Getting Personal Over Personalized Medicine

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-06-01-2011, Volume 20, Issue 6

A potential solution for many, personalized medicine still faces economic, regulatory, and cultural challenges.

Optimists are seizing on personalized medicine as the future panacea for all ills. Pessimists are increasingly skeptical over both the concept and the prospects. Both sides came together in Brussels in mid-May, at the European Union's two-day conference on "European perspectives in personalized medicine"—and seemed to go away with as many questions as they arrived with, not least in the area of clinical development.

Peter O’Donnell

The difficulties of shifting potential into clinical use run into economic, regulatory, and cultural obstacles. For some, the big difficulty will reside in modifying the innate conservatism of regulators, general practitioners, or health insurance agencies to take on new therapeutic possibilities. "The science is fantastic," admitted Alastair Kent, Chairman of the European Platform for Patient Organizations, Science, and Industry. But getting any products out there onto the market requires "a level of precision that cannot translate into clinical practice under current circumstances."

For others, the problems are upstream, in the regulatory barriers—diverse approval procedures for diagnostics and therapeutics, or data protection rules inhibiting the wide exchange of data that is seen by many as fundamental to the science on which personalized medicine depends. The elephant in the room was, as always, the lack of a satisfactory economic model for developing such medicines.

Despite the wealth of new possibilities that the "omics" offer for personalized medicine, still-unresolved issues hamper the take-up—by clinicians, by industry, and by health insurance agencies, it emerged from the presentations. Among the areas identified as particularly problematic were how to foster uptake of validated "omics" technologies in clinical practice, and how to apply new technologies for biomarker discovery. Since stratification of biomarkers are an important element in facilitating disease prevention and drug development, reference to biomarkers may come to be included in clinical guidelines—but this will pose new problems in formulating advice to drug developers.

"New thinking is required!" proclaimed headline speaker Jonathan Knowles, former Roche research boss and now Professor of Translational Medicine in Lausanne and of Personalized Healthcare in Helsinki. There is an urgent need for new ways to assess efficacy, since the classical double-blind trial is not appropriate for the small populations envisaged, he said, calling for rapid and pragmatic action rather than the intense introspection that characterized some of the current discussions on personalized medicine.

Access to data

One of the most contentious areas was access to data. Speaker after speaker underlined the challenges of obtaining data from wider population pools in order to focus more tightly on more patient-specific treatments. There are at present few mechanisms for the necessary coupling of high quality sampling with broad phenotypic information, or for supporting clinical bioinformatics so as to link "omics" expertise and clinical research.

Clinical Pharmacology Professor Munir Pirmohamed of the University of Liverpool remarked on the critical lack of access to data across borders. It is a major handicap for meta analysis, he observed, and attitudes are changing too slowly against conservative resistance.

Jane Kay, Director of the Center for Law, Health, and Emerging Technologies at Oxford University, argued for closer collaborative partnerships and better biobanks embedded in healthcare structures, with access to detailed information on populations and individuals. She proposed a portal that would afford access to a range of data sets for personalized medicine. What is needed, she said, is "a conceptual change, from paper to digital, from national to global, from individuals to networks"—which can both allow the right sort of access, but at the same time provides due protection for data.

Regulatory barriers

It is not only data access that regulation weighs too heavily on. The difficulties of overcoming multiple obstacles in obtaining trial authorizations were repeatedly raised. Pirmohamed remarked that he had to obtain 133 approvals just to get one saliva sample for a trial in the United Kingdom. Much more needs to be done to achieve greater harmonization and to reduce governance burdens, he insisted, highlighting the differences that exist from country to country in ethics requirements, regulatory requirements, and trial insurance requirements. Current barriers to the multicenter trials that will be necessary to validate personalized medicine will have to be demolished, he said.

Kay reinforced the point. Current research governance structures and mechanisms simply do not work, she said bluntly. There was too much focus on consent forms signed up front and at a fixed point in time on paper, on ethics committees, and national approaches. The systems are not designed for networks, and do not allow for the engagement with and dynamic link to patients over time that personalized medicine needs.

There are real synergies that can be exploited to answer complex pathologies better with a panel of biomarkers allowing better sensitivity and specificity of the clinical diagnostic, said Catherine Larue, Business Unit Director for Bio-Rad. However, new candidate biomarkers are needed to accompany drug development and decrease the attrition rate for pharmaceuticals. This means registration procedures that allow for better matching diagnostics and therapeutics, she said.

Krishna Prassad, a Clinical Assessor in the UK's Medicines and Healthcare Products Regulatory Agency, outlined some of the challenges in developing and validating biomarkers. There are no agreed levels of evidence required in regulatory terms, and it is still not clearly established whether randomized clinical trials are mandatory for them as diagnostics. In addition, they are not covered by EU medicines legislation and fall outside the remit of the European Medicines Agency (EMA), and many national medicines regulatory agencies. Only some limited guidance is available from EMA, he said, on codevelopment and on methodological issues and clinical trial methods for genomic markers.

European Health Commissioner John Dalli made an appearance at the conference to pose further questions. "We will have to look into whether improvements are needed to make personalized medicine products more quickly available to patients," he mused. "For example, does the defined or limited patient population pose additional challenges for conducting clinical trials?" he pondered. "It is clear that we need a framework which allows it to organize clinical trials in the EU across borders in an efficient manner." But he had no answers to his questions. Merely the assurance that "This is one of the important aspects I will be considering when the clinical trials directive is revised next year."

Economic challenges

Small populations will deliver only small revenues, the basic industry argument runs. So the costs of development will not be easily recouped. The incentives are currently lacking, believe many industry executives.

Richard Bergström, who took over as Director General of the European Federation of Pharmaceutical Industries and Associations this spring, ran through some of the post-approval challenges. The real hurdle, he said, is not so much obtaining marketing authorization as overcoming the hurdles of pricing, reimbursement, and health technology assessment. For personalized medicine, the challenges are compounded, because of the difficulties of comparing the advantages with current alternatives. In addition, pricing and reimbursement systems are not designed for assessing and paying for the composite products from distinct suppliers that are at the heart of personalized medicine.

The intervention by Commissioner Dalli did nothing to assuage industry anxieties. He told the meeting that he hoped that "the costs for personalized medicine could be compensated by efficiency gains for public health budgets." But even with possible efficiency gains, he warned, "it will be a true challenge for policy makers to reconcile high prices with the growing demands of healthcare from an aging population, and against the backdrop of economic and budgetary austerity."

No panacea there, then. Dalli's suggested solution to the economic challenges—of more comprehensive use of health technology assessment in making pricing and reimbursement decisions—will not recommend itself universally to medicine developers, either. Through European cooperation, he said, "we want to enable effective reuse" of the information derived from health technology assessment from one member state to another. For him, this has the merit of "reducing duplication of work both for the member states and the European health industry." But as this column has pointed out before, many in the European health industry want clearer agreements on how this sort of information will be used from country to country before it is circulated for "reuse."

Given Dalli's parting shot, those anxieties are not allayed. The commissioner concluded: "If we want successful uptake of personalized medicine in Europe, we must ensure that methods take into account the specificities of these technologies." His remark is seen as something of a two-edged sword: welcome if it carves a way through the current uncertainties and encourages product development with adequate economic incentives, but something to be feared if it is used to chop up every new product application and reduce its price to the level of the cheapest treatments on the market.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.