In the age of the Internet, don’t you love it when you get a real letter? Especially a letter from your friendly FDA regulator. That’s how the field learned that the Food and Drug Administration is—now a bit more formally than before—in favor of using certain biomarkers as tools to help select clinical trial participants in the earliest stages of Alzheimer’s and Parkinson’s diseases.

In three letters signed last week by Janet Woodcock, who directs the agency’s Center for Drug Evaluation and Research, the FDA backed commonly used markers: hippocampal volume and CSF measures of Aβ42, tau, and phospho-tau for prodromal AD; and dopamine transporter imaging for early PD. The public letters were issued to the Tucson, Arizona-based Critical Path Institute’s Coalition Against Major Diseases (CAMD), in response to the coalition’s recent submission of data supporting the use of the markers. While the letters signify the FDA’s support of the biomarkers, the agency will require more clinical trial data before officially qualifying any of them. Qualification would mean that the agency agrees the markers predict disease progression reliably enough for the purpose of trial enrichment.

These biomarkers are already widely used in drug development, so who needs FDA qualification? According to Diane Stephenson of CAMD, FDA qualification would relieve trial sponsors of the burden of having to convince the agency that the biomarkers are reliable and reproducible every time they run a trial. “Clearly, trial sponsors have been using biomarkers for a long time, and continue to do it without formal regulatory qualification,” Stephenson said. “But qualification could save both the FDA and sponsors a tremendous amount of time and money.”

The Critical Path Institute was founded 10 years ago by the FDA and industry partners to help streamline the qualification process (see Dec 2010 conference news). C-Path acquires data from clinical studies, pools and analyses them further in some cases, and presents them formally to the FDA. CAMD endorses no specific diagnostic tool, ligand, assay, or company. In 2011, it submitted biomarker data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) and other studies to the European Medicines Agency (EMA), which then recommended approval of hippocampal volume as a biomarker that could identify people likely to develop AD (see Oct 2011 news). The EMA had previously approved CSF Aβ and tau for this purpose.

However, to fully qualify those same markers in the United States, the FDA requests additional detailed data from clinical trials demonstrating that the biomarkers sufficiently enriched the participant pool with people who developed disease, Stephenson said. To encourage study leaders to submit such data, in October 2014 the FDA introduced “letters of support” into their drug development tools approval process. These letters convey that the FDA recognizes the potential value of a biomarker and encourages its further evaluation. Five such letters, including the three new ones, have been issued, all to C-Path (see letters here). The first two were for plasma markers of renal and skeletal injury, which could be used in the context of safety trials.

Submission through C-Path is not required for FDA endorsement, but Stephenson said the agency sees value in compiling data from several sponsors in a noncompetitive setting, rather than receiving data from one sponsor at a time. Individual diagnostic assays or markers can also be approved directly, but that comes without a blanket endorsement. For example, the FDA approved, one by one, three amyloid PET tracers for detecting the presence of amyloid in brain, but it has not issued a general qualification for using amyloid PET to enrich for participants likely to develop AD. Stephenson said such a qualification would be useful, but CAMD is not seeking it due to limited resources (see May 2014 news).

To woo the FDA’s support for hippocampal volume and CSF markers as indicators of early AD, CAMD compiled MRI data from ADNI and various literature studies. The group used data from the Parkinson’s Progression Marker Initiative (PPMI), as well as from the PRECEPT trial to support DAT scans for enriching for early PD. To gain full qualification, Stephenson said CAMD will need to submit more data. Novartis recently shared data from the placebo arm of its rivastigmine trial with CAMD (see Feldman et al., 2007).

Qualification may take time because clinical trial biomarker data on presymptomatic populations remains scarce while such trials are still ongoing, Stephenson said. She hopes the letters may dangle a carrot in front of investigators and persuade them that it would be worth their while to share the data. Stephenson pointed out that data sharing has succeeded in the past. In 2013, CAMD and several companies together created a clinical trial simulator that both the FDA and EMA approved (see Jul 2013 news). Alzforum will run a Webinar next month on trial simulation tools and modeling.

Researchers welcomed the letters but pointed out their limitations. “This support is a good step forward, but it’s not clear how it directly relates to the drug development tool qualification process,” commented Johan Luthman of Eisai, Inc., in Philadelphia. Luthman added that the FDA already commonly allows the use of biomarkers for trial enrichment.

With qualification, the FDA would also set common rules about how the biomarkers should be used. For example, qualification of CSF markers might include information about appropriate concentration cut-points, or about what the FDA expects in terms of the markers’ concordance with amyloid PET scans, he said. These guidelines would ease sponsors’ minds and save time, because as of now there is never a guarantee the FDA will ultimately agree with the way a marker was used, said Luthman. He added that the FDA’s support may also help break down some of the barriers to the lumbar puncture procedure, which some patients and physicians still avoid.

Henrik Zetterberg of the University of Gothenburg in Sweden said the letters could help raise the bar for biomarker research. “I think the major effect of letters like this is to make it easier for the field to understand what is needed to qualify a biomarker for use in clinical trials,” he wrote. “This will increase the rigor in the biomarker work, which will increase the interpretability of clinical trial outcomes and facilitate the development of novel treatments.” Zetterberg added that the EMA’s endorsement of CSF biomarkers had this effect in European trials.

Pierre Tariot of the Banner Alzheimer’s Institute in Phoenix commented that embedding biomarkers in clinical trials, with support from regulatory agencies, could ultimately facilitate their use as both prognostic and therapeutic indicators. “This will all happen faster if we work on ways of sharing data across studies,” Tariot wrote. “The point here is that the action from the FDA is certainly good news for the field.”—Jessica Shugart


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News Citations

  1. DC: Standard Data—Music to Regulators’ Ears
  2. The EMA Deems Brain Atrophy Valid Trial Selection Measure
  3. Three’s Company: Florbetaben Approved, Excludes AD Diagnosis
  4. AD Trial Simulation Tool Receives Regulators’ Blessings

Paper Citations

  1. . Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study. Lancet Neurol. 2007 Jun;6(6):501-12. PubMed.

External Citations

  1. here

Further Reading

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