Government & Medicine

Someone call a plumber

New drug high hopes inspired by the human genome project have got stuck in the pipeline. The FDA applies some regulatory drano

By Susan Usher

Innovation stagnation. That's not what anyone expected for pharmaceutical development after the sequencing of the human genome. After targeting just 250 genes throughout the whole history of drug development, suddenly there were 35,000 genes mapped out and ready to be investigated for their relation to disease and response to therapy.

But advances in basic sciences have not been matched by increases in the number of new drugs being approved. In fact the opposite has happened. The number of new molecular entities submitted to the US Food and Drug Administration (FDA) for approval fell from 50 in 1995 to 25 in 2003, even as the investment required for one successful drug launch rose from $1.1 billion US in the 1995-2000 period to $1.7 billion US after 2000.

The same pattern has been evident in Canada. Here, the number of applications for market authorization has gone down from about 35 new active substances in 1998-99 to 15-17 in 2003-04, according to Dr Robert Petersen, Director General of the Health Products and Food Branch at Health Canada. He anticipates the downward trend will continue for the next couple of years. "Recognizing that new drug applications are developed globally, this is an international issue," he says. "The applications for new active substances are developed on an international basis, so the decrease has been seen in the US and here, but also in Japan and Europe."

WHAT'S UP?
The FDA is trying to find out exactly what's going on and what can be done about it. Their mission is to not only ensure the safety, affordability and efficacy of drugs, but also to help speed up the innovations that make those drugs possible. They're particularly well placed to do this since the details of most failed programs cannot be shared publicly and the FDA holds the world's largest repository of both trial data and knowledge about how products fail and why therapeutic areas remain underdeveloped.

The FDA's diagnosis of this so-called 'pipeline problem' is reported in their March publication entitled Innovation Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. The report states that "only a concerted effort to apply the new biomedical science to medical product development will be successful in modernizing the critical path." The FDA is now leading a research program to identify and prioritize the greatest opportunities for rapid improvement.

GREAT HOPES
There is hope that proteomic and toxicogenomic approaches, as well as predictive toxicology using computer analysis, could reduce the overall cost of drug development by up to 50%, the FDA reports. Its data repository could be used to research predictive safety models. New tools to assess risk of heart rhythm disturbances (research Canada has been leading) are being developed to predict problems earlier in the development process. Safety standards have grown increasingly stringent over the years, and the FDA attributes the conservativeness of standard setting partly to the uncertainties inherent in current techniques.

The FDA is promoting targeted research efforts to improve the way we assess efficacy. It has already adopted surrogate markers for anti-HIV drug approvals and for duodenal ulcer healing, greatly reducing the time and cost of trials. The Agency is now focusing on identifying additional biomarkers and surrogate markers to guide product development. It anticipates much pressure on the disciplines of pharmacology and clinical pharmacology to develop the capacity needed to develop and evaluate these markers. FDA scientists are using, and working with others to refine, quantitative clinical trial modelling using simulation software in order to improve trial design.

The advances in translational and critical path science this research produces will fundamentally change the way products are developed and evaluated. At the same time, the internationalization of standards through the International Conference on Harmonization (ICH), a joint initiative involving both regulators and industry in Japan, the US and Europe in improving and harmonizing the testing procedures for new therapies, means that advances will be incorporated quickly into regulatory systems everywhere.

Dr Petersen feels that Canada is well prepared for changes on the horizon. "We only have 2% of the world market for pharmaceuticals, but we have a great deal of experience and a very strong reputation internationally. The approval process is very fluid in incorporating new ways of assessing products." While the Therapeutic Products Directorate lacks the FDA's in-house research mandate, it does have a linkage with research funding bodies and therefore an opportunity to steer research into priority areas. "The regulatory portions of Health Canada have representation on the advisory boards of a number of the Canadian Institute for Health Research Institutes. The specific purpose of that is to allow for continuity between the regulatory and research functions," says Petersen.