C-Path’s PSTC Releases Points to Consider Outlining Recommendations for Analytical Validation of Assays Used in Qualifying Biomarkers

The document serves as a guide to the analysis of biomarkers in drug development

 

TUCSON, Ariz., June 11, 2019 — The Critical Path Institute’s (C-Path) Predictive Safety Testing Consortium (PSTC) has released a new consensus paper titled, “Points to Consider Document: Scientific and Regulatory Considerations for the Analytical Validation of Assays Used in the Qualification of Biomarkers in Biological Matrices.”

Once biomarkers are qualified as drug development tools (DDTs) by regulatory entities, such as the US Food and Drug Administration’s (FDA) Biomarker Qualification Program within the Center for Drug Evaluation and Research (CDER), supporting information is made publicly available for use by drug development programs, which can result in increased opportunities to improve safety, efficiency and innovation in the drug development process.

The points to consider document outlines PSTC-recommended scientific and regulatory considerations for the analytical validation of assays for fluid-based biomarkers qualified by regulatory agencies for use as DDTs.

“Assays used to measure biomarkers produce critical evidence for both drug development programs and regulatory agencies,” explained John-Michael Sauer, PhD, Program Officer of C-Path’s Biomarkers Program and PSTC Executive Director. “It’s imperative, then, that these assays undergo extensive testing and rigorous analytical validation to ensure accuracy in measurement of the biomarkers being studied, and the ability to generate reliable and consistent results that can be properly analyzed.”

“This is the result of collaboration among many biomarker stakeholders, including scientists from the FDA, and contains a complete description of necessary approaches that can be applied to most analytical situations that will be encountered in fluid-based biomarker qualification and can serve as a guide to the analysis of biomarkers in drug development,” said Steven Piccoli, PhD, Head of Clinical Biomarkers, Experimental Medicines at GlaxoSmithKline.

Topics discussed in the document include considerations for assay design and technology selection, optimization of pre-analytical factors, core assay performance expectations, and setting minimally acceptable assay performance criteria. It addresses seven key analytical parameters, including figures and examples to aid in assessing the impact of these analytical parameters on assays that will be utilized for biomarker qualification. Two case studies are contained in the document as examples.

The points to consider document represents the efforts of a diverse, dedicated, and expert working group that leveraged current scientific peer-reviewed literature, input from discussion sections at scientific meetings, and public expert opinion to develop valuable consensus on best practice approaches that can be applied to the development, characterization, and validation of assays to support fluid biomarker qualification.

 


 

About Critical Path Institute

C-Path (Critical Path Institute) is an independent, nonprofit organization established in 2005 as a public and private partnership. C-Path’s mission is to catalyze the development of new approaches that advance medical innovation and regulatory science, accelerating the path to a healthier world. An international leader in forming collaborations, C-Path has established numerous global consortia that currently include over 1,500 scientists from government and regulatory agencies, academia, patient organizations, disease foundations, and dozens of major pharmaceutical and biotech companies. C-Path is headquartered in Tucson, Arizona, with additional staff in multiple remote locations. For more information, visit www.c-path.org.

 

Media Contact:

Kissy Black
615.298.1144
kissyblack@lotosnile.com

Critical Path Institute Receives Regulatory Support for Liver Injury Biomarker

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Tucson, AZ — January 22, 2018Critical Path Institute (C-Path) announced today that the European Medicines Agency (EMA) has issued a Letter of Support for measurement of glutamate dehydrogenase (GLDH) as a biomarker of hepatocellular liver injury. The letter was awarded to C-Path’s Predictive Safety Testing Consortium (PSTC) and Duchenne Regulatory Science Consortium (D-RSC) to encourage the further study of serum GLDH for monitoring hepatocellular liver injury.

