinical follow-up will be mandatory – including a post-market surveillance plan. The European Parliament has additionally proposed that CDx should demonstrate clinical utility by showing the impact of a positive or negative test on patient care and health outcomes when used with the companion medicine.

A third significant area of change will be the potential introduction of increased clinical data transparency requirements for IVDs, including CDx. Although the position has not yet been finalised, public access is envisaged for the EU database, specifically relating to registration data for interventional clinical performance studies or trials involving patient safety risks, while the European Parliament has proposed publication of full study datasets collected during pre- and post-market studies. As well as the patient confidentiality concerns which this raises, it is also an important consideration for IVD manufacturers, taking into account the relatively low level of patent protection currently in this product area.

In addition to the predictably enlarged costs for IVD manufacturers resulting from the intensification of data requirements and third-party interventions, this proposed legislative change coincides with a significant tightening of the scrutiny and requirements upon notified bodies. This has led to widely publicised expectations that the overall numbers of notified bodies will reduce. The IVD industry may therefore face a bottleneck when the EU regulation comes into effect, due to companies seeking approval from a reduced number of notified bodies of both new and existing products, in order to avoid mandatory withdrawals of non-upgraded products.

Market Access

A silo approach characterises the post-market space where EU member states each operate their own increasingly complex cost-containment strategies via health technology assessment and centralisation/decentralisation of healthcare payers. This means each acts as a 'gatekeeper', potentially preventing or slowing effective uptake of personalised medicine across the EU – or indeed across national markets – as availability is dependent not only on product authorisation, but also upon funding by healthcare payers. Individual member state controls over market access mean that smaller companies are unlikely to be able to launch across multiple member states, unless they successfully partner with larger companies which have the experience and personnel able to negotiate pricing and reimbursement.

Another difficulty is what McKinsey & Company refers to as the “cost-plus mindset for reimbursement” of Dx. In the EU, this means that Dx manufacturers frequently fail to set a fair price for the technology they develop, because the reimbursement arrangements for lab testing often make it more cost-effective for non-commercial laboratories to rely upon the exemption from CE marking for in-house tests. Similarly, some pharma companies have had to fund testing with CDx themselves to achieve market access, absorbing the cost of the CDx into the price set for the medicine.

Innovation at Risk

In summary, although the recent legislative changes demonstrate an intention to promote the development and uptake of personalised medicine within the EU, there is still much required by way of harmonisation. In particular, there appears to be a tension between the justified focus on increasing patient safety in specific product areas, and the need to develop the type of holistic approach advocated by the European Commission. Unless firmer measures are taken, the risk of inhibiting innovation in IVD technology available in the EU is likely to persist.


1. The Analysis Group, 2009
2. Personalized Medicine: The Path Forward, McKinsey & Company, 2013
3. Commission Staff Working Document: Use of ‘-omics’ Technologies in the Development of Personalized Medicine, October 2013
4. Guidelines on the Qualification and Classification of Stand Alone Software used in Healthcare within the Regulatory Framework of Medical Devices, MEDDEV 2.1/6, January 2012
5. Qualification of Novel Methodologies for Drug Development: Guidance to Applicants, 6 January 2014
6. Reflection paper on methodological issues associated with pharmacogenomic biomarkers in relation to clinical development and patient selection, 9 June 2011
7. Reflection paper on co-development of pharmacogenomic biomarkers and assays in the context of drug development, 24 June 2010
8. Reflection paper on pharmacogenomic samples, testing and data handling, 15 November 2007
9. Concept paper on good genomics biomarker practices, July 2014
10. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical Trials on Medicinal Products for Human Use

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Shuna Mason is a Partner and Head of Regulatory at law firm CMS. She is one of the few lawyers specialising in the law and regulation of life sciences and consumer products, covering pharmaceuticals, medical devices, in vitro diagnostic devices, human tissue, cosmetic and plant protection products.
Shuna Mason
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