This is Part 1 of a four-part series. See also Part 2, Part 3, and Part 4. See also a PDF of the entire series.
21 December 2010. Follow the coverage, on Alzforum and in the general media, of clinical trial failure after failure in recent years, and you’ll come away thinking that nothing works in Alzheimer’s disease. But while public awareness of the disease’s looming public health threat rises in parallel with an anguished recognition of a federal research funding crisis, one piece is getting lost amid the noise: Between scientific discovery and new drugs for the patient, there lies an important, if obscure, area of coordination and regulatory work to improve a fledgling drug program’s chance at success. While this area is difficult to communicate, it is where some of the perhaps most pressing—some say most promising—innovation is happening in the AD field at this point.
By this measure, the field is not stuck at all; rather, it’s gearing up to test candidate drugs faster and to freely share data from negative trials across companies so everyone in industry and academia can learn from them. The catchwords are data standardization, simulation model, and biomarker qualification—stuff too dry for nightly television, not fit for print in the nation’s flagship newspapers. And yet, anyone who cares about better treatment for AD may want to take note. A neutral group called Coalition Against Major Diseases (CAMD) is driving a large-scale effort at reforming the drug trial and drug approval process, and doing it all hand-in-hand with the regulatory authorities in the U.S. and Europe. On 30 November 2010, the group met in Washington, DC, for a daylong powwow on what they achieved in 2010 and what to do in 2011. Here is a summary of its parallel projects; the who, the why, and the when.
This CAMD meeting clearly illustrated that none of the stakeholders in AD drug development—individual pharma companies, academic trialists, a regulatory agency, or a patient group—can break the current logjam on their own. Together, perhaps they can. This means data sharing. Not in a casual “sure, let’s collaborate” sort of way, but by doing the hard, sustained work of standardizing and pooling large clinical datasets for everyone’s benefit. Marc Cantillon, CAMD’s executive director, summarized it like this: “Our original vision was the sharing of knowledge for faster and safer drug development. We wanted to develop tools to innovate the processes. This cooperation in the pre-competitive space, developing tools for all, is game changing. Sharing of data has been talked about for decades, but never done in this way.”
Companies, perhaps humbled by their setbacks, are cooperating. Said a director at Pfizer, “Continued investment in Alzheimer’s requires success, and success requires pre-competitive teamwork across organizations. CAMD provides the team framework. We do not want AD to be like stroke.” Due to its history of failure, stroke is often called a “graveyard for drug development.” An executive from Bristol-Myers Squibb added this: “Drug development is getting harder. CAMD is innovative, and a huge opportunity for us.” [Editor’s note: This news story does not cite most company officials by name to avoid delays from corporate communications policies.] Former Food and Drug Administration commissioner Marc McClellan, who now directs the Engelberg Center for Health Care Reform at the Brookings Institution, said, “New drugs are not made just by putting more funds into labs. Collaborative efforts like CAMD are indispensable. There is no alternative out there to what they do.” Other speakers agreed that a shrinking pharma industry would be well advised to participate in CAMD’s projects.
What, then, is CAMD? Led jointly by Cantillon, formerly of Schering-Plough (Merck), and Frank Casty of AstraZeneca, CAMD is an industry-government collaboration with patient organizations and academic consultants. Started in 2008, CAMD is one of the coalitions formed by the Critical Path Institute (C-Path, for short) based in Arizona and Maryland and founded in 2005 by Ray Woosley. This independent nonprofit institute serves as a third party that brings scientists from academia, industry, and the FDA and the European Medicines Agency (EMA) together on pre-competitive projects. Funded by the government and philanthropy, the institute was inspired by the FDA’s 2004 Critical Path Initiative developed by then-commissioner McClellan and FDA official Janet Woodcock. That initiative grew out the painful recognition that, despite growing NIH expenditures for biomedical research funding, few innovative medical products were coming online. The initiative called for applied science to plug this alarming hole in the product development pipeline. C-Path formed with the charge to develop enabling tools and processes, and CAMD is C-Path’s Alzheimer’s and Parkinson’s group. (CAMD just expanded its efforts to include Huntington’s by including the Cure Huntington’s Disease Initiative as a member.)
The problem CAMD is addressing is intensifying. Since the approval of the current Alzheimer’s drugs in the 1990s and early 2000s, not a single drug program has succeeded, even though research has flourished. This includes most prominently a handful of anti-amyloid treatments, but also others, from Dimebon, valproate, DHA, statins, to rosiglitazone, NSAIDs, estrogen, leuprolide, vitamins E and B, homocysteine, and prevention with gingko biloba extract, for example. Not mentioned are countless lesser-known pharmaceutical compounds that died for various reasons without much public notice. In the last six years, Alzheimer’s disease has seen a 46 percent increase in mortality, where some other big diseases have had a modest decrease, said Cantillon. “This reflects our absolute frustration of not coming up with better treatments,” he said.
The litany of failure has created worry that senior executives in pharma companies won’t commit funds to AD programs anymore because they view them as too risky. Regardless of pharma’s popularity in the eye of the individual, this concern matters hugely. Despite some public misperception to the contrary, academic scientists or practicing doctors do not develop new drugs; biopharma companies do, and AD scientists there are finding their disease an increasingly hard sell. One pharma scientist summarized the present situation this way: “We compete internally for resources with other indications. For example, we compete with anti-infectives, where a study runs for weeks, not years. We do that with a success rate that gets calculated. We go to our governance and ask for money. They want to know why AD is a good area to invest in. Yes, the medical need is huge, but the risk is huge, too. Our primary product has been dead compounds. We need arguments that the success rate can go up.”
“The trial failures have marked the AD story for the past five years, and we don’t know why,” Cantillon said. “Thousands of patients have gone into trials, and we can’t even say if the trials had worked if some aspect had been done differently.” One reason lies in “wasted” data. There may well be drugs on shelves that could be helpful, but no one knows it because the data are not being used. Each drug sponsor, public or private, recruits and assesses patients in its own way, and when a trial fails, the data move into storage. As a result, the FDA has “warehouses” of data in separate formats that do not speak to each other and can’t be used. CAMD is working on a set of interconnected projects to change that. The coalition is proposing a data standard by which data from many trials can be analyzed together in a shared database. This is useful to see, for example, if failed drugs actually worked for some subgroup of patients. Moreover, the database enables the building of a quantitative model of disease progression and drug response—blessed by the regulators—that trial designers can query to design trials in the future. Finally, it is working to get biomarkers FDA validated (aka “qualified” in preferred regulatory lingo) for use in those trials. For more on these projects, see Part 2, Part 3, and Part 4 of this series.—Gabrielle Strobel.
This is Part 1 of a four-part series. See also Part 2, and Part 3, and Part 4. See also a PDF of the entire series.