The letter—in response to data submitted by the PSTC Hepatotoxicity Working Group (HWG) and D-RSC—describes EMA’s thoughts on the value of GLDH and supports further evaluation. In it, EMA encourages PSTC and D-RSC to investigate “the voluntary and complementary use of serum GLDH, in conjunction with currently used biomarkers of liver injury, as a clinical biomarker of liver injury.” EMA also supports PSTC’s generation of additional clinical safety data, and plans for further clinical studies to potentially enable formal qualification of GLDH in the future.

“Many of the proteins currently monitored to evaluate liver safety are also found in muscle tissue,” says Jane Larkindale, D.Phil., Executive Director of D-RSC. “In situations where a patient has underlying muscle injury, such as muscular dystrophies, levels of these enzymes may be high in the absence of liver injury. Monitoring of GLDH levels may allow liver injury caused by novel drugs to be detected in this population of patients.”

D-RSC is dedicated to developing tools to accelerate development of safe drugs for Duchenne, and monitoring safety of such drugs is important. PSTC is dedicated to the development of safety biomarkers, so collaboration between the two C-Path consortia accelerated development of this biomarker.

“At C-Path, we are constantly looking to work in partnership across our many consortia, and the GLDH biomarker qualification presented the perfect opportunity for such a collaboration between PSTC and D-RSC,” says John-Michael Sauer, PhD, Biomarker Program Officer and Executive Director of PSTC.

EMA support encourages the biomarker’s use in both nonclinical and exploratory clinical studies as a marker of hepatocellular liver injury, and indicates that this biomarker has strong potential for use in humans and warrants additional exploration and gathering of data.

Says C-Path President and CEO Martha A. Brumfield, PhD, “The data package submitted to EMA supporting use of this liver-injury biomarker, developed by PSTC and D-RSC in partnership, exemplifies successful cross-consortium collaboration at C-Path, and EMA’s support of this biomarker is a harbinger of future success for both consortia. Developing reliable biomarkers remains one of the most productive methods of aligning and streamlining research and regulatory processes.”

The Letter of Support for this biomarker is posted on the EMA website, and can also be accessed via the C-Path PSTC website.

 


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Critical Path Institute (C-Path) is an independent, nonprofit organization established in 2005 with public and private philanthropic support from the Arizona community, Science Foundation Arizona, and the US Food and Drug Administration (FDA). C-Path’s mission is to catalyze the development of new approaches that advance medical innovation and regulatory science, accelerating the path to a healthier world. An international leader in forming collaborations, C-Path has established 12 global, public-private partnerships that currently include over 1,450 scientists from government and regulatory agencies, academia, patient advocacy organizations, and dozens of major pharmaceutical companies. C-Path is headquartered in Tucson, Arizona. For more information, visit www.c-path.org.

 

C-Path Contact:
Kissy Black
+1.615.298.1144
kissyblack@lotosnile.com

 

IMI SAFE-T and C-Path PSTC Obtain Regulatory Support for New Liver Safety Biomarkers

Oct 17, 2016

 

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IMI SAFE-T and C-Path PSTC Obtain Regulatory Support for New Liver Safety Biomarkers

US FDA and EMA Letters of Support Pave the Way for Clinical Qualification

 

The Innovative Medicines Initiative (IMI) SAFE-T (Safer and Faster Evidence Based Translation) Consortium and Critical Path Institute (C-Path) Predictive Safety Testing Consortium (PSTC) announced today that the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) each issued a Biomarker Letter of Support for new liver safety biomarkers investigated by the SAFE-T Drug-Induced Liver Injury Work Package and the PSTC Hepatotoxicity Working Group. The Drug-Induced Liver Injury Network (DILIN) in the US, an expert network established by The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), contributed their expertise to the research, as well as rare samples from individuals with severe liver injury.

The liver safety biomarkers—cytokeratin 18 (CK-18), high mobility group protein B1 (HMGB1), osteopontin, and macrophage colony-stimulating factor 1 receptor (MCSFR1, or CSF1R), are proteins that can be measured in human serum. Both FDA and EMA acknowledged that higher levels of these biomarkers in patients diagnosed with Drug-Induced Liver Injury (DILI) could indicate a risk for progression toward liver failure, which may result in death or the need for liver transplantation. DILI is an adverse drug reaction that has, for decades, been a major cause for late-stage failures in drug development and post-marketing withdrawals.

