The European Union's plan to transform Europe's drug discovery industry borrows some of its style from the US - but not everything.
The blueprint for how the initiative will operate, known as the. Strategic Research Agenda (SRA), was published in draft form last July. A final and slightly amended version is due out at the end of this month.
US backs Critical Path
US Health Secretary Michael Leavitt gave his backing to the FDA’s Critical path programme, pledging to spend his final 1,000 days in office working to re-invent the regulatory process and pave the way to personalised medicine.
“The changes that are needed will be disruptive. Our regulatory structure is no longer prepared to deal with it,” he told delegates. “We have to reengineer the regulatory process.”
Leavitt said the agenda needed to accomplish the changes has been constructed. “The FDA Critical Path is an important element.” The National Institutes of Health Roadmap, which is reforming the way clinical research is carried out, is a also key component.
Delivering the vision of personalised medicine requires closer collaboration between agencies, particularly the FDA and the NIH, to speed up the development and approval of innovative treatments and diagnostic tools.
Leavitt has set up a team to work on the project and promised to wake up thinking about it every day for the next 1,000.
He also acknowledged that many more drugs could be developed profitably if clinical trials and the associated regulatory process were faster and less bureaucratic. Many innovative drugs for rare diseases or patient subgroups were not developed because the market is too small. “Today many drugs that could produce miracles are cast aside for financial reasons.”
But privacy will still will be a critical barrier. “People worry about their personal and medical information being misued. It will not be the technology or the science that limits the adoption of personalised medicine, it will be the sociology,” he said.
The SRA is expected to cost €440 million a year to implement. It contains recommendations on how to remove bottlenecks in the R&D process using a “pre-competitive” approach and thereby increase the global standing of European biopharmaceutical R&D as part of an objective to build the “most dynamic knowledge-based economy in the world by 2010”.
It is Europe’s equivalent of the US FDA’s much heralded Critical Path Opportunities List. While the two are more alike than dissimilar – each stresses the value of biomarkers and improved clinical trial design to speed drug development – there are some big differences.
The Critical Path Opportunities List is divided into six broad categories: development of biomarkers; clinical trial designs; bioinformatics; manufacturing; public health needs; and paediatrics. The Innovative Medicines Initiative SRA identifies four main topics: improved predictivity of safety evaluation, improved predictivity of efficacy evaluation; improved knowledge management and improved education and training to develop the talent base needed for the EU biomedical environment of the future.
“[The Americans have] picked out some different disease areas that we haven’t focused on particularly, such as presbyopia and pregnancy,” says Ian Ragan, chair of the European Federation of Pharmaceutical Industries and Associations (EFPIA) and Executive Consultant, European Scientific Affairs, for Lilly UK. “Otherwise, they have identified similar conditions such as infectious diseases, cancer, autoimmune, neurospychiatric and metabolic diseases.”
The EFPIA represents the voice of around 2,000 companies and 29 national pharmaceutical industry associations across Europe. Its views on how to transform the R&D process were sought by the European Commission, and the SRA is the outcome of almost two years joint working.
Efficacy and safety a priority
“The Critical Path list has quite a bit on manufacturing which we didn’t deal with,” Ragan continues. “We’re thinking more about how to reduce attrition in drug discovery and to shorten the path the market. With the rise in the number of new potential targets emerging from the human genome, failure rates due to lack of efficacy are increasing rather than decreasing.
“So although we’re trying to be more innovative, we’re failing more because we pick the wrong target in the first place. From my initial reading, the Critical Path seems to be devoted to the development path itself – from entry to clinical trials to the market. The view of the Europeans is that you can produce a beautiful development path but if the drug you’ve chosen is wrong in the first place it’s going to fail.”
Integral to the development of improved preclinical tests to better predict efficacy is the development of more predictive toxicology tests to weed out those compounds that will fail in later, costlier stages. Until now, the development of toxicology screens—or drug safety screens as they’re more apt to be described today—has been largely an internal affair for pharmaceutical companies.
But in toxicology just as in the rest of the R&D pipeline, obsolete regulation now stands in the way of efficient use of recent advances in technology and basic science, such as toxicogenomics.
Peter Lord, director of mechanistic toxicology at Johnson & Johnson explains: “We are obliged to provide all information on a drug’s safety, which may include results from early toxicology screening assays such as an Ames Test for mutagenicity, for example. Regarding some of the newer screening approaches such as gene expression studies, the debate continues about how much of these data should be included in a submission. Together, industry and regulators are together trying to evaluate these novel approaches to see how they fit in a regulatory setting.”
