At a meeting of the Coalition Against Major Diseases on 30 November 2010 in Washington, DC, speakers focused on this group’s goal of garnering the official seal of approval by the U.S. and European drug regulatory agencies for biomarkers in AD drug development. Holly Soares, formerly of Pfizer and now at of Bristol-Myers Squibb, heads this working group, which has been split into five subgroups because the task is so complex. Each of them is working on three things: to pinpoint biomarkers in AD that can advance clinical trials within a specific context of use, to reanalyze the available data on the performance of those markers, and submit a qualification (aka approval) package to the agencies.

This ongoing effort echoes what the FDA requests in a draft guidance called Qualification Process for Drug Development Tools that the agency issued to all industry in October 2010. In this document, the FDA calls for companies to collaborate on the work needed to gain biomarker qualification. “It is in the interest of companies to work with CAMD,” said former FDA commissioner Mark McClellan, who is now at the Brookings Institution.

Initially, the CAMD biomarker group’s work was slowed by the confusing terminology used to describe earlier stages of Alzheimer’s disease, Soares noted. In the spirit of Bruno Dubois and colleagues’ redefinition of the lexicon (Dubois et al., 2007; Dubois et al., 2010), the CAMD group now calls this stage “symptomatic pre-dementia AD,” Soares said. These are people who complain about a memory problem, show a decrement on a test, and have an abnormal biomarker reading. The CAMD workgroup decided against considering cognition a biomarker, in part because they did not want to settle on a particular test.

For fluid biomarkers, the group heard from the agencies that ADNI data would be insufficient; hence, it is including data from U.S. studies done at Washington University, St. Louis, and a European consortium study analyzed at Sahlgrenska Hospital in Göteborg, Sweden, as well. Of all biomarkers, fluid analytes are furthest along on the road to qualification, Soares said. However, even though findings of CSF Aβ reduction and tau increase are robust, work remains to bring down variability in the assays and collection methods (see ARF related news story on worldwide quality control). On MRI, standardization remains a challenge, and other imaging markers at present remain underrepresented in the CAMD effort.

The CAMD biomarkers group has fielded feedback on its draft research plan from the FDA and the EMA, and is aiming to submit a formal package in summer 2011. The stakes are high for biomarker qualification, some scientists noted. Because their use will drive up the cost of a trial in AD, they had better prove their worth by boosting its chance of success, or at least making it shorter. Unlike the disease model group, the biomarkers group has not yet found a champion who has volunteered to prepare the regulatory package. “We need more industry folks actively involved and committed to these large tasks,” said an AstraZeneca scientist.

This is true of all of CAMD’s efforts in Parkinson’s disease. PD is high on the agenda with similar goals as AD—a data standard, a trials database, a disease model, biomarker qualification—but most lag behind AD at this point. Partly, it’s just a question of doing the work, but partly, the lag results from more tepid industry interest, some attendees said. Existing PD drugs are more effective than AD drugs, raising the bar in the argument for urgent medical need, and biomarker research is less developed. However, early detection and disease modification of Parkinson’s are badly needed, Marc Cantillon, CAMD’s executive director, said. CAMD recently signed on the Michael J. Fox Foundation and Orion Pharmaceuticals, which makes entacapone for PD, in hopes that these partners will galvanize support for PD projects.

On almost all its projects, CAMD scientists need more help. Of the 12 member companies, about half last year provided some in-kind help, but only a quarter of the more than 100 industry scientists who are nominally involved in CAMD participate actively. This small group shouldered most of the work that led to CAMD’s tangible successes in 2010—the standards, the database, and the research plans for the model and biomarkers. “How can we engage more of you?” asked Frank Casty of AstraZeneca, who co-directs CAMD. The scientists cited reasons ranging from overwork of remaining employees as pharma lays off to the fact that pre-competitive collaboration works best if it is formally included in a scientist’s day job so (s)he can allocate time, get credit for this work, and need not fit it in on Saturday nights. CAMD does not pay industry scientists for their time. Like all distributed collaborations, CAMD work requires intense project management, communicating clearly who does what and by when, and keeping all partners up to date. This, too, is difficult when everybody piles collaborative work onto an already overflowing plate.

In addition, CAMD faces a communication challenge. Applied science and regulatory lingo do not lend themselves to snappy stories on the evening news shows or pithy sound bites to Congress, though Cantillon did testify on the Hill on 9 December 2010 in advance of last week’s passing of NAPA (download from CAMD website; see ARF brief on NAPA). At this early juncture, Louis Kirby of C-Path said, CAMD’s primary audience is clinical scientists in academia and pharma. Once they learn about its work and decide to adopt the Clinical Data Interchange Standards Consortium (CDISC) data standard and to offer their trials to the C-Path Online Data Repository (CODR), the coalition will achieve its other goals. “You need a tangible success to get more support, not just in-kind, but also financial. Biomarker qualification would go a long way,” said McClellan. Other attendees recalled that ADNI for the first two years struggled to maintain interest in the research community until data started rolling in.

The crunch in the current fiscal environment does not help matters, as the FDA is unlikely to receive a much-needed infusion of funding to expand its work on Critical Path initiatives. “Given current budgetary limitations, CAMD’s work is now more urgent than ever,” McClellan told the assembled coalition scientists. Said a senior executive at Bristol-Myers Squibb, “I encourage industry to redouble their efforts to support this initiative.”—Gabrielle Strobel.

This concludes a four-part series. See also Part 1, Part 2, and Part 3. See also a PDF of the entire series.

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References

News Citations

  1. Worldwide Quality Control Set to Tame Biomarker Variation
  2. DC: CAMD Convenes Stakeholders to Reform Alzheimer’s Trials
  3. DC: Standard Data—Music to Regulators’ Ears
  4. DC: Shared Pain Is Lessened—Open-Trial Data Gain AD Model

Paper Citations

  1. . Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007 Aug;6(8):734-46. PubMed.
  2. . Revising the definition of Alzheimer's disease: a new lexicon. Lancet Neurol. 2010 Nov;9(11):1118-27. PubMed.

Other Citations

  1. ARF brief on NAPA

External Citations

  1. Qualification Process for Drug Development Tools
  2. CAMD website
  3. Clinical Data Interchange Standards Consortium
  4. C-Path Online Data Repository

Further Reading