In addition, EMA considered results promising for serum biomarkers total HMGB1, total and caspase-cleaved keratin 18, miR-122, and GLDH in terms of possibly improving early prediction of liver injury in clinical trials with compounds having the potential to cause intrinsic liver toxicity, similar to paracetamol (acetaminophen).

The Letters of Support indicate the new biomarkers have potential for use in humans, which warrants additional exploration and data generation, and are intended to encourage scientists to collect additional data from nonclinical and exploratory clinical studies. With this milestone, in-depth research can continue toward the qualification of the new biomarkers for use in clinical trials on top of standard safety tests.

“Many current obstacles in drug development pose substantial scientific and logistical challenges to industry and public health that are impossible to tackle by individual companies or research organizations alone. Large scale public-private partnerships are an indispensable prerequisite to solve complex tasks such as development and qualification of new safety biomarkers, as exemplified by IMI’s SAFE-T and C-Path’s PSTC,” said Pierre Meulien, PhD, IMI Executive Director.

“The collaboration demonstrated by these specific IMI and C-Path programs has enabled this significant advance which encourages utilization of these novel liver biomarkers by sponsors. Acquiring more experience and data with these biomarkers will provide greater confidence and refinement in their utility, thereby assisting decision making within drug development programs and by regulatory authorities.” Martha A. Brumfield, PhD, President & CEO, Critical Path Institute.

”The success of the SAFE-T/PSTC collaboration nicely demonstrates the benefits of working together across public private partnerships on a global scale. Shared scientific enthusiasm, persistence, and team-spirit were the key foundation for this achievement”. Michael Merz, MD, Novartis Institutes for BioMedical Research, IMI SAFE-T project coordinator.

“The SAFE-T/PSTC collaboration represents the best collaborative science, bringing together experts from Europe and North America around the common goal of qualifying safety biomarkers. This relationship demonstrates how two public-private partnerships can work together in support of their members’ goals and visions.” John Michael Sauer, PhD, Critical Path Institute, PSTC Executive Director.

The FDA Letter of Support is posted on the FDA website, the EMA Letter of Support on the EMA website. Additionally, the documents can be accessed via the SAFE-T website, or via the C-Path PSTC website under the Regulatory Successes tab. The PSTC website includes a summary data package describing the studies that support the use of these liver safety biomarkers.

The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115003, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.

About the organizations:

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The Innovative Medicines Initiative (IMI) is working to improve health by speeding up the development of, and patient access to, the next generation of medicines, particularly in areas where there is an unmet medical or social need. It does this by facilitating collaboration between the key players involved in healthcare research, including universities, pharmaceutical companies, other companies active in healthcare research, small and medium-sized enterprises (SMEs), patient organisations, and medicines regulators. This approach has proven highly successful, and IMI projects are delivering exciting results that are helping to advance the development of urgently- needed new treatments in diverse areas.
IMI is a partnership between the European Union and the European pharmaceutical industry, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA). Through the IMI 2 programme, IMI has a budget of €3.3 billion for the period 2014-2024. Half of this comes from the EU’s research and innovation programme, Horizon 2020. The other half comes from large companies, mostly from the pharmaceutical sector; these do not receive any EU funding, but contribute to the projects ‘in kind’, for example by donating their researchers’ time or providing access to research facilities or resources.
For more information, visit www.imi.europa.eu.


 

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Critical Path Institute (C-Path) is an independent, nonprofit organization established in 2005 with public and private philanthropic support from the Arizona community, Science Foundation Arizona, and the US Food and Drug Administration (FDA). C-Path’s mission is to catalyze the development of new approaches that advance medical innovation and regulatory science, accelerating the path to a healthier world. An international leader in forming collaborations, C- Path has established 12 global, public-private partnerships that currently include over 1,450 scientists from government and regulatory agencies, academia, patient advocacy organizations, and dozens of major pharmaceutical companies. C-Path is headquartered in Tucson, Arizona. For more information, visit www.c-path.org.

