The summer of 2011 revealed a potentially historic breakthrough in medicine: MIT’s broad-spectrum antiviral therapeutics. It is a real breakthrough, although it has only been tested in the laboratory and not yet on humans. So although it is at least ten years from going on the market, it does look very promising and is surely a development that may one day be considered as significant as the introduction of penicillin. It is important to detect most infections quickly to ensure treatment is effective and make it as personalized as possible. Currently, most patients afflicted with viral infections are simply told to go home and let nature take its course. In a few decades time, this absence of any useful medical intervention will be seen as primitive and totally unacceptable. Emerging and rapidly evolving viruses are a threat to human health on a truly global scale, and providing an appropriate and matched therapy is going to become ever more important, especially for influenza.
The multiple drug resistance (MDR) and extreme drug resistance (XDR) of many pathogens to antibiotics is another potentially major threat to human health on a global scale. Of great concern to the World Health Organization (WHO) is the increasing resistance to the treatment of tuberculosis. The WHO believe that 1 in 3 people in the world is now infected with dormant TB bacteria, and during 2004, there were almost 500,000 cases of MDR-TB with up to 19% of these being XDR. This year has seen a greater focus on this important matter, and the support for molecular diagnostics to determine the genetic profile of pathogens to enable appropriate therapies for specific diseases is increasing. This approach will hopefully replace the empiric method of guessing (albeit educated guessing) based on previous patients and limited testing of a sample of a population during a disease outbreak. Encouragingly, the EU and the U.S. are now bringing more resources to focus on these important issues, with some people trying to inject a sense of urgency into the war on bugs. The war against anti-microbial resistance cannot just be about price or cost effectiveness. Diagnostics, pharmaceuticals, and systems are needed to combat the threat of large scale anti-microbial resistance continually and to serve as a contingency when a particularly deadly pathogen hits the world. This could happen at short notice at any time.
Another important landmark was FDA’s latest “Strategic Plan: Advancing Regulatory Science,” which was published this past summer. This plan has as its second priority stimulating innovation in clinical evaluations and personalized medicine to improve product development and patient outcomes. In the UK, the Technology Strategy Board’s (TSB) current investment budget for assessing the impact of near-patient testing is around $1.6 million, and the budget for other related projects total around $11.2 million. More recently, TSB has made $13.5 million available for projects that can assist in detecting and managing sepsis. The European Commission (EC) and Innovative Medicines Initiative have put more than $32 million into two important diagnostic projects: TheraEDGE and RAPP-ID. The EC has also put around $40 million into twenty projects concerned with bacterial infections, seven viral infection projects, four protozoan infection projects, and one fungal infection project (although many of these overlap and are complementary in various ways).
Currently, the use of antibiotics is rarely based on the results of a diagnostic test, and the initial patient diagnosis is empiric. An example project that could prove very useful in both the commercial and clinical exploitation of point-of-care (POC) tests is the TEMPOtest-QC, an integrated tool-kit for the clinical evaluation of microbial detection and antibiotic susceptibility.
To reinforce these important strategic directions, a workshop was held during late September that resulted from the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR), a high level group involving some of the very best people in the field globally who have produced recommendations following summit meetings between U.S. and EU officials concerned with antimicrobial resistance. There is a strong desire to cooperate on this very important health priority by both the US and EU: The EU-US Summit Declaration agreed upon on 3 November 2009 called for the establishment of “a transatlantic taskforce on urgent antimicrobial resistance issues focused on appropriate therapeutic use of antimicrobial drugs in the medical and veterinary communities, prevention of both healthcare- and community-associated drug-resistant infections, and strategies for improving the pipeline of new antimicrobial drugs, which could be better addressed by intensified cooperation between us.” The objectives of the taskforce are to increase the mutual understanding of the U.S. and EU activities and programs relevant to the antimicrobial resistance issues, deepen the transatlantic dialogue, provide opportunities to learn from each other, and promote information exchange, coordination, and cooperation. The outcomes of the taskforce will include a proposal with suggestions for areas of future cooperation between the EU and the U.S. to be presented at the EU-US Summit in 2011.