To progress the field the FDA announced a new initiative on 16 March aimed at modernising drug safety evaluation, the Predictive Safety Testing Consortium. Members will share internally developed laboratory methods to predict the safety of new treatments before they are tested in humans and cross validate toxicogenomic profiles in an effort to streamline the cost and time of preclinical drug safety evaluation.
Johnson & Johnson is one of the eight pharmaceutical companies that have signed up to the consortium. Lord told Science|Business: “Regulators have known for a number of years we’ve been applying these new technologies in our day-to-day business and now they’re trying to figure out what they’re going to see in submissions and how they’re going to handle that. We need to decide which experiments are appropriate for a submission in support of a safety claim and which are not. Each company has picked out certain profiles of gene expression which are indicative of toxicity from some of its short term studies. So rather than us each spending more time on the validation of individual tests, it makes sense to pool our resources and see how good an indicator of toxicities these tests are from lab-to-lab.”
Perhaps less well known is that Europe has had a similar programme in operation since last November. Set up under Framework 6, it is an integrated project involving 13 large companies, three universities and one biotech company or SME (small or medium-sized enterprise). Like the American consortium, members test compounds and compare the predictive marker data with results obtained in conventional toxicology testing, which is the in-house data that the companies contribute.
Much has been made in the press of the notion that pharmaceutical companies are prepared to collaborate on toxicology testing – even the FDA used it as a promotional point for the Predictive Safety Testing Consortium. But industry insiders don’t know what the fuss is about.
“It’d be very hard for a single company to convince the regulatory authorities that some toxicology tests could be thrown out or replaced by something better,” explains Ragan. “What would they say? ‘Here’s my home grown test, I’ve used it for 10 years, how would you like to make it part of the regulatory establishment?’ Other companies wouldn’t sign up to that and the regulators wouldn’t accept it if there wasn’t a body of evidence it was going to contribute to human safety. That’s why you need a consortium approach.”
Lord adds, “We gain competitive advantage by having the best drug on the market, not for having the best test for an adverse effect.”
In fact, the concept of consortia working is another subtle difference between the US and European strategies. The Innovative Medicines Initiative would not be supported by the European Parliament unless it was a clearly defined public-private-partnership. This principle was stated at the outset – although the pharmaceutical industry will lead the initiative in terms of defining what the problems are, academics, patient groups, regulators, SMEs and others must be included.
“There was initial scepticism that industry couldn’t possibly work together,” admits Ragan. “And then there was the opposite view that we were forming a cartel, which is why we’re restricting ourselves to pre-competitive research, i.e. working on the tools to develop drugs and not the drugs themselves. That would become competitive research if we worked on molecules.”
Show me the money
A further, important difference between the Critical Path initiative and Europe’s SRA is in funding. The FDA has requested $5.9 million from the President's budget this year for staff funding to develop guidance and for small grants to seed projects, but much more money will be needed to finance the research underlying the programme. At present, its unclear where the extra support will come from.
By contrast, the financial backing for the Innovative Medicines Initiative is potentially more substantial: around €2 billion has already been requested for the project as part of Framework 7 – half from the European Commission and half from industry. Any delay in releasing funds beyond the start date of 2007 would lose Europe the competitive edge it has keenly identified as its goal.
Education and training is another interesting divergence between the two plans, being absent from the FDA strategy but a prime objective of the European scheme. This may reveal European nervousness about the “brain drain” to the US in recent few years and also reflect the fact that Europe is still much less of a united states of Europe than the United States of America, and educational standards across the member states vary greatly.
“You can put into place all the wonderful technologies and methodologies you like, but unless you’ve got people to do them, there doesn’t seem much point,” says Ragan.
Finally, the revised version of the Innovative Medicines Initiative SRA will contain an amendment including a topic not addressed in the Opportunities List: tools for better pharmacovigilance, following side and adverse effects once a drug is on the market.
The rationale behind its inclusion is that regulators will look more favourably on applications containing improved post-marketing surveillance procedures because knowing how potential problems will be dealt with can go some way to reducing the risk:benefit ratio for a drug – in other words, the development of biology-based scientific tools for pharmacovigilance dovetails with shortening the development path because it helps with drug approval.
Regardless of the variations between the initiatives, they share the same goal—to bring new medicines more safely, quickly and cheaply to market to benefit patients. It’s of no concern to the pharmaceutical industry whether the bottlenecks in the R&D pipeline are solved in Europe or America as most are global companies. “And it’s of no concern to the European Commission which pharmaceutical companies solve the problems, as long as the work is done in Europe,” says Ragan, “thus salvaging Europe’s R&D base.”