Experts Move Toward Standardization in 'Wild West' of Parkinson's Biomarkers

Deborah Brauser

August 27, 2018

A group of experts from more than 30 organizations, including the National Institute of Neurological Disorders and Stroke (NINDS) and the Michael J. Fox Foundation for Parkinson's Research, is calling for standardization in the field of Parkinson's disease (PD) research.

This includes recommendations for the types of biomarkers researchers should identify to aid in the development of new treatments, with a shift toward focusing on those that look within the disease itself rather than just those that distinguish patients with PD from individuals with Alzheimer's disease or who are healthy.

The paper, which was published online August 15 in Science Translational Medicine, also proposes that specific research principles be followed and lists resources for helpful collaborations.

"In the biomarker field in Parkinson's disease, it's been a little bit of a 'Wild West' in everything, including how people collect and process samples," lead author, Alice Chen-Plotkin, MD, Parker Family Associate Professor in the Perelman School of Medicine, University of Pennsylvania, Philadelphia, told Medscape Medical News.

Dr Alice Chen-Plotkin

"I think that, particularly in things with a clinical application like this, you need real transparency and you need reproducibility — and the only way to get that is to work it out as a community. So we put together a recommendation to move towards standardization," said Chen-Plotkin.

Four Million Affected

Second only to Alzheimer's disease, PD is the most common neurodegenerative disorder and affects more than 4 /million people globally — "with numbers projected to double in the next few decades," the investigators note.

They add that ClinicalTrials.gov lists more than 550 open studies for PD, but less than 10% of these are assessing neuroprotective or disease-modifying treatments. Of those that are evaluating these types of treatments, only 2 are in phase 3 trials.

"Biomarkers may represent an important tool for bolstering the therapeutic drug discovery pipeline," the authors write.

Although there have been previous recommendations regarding PD biomarker research, these are "the first developed in collaboration with institutions outside of academic medicine."

Chen-Plotkin reported that the current report's origins date back to discussions at a workshop on biomarkers that was conducted in 2016 by the Michael J. Fox Foundation. Ideas from there were further developed 5 months later, during talks at the NINDS PD Biomarkers Program (PDBP) annual meeting.

The current paper's authors are affiliated with more than 30 organizations, including government groups, such as the National Institute on Aging; academic institutions; nonprofit funding agencies; and pharmaceutical companies.

"These players at times have acted in separate worlds, but with a disease affecting so many and lacking in disease-modifying therapies, we're coming together for essential collaboration and innovation. Biomarkers to bolster our efforts to develop new therapies are urgently needed," Chen-Plotkin said in a press release.

The new recommendations highlight the PD biomarker types "that are likely to have the greatest immediate impact on the development of disease-modifying therapies," the authors write.

"We stress the urgency of finding such biomarkers in the near future, given the likely entry of several classes of mechanism-based therapies — such as those targeting the aggregation or propagation of α-synuclein or the activity of LRRK2 kinase — into early human clinical trials," they add.

They note that "useful" PD biomarkers are those that have a reasonable effect size, demonstrate reproducibility across patient groups, and can be verified in proven cases of PD.

Objective markers are also needed that will predict a patient's disease progression, the authors write. 

Biorepository Data

There are already several "biobanks" around the world that hold thousands of biological samples, note the authors.

"Before the advent of these shared biobanks, investigators depended on their own ability to collect hundreds or thousands of samples for testing, preventing potential researchers lacking access to large clinical populations from entering the biomarker discovery arena," Chen-Plotkin said.

However, several public-private efforts "have laid the groundwork" for researchers from all backgrounds to access clinical samples, she reported.

"These repositories are all open for collaboration to improve the pipeline to take Parkinson's biomarkers from concept to clinic," added Chen-Plotkin.

The list of recommended biobanks includes NINDS's PDBP, which launched as a longitudinal study in late 2012. Its dedicated repository has DNA, RNA, and biofluid samples from more than 1000 individuals from the United States, including more than 600 who had PD.

Other biobanks mentioned include BioFIND; the Parkinson's Progression Marker Initiative, which has a replication cohort; the National Brain and Tissue Resource for PD and Related Disorders; the De Novo Parkinson's Study biorepository in Germany; the Norwegian ParkWest study; the Oxford PD Center; and the Harvard Biomarkers Study.

The Biospecimen Review Access Committee already reviews requests for samples from PDBP, BioFind, and the Harvard Biomarkers Study in order to "harmonize efforts," but standardization for the collection and storage of biofluid samples for other research groups are needed, the authors write.

They also call for standardization in developing biomarker assays and recommend using resources from the US Food and Drug Administration (FDA), including the FDA Biomarker Qualification Program.

As for clinical trials, the authors call for larger sample sizes and replication across multiple patient groups.

"Harmonization among biomarker development efforts remains a daunting challenge. Currently, platforms, methods of processing raw data, and analysis of the processed data may all differ by investigator or biomarker," they write.

However, they add that "there is hope," based on the history of standardization in the early days of RNA expression analysis and in the field of Alzheimer's biomarkers.

Success in the field of PD biomarkers "depends on close collaboration across multiple sectors," write the authors.

"We didn't want to say, 'This is the only way you can do things,' especially because all of this is very new. But in the field, people are still doing things in many different ways," said Chen-Plotkin.

"It really is all about reproducibility; and to be reproducible, people need to be really open" to standardization, she said. "As mentioned earlier, it really has been the Wild West. So we wanted to provide a little bit of a map, including resources that exist within this area."

Alzheimer's Parallel

Commenting on the findings for Medscape Medical News, Michelle M. Mielke, PhD, professor of epidemiology in the Department of Health Sciences Research and professor of neurology at Mayo Clinic College of Medicine, Rochester, Minnesota, noted that "this well-written article" raised several important points regarding how to develop better PD biomarkers.

Dr Michelle M. Mielke

"This parallels quite a bit with what we're also trying to do with Alzheimer's disease biomarkers, including how important standardization is," said Mielke, who was not involved with the current paper.

"They're also trying to move forward from just looking at Parkinson's cases and controls to possibilities for other biomarkers that might be helpful — both for the development of new drugs and then further down the road, for clinical purposes," she added.

Mielke noted that avenues worth pursuing might be trying to predict how fast a patient will decline, who will develop cognitive impairment and when, or who will develop behavioral disturbances.

"There are also biomarkers that are needed to try and track disease progression, which could be used in clinical trials and in conjunction with a new therapy. But there are still a lot of questions that need to be answered," she said.

She noted that she is heading up the Alzheimer's Association's International Society to Advance Alzheimer's Research and Treatment (ISTAART) Biofluid Based Biomarkers Professional Interest Area committee, which has released some standardization guidelines of its own.

"Those suggestions were based on how blood was collected, which is something that can be standardized up front. But when it comes to standardization procedures for assays, that's something that will have to be developed along with the assay. So there is a little bit of work that can be done now — but other things will have to wait," said Mielke.

As for clinicians, "at this point, this is just a message of letting them know what's going on. This is a very important area of interest in the research world, and a lot of researchers are really focusing on this and trying to bring something into the clinic. It's certainly not ready for clinic use yet but researchers hope to be there soon."

The study and/or authors were funded by grants from the National Institutes of Health and NINDS and by the Burroughs Wellcome Fund, the Benaroya Fund, and the Michael J. Fox Foundation. Chen-Plotkin consults for the Michael J. Fox Foundation and has collaborated scientifically with 23andMe. A full list of disclosures for the other authors is in the original article. Mielke reports having consulted for Eli Lilly in the past and has received research grants from BioGen and Lundbeck.

Sci Transl Med. Published online August 15, 2018. Abstract

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