The European Centre for Disease Prevention and Control (ECDC) provides the secretariat for the taskforce and publishes documents relating to the taskforce’s work. The TATFAR report, “Transatlantic Taskforce on Antimicrobial Resistance: Recommendations for Future Collaboration between the U.S. and EU 2011,” covers many important topics and includes high level recommendations. As a result of TATFAR, a collaborative public meeting was held during late September called “EU-US Workshop: Challenges and Solutions in the Development of New Diagnostic Tests to Combat Antimicrobial Resistance.” This meeting was co-sponsored by the National Institute of Allergy and Infectious Diseases and the EC’s Directorate General Research and Innovation and was held in Brussels. The speakers were leaders in their fields, and the meeting was very comprehensive in what was covered. The presentations and findings should eventually be published and should provide many insights to those concerned with the fight against bacterial infections.
A More Regulated Europe
It is crucial to pay attention to the recast of the EU’s medical device directives and to make opinions known as the proposals are becoming finalized. The impact assessment of the recast of the medical device directives has been completed, and two texts will most likely be released during March or April 2012, which will propose the new direction of medical technology regulations for many years to come. The first text was thought most likely to be a consolidation of the three main medical device directives (the Active Implantable Medical Device Directive, the Medical Devices Directive, and the In Vitro Diagnostics Directive), while the second will be the technical revision of the IVD Directive. Notably this technical revision of the IVD Directive is most likely to be a regulation and will therefore become a mandatory pan-European requirement once it is published. However from very recent reports it now seems both texts will be revisions that will be published as regulations and hence come into mandatory force much quicker than many had anticipated. Seasoned observers believe that whatever the final process surprises are, late surprises are possible and even probable.
Discussions about the choice of a central controlling authority continue and have not yet been finalized. Reliable sources suggest that the Central Management Committee option appears to have been dropped, with the European Medicines Agency (EMA) or Joint Research Centre as the proposed alternatives. The EMA based in London is now considered to be the clear favorite.
It is clear that IVDs will now be subject to a risk-based classification in Europe, in line with the Global Harmonization Task Force (GHTF) approach. It is also likely that other GHTF approaches will be adopted now or in the near future following Study Group 5’s most recent publication on the September 16 entitled, “Clinical Evidence for IVD Medical Devices: Scientific Validity Determination and Performance Evaluation.”
There were a number of useful points raised at the EU-US workshop on anti-microbials and diagnostics, including regulatory work being undertaken on both sides of the Atlantic. Those companies that market globally or even just in the EU would be well advised to examine recent FDA guidance documents and pay attention to how the burden of compliance is increasing. For instance, the risk-based approach to IVD classification will mean that POC and molecular diagnostic tests in the EU will be subject to intervention and scrutiny by a suitably qualified notified body. Professor Rosanna Peeling, Chair of Diagnostic Research, London School of Hygiene and Tropical Medicine, suggested that the required diagnostic tests take 2-10 years and $10-100 million to develop, 2 -5 years to get through regulatory approvals, and another 5-7 years to get adopted. This means it could take around 9-22 years before a test is in widespread routine use.
In July 2011, FDA published its “Draft Guidance for Industry and FDA Staff: In Vitro Companion Diagnostic Devices,” which has been distributed so that interested parties can comment on it. This guidance is likely to be examined by GHTF and the EU with convergence of regulations in mind. It is also noteworthy that on the October 13, 2011, FDA held a public meeting on advancing regulatory science for highly multiplexed microbiology devices. The 510(k) reform at FDA is also more likely to add, or at least reinforce, clinical validation requirements of sophisticated diagnostic tests.
However, the EU directives and FDA are not the problem. Rather, it is how individuals and companies comply with them, to the letter of the law and to the spirit of their intent in order to ensure excellence that really matters. All European new approach directives have a state-of-the-art argument within them and demand that products are fit for their purpose. Everyone involved should try to ensure the best outcomes are based on an appropriate, proportionate, and cost effective approach.
Most important of all, if industry and regulators do not make good progress in the next few years, then a worse alternative is very likely: those currently demanding a prescriptive and draconian style of regulation, with excessive demands and requirements and based on a pharmaceutical approach, will prevail.
Trevor Lewis, Principal Consultant of Medical Device Consultancy (MDC), has been an independent consultant for more than 16 years, after working in industry for more than 10 years. MDC provides specialist business development assistance for universities, medical device, IVD, biotechnology, and pharmaceutical companies. He supports and mentors senior management with their strategic planning, marketing, product management, quality systems, and regulatory compliance in the U.S. and Europe. He has become a well known and respected regulatory expert, ultimately leading him to assist in the training of national regulatory authorities and senior officials in the European medical device directives, especially in Egypt and Turkey. He is a partner in the major European Commission-funded diagnostic project TheraEDGE and an advisor to another large scale diagnostic project funded by the Innovative Medicines Initiative know as RAPP-ID.