Companion Diagnostics – current regulatory status in Europe
A ‘companion diagnostic’ is a diagnostic test that allows for identification of those patients who are likely to benefit from treatment with a particular drug. Such a diagnostic should predict both the efficacy and likelihood of undesired effects of a medicine in individual patients. It may be critical for ensuring a positive risk/benefit ratio for a medicine, and so should be available for clinical use at the time when the medicine is approved. The growing interest in companion diagnostics is a consequence of the rapid advances seen in molecular biology, including genomics, proteomics, metabolomics and cell technologies, over the last two decades.
Companion diagnostics are part of a larger drive for personalised medicine. Also known as stratified medicine, this is the concept that individual patients respond differently to a therapeutic intervention based on their own particular genetic make-up, or the specific molecular pathways involved in the disease from which they are suffering. Intrinsic to this is the idea that specific biomarkers may be used to identify patients who might benefit from a particular therapy, or who might be at particular risk of adverse effects. The goal of stratified medicines is to give “the right drug to the right patient at the right time.”
The stratified medicines
Stratified medicines are not completely new. Approximately 20% of products authorised by the European Medicine Agency (EMA) through the Centralised Procedure contain some form of genomics information to personalise their use (eg. dose adjustment for CYP450 polymorphisms), while at least 13 targeted medicines in the areas of oncology, HIV infection and injury require mandatory diagnostic testing prior to their use for reasons of safety or efficacy. It has been said that between 12% and 50% of company pipelines consist of stratified medicine projects, and the EMA reports seeing a small but steadily increasing number of requests for Scientific Advice (SA) regarding the development of new stratified or targeted medicines. Roche Pharmaceuticals is an industry leader in this field, having developed trastuzumab (Herceptin), which has shown significant benefit in patients with breast cancer and metastatic gastric cancer whose tumours overexpress human epidermal growth factor receptor type 2 (HER2). Herceptin was first registered more than a decade ago. More recent examples include panitumumab (Vectibix, Amgen), which improves survival in patients with metastatic colorectal cancer who do not have a mutation of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, and gefitinib (Iressa, AstraZeneca), which similarly benefits patients with non-small cell lung cancer who test positive for an activating mutation in the epidermal growth factor receptor (EGFR) gene (see table).
The regulatory challenge
Some regulators consider that a companion diagnostic is essentially part of a combination product which consists of an in-vitro diagnostic medical device (IVD) and a therapeutic drug. The main challenge is that historically, drugs and devices have been regulated by different organisations using differing approaches, and are subject to different legislation and different timelines. IVDs are usually subject to review by Notified Bodies, who verify their conformity with a range of performance requirements, whereas related therapeutic drugs are mostly authorised by the EMA through the Centralised Procedure. These differing regulatory processes may create hurdles for innovators.
The way forward
One vision for the future includes a single coherent regulatory system for all medical products, which addresses both aspects – for an IVD and a drug – in an appropriate way. This system should be risk-based and modular in design, and should lead to the combination medicine and companion diagnostic device being jointly authorised as a medicinal product. The level of regulatory scrutiny and burden of proof required will vary, depending on the risks inherent in the technologies employed. As a first step in this process, the European Commission is hoping to revise the In Vitro Diagnostics Directive 98/79/EC along with associated standards and guidelines in the near future. Results of the public consultation, published in February 2011, highlight the need for a risk-based classification of IVDs in order to address the perceived insufficient level of scrutiny for many such devices, in particular those used as companion diagnostics. Public consultation is also highlighted as an important obstacle to development the different approach taken by regulations for medicinal products and IVD medical devices, along with what stakeholders see as a lack of understanding and cooperation between the EMA and Notified Bodies. While it is unlikely that the current dual approach will completely disappear, it is hoped that changes will include provision for integrated early dialogue for companion diagnostics. The European Commission is aware of the potential benefits of such products to patients, and encourages pharmaceutical companies to explore the use of companion diagnostics during drug development. Special incentives are provided to small & medium size enterprises (SMEs) to reduce the cost of developing innovative products. For its part, the EMA has moved to encourage and support the development of stratified medicines by establishing the Pharmacogenomics Working Party (PGWP) a little over two years ago, along with a number of platforms such as the Innovative Task Force (ITF) and the Biomarker Qualification Process, which provide advice on innovative methods or drug development tools. While existing companion biomarkers have often been developed only after a drug is already on the market, the EMA has indicated a preference for co-development of drugs and companion diagnostics. Recent reflection papers from the CHMP on the co-development of pharmacogenomic biomarkers and assays (EMA/CHMP/641298/2008; June 2010), and on methodological issues associated with the clinical development of biomarkers (EMA/446337/2011; June 2011) provide evidence that the EMA is moving towards clearer regulation of companion diagnostics. In addition, the new ICH E16 guideline on Genomic Biomarkers Related to Drug Response provides a solid basis for a global regulatory framework.
Early scientific advice is crucial
For the moment, however, the best advice to any company planning to develop a companion diagnostic is to engage early with the EMA. In fact, the EMA specifically encourages those engaged in pharmaceutical development to avail themselves of formal Scientific Advice. The SA procedure provides a forum for industry and regulatory authorities to work together to address the uncertainties inherent in these relatively new technologies, and to agree an appropriate development program and regulatory strategy upfront. Companies should consider also involving a Notified Body in the SA procedure. While such an approach is still novel, it may help to identify and thus overcome the obstacles between the involved parties. It is clear that in the future, stratified medicines – including companion diagnostics – will play an increasing role in pharmaceutical development. This will be reflected in the regulatory processes involved in their approval. Industry is encouraged to enter into contact with the regulatory agencies to obtain advice as early as possible in the development process.
However, the current landscape remains complicated by the fact that the EMA still currently has no power over the licensing of diagnostics, this being the responsibility of the Notified Bodies. New stratified medicines and companion diagnostics may not always be developed by the same company; also, existing diagnostics may be further developed independently of the development of new medicines. The lack of clear guidelines, coupled with the lack of certainty on issues such as intellectual property and reimbursement, mitigate against successful partnership between the pharmaceutical and diagnostic industries. It is hoped that changes planned for the near future will serve to remove at least some of these hurdles. D
Dr. Regenold GmbH
International Regulatory Affairs
Strategic Advice & Implementation
Am Berg 4