For more information:

C-Path Contact:
Kissy Black
+1.615.298.1144
kissyblack@lotosnile.com
SAFE-T Contact:
Dominique Brees 
Novartis Institutes for BioMedical Research
dominique.brees@novartis.com

 

Critical Path Institute Secures Regulatory Support For Skeletal Muscle Safety Biomarkers

April 13, 2015
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Critical Path Institute Secures Regulatory Support For Skeletal Muscle Safety Biomarkers

FDA and EMA Letters of Support Suggest Valuable Research Potential

TUCSON, Ariz., April 8, 2015 – The Critical Path Institute (C-Path) announced today that both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have issued Biomarker Letters of Support for four skeletal muscle safety biomarkers identified and evaluated by C-Path’s Predictive Safety Testing Consortium (PSTC)’s Skeletal Myopathy Working Group. This is the second time the two agencies have provided a Biomarker Letter of Support to PSTC in the past six months, following FDA and EMA support for the kidney safety biomarkers osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL).

“This Letter of Support intends to encourage scientists to collect data from exploratory studies, which may lead to qualification of these types of biomarkers,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “We are optimistic about how this effort will further advance biomarker development.”

The skeletal safety biomarkers – myosin light chain (Myl3), skeletal muscle troponin I (sTnI), fatty acid binding protein 3 (FABP3), and creatine kinase muscle type (CK-M, the homodimer CK-MM) – are proteins that can be measured in plasma or serum. Higher levels of these biomarkers could indicate that skeletal muscle injury is occurring.

“The development of accurate, reliable biomarkers continues to be one of the most productive methods of aligning and streamlining the research and regulatory processes,” says C-Path President and CEO Martha A. Brumfield, PhD. “The support of these skeletal muscle safety indicators by the FDA and EMA is an encouraging development in the PSTC’s larger mission of facilitating scientific validation and regulatory qualification of novel safety biomarkers.”

Each agency’s Letter of Support for Myl3, sTnI, FABP3, and CK-M is intended to encourage the biomarkers’ use in both nonclinical and exploratory clinical studies as markers of skeletal muscle injury. Combined FDA and EMA support indicates that these biomarkers have strong potential for use in humans and warrants additional exploration and gathering of data. With this milestone, work will continue in earnest on the qualification of Myl3, sTnI, FABP3, and CK-M for use in clinical trials.

Letters of Support for these skeletal muscle biomarkers are posted on the FDA DDT website and the EMA website, and can also be accessed via the C-Path PSTC website, along with a summary data package describing the studies that support the use of these kidney safety biomarkers.



About the Critical Path Institute

The Critical Path Institute (C-Path) is an independent, non-profit organization established in 2005 with public and private philanthropic support from the Arizona community, Science Foundation Arizona, and the U.S. Food and Drug Administration (FDA). C-Path’s mission is to catalyze the development of new approaches that advance medical innovation and regulatory science, accelerating the path to a healthier world. An international leader in forming collaborations, C-Path has established seven global, public-private partnerships that currently include over 1,000 scientists from government and regulatory agencies, academia, patient advocacy organizations, and dozens of major pharmaceutical companies. C-Path is headquartered in Tucson, Arizona. For more information, visit http://www.c-path.org.

C-Path Contact:
 Kissy Black
+1.615.298.1144
kissyblack@lotosnile.com

 

Critical Path Institute Secures Additional Regulatory Support For Kidney Safety Biomarkers

January 12, 2015

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Critical Path Institute Secures Additional Regulatory Support For Kidney Safety Biomarkers

EMA Letter of Support Opens Door for Clinical Qualification

TUCSON, Ariz., January 12, 2015 – The Critical Path Institute (C-Path) announced today that the European Medicines Agency (EMA) issued a first-of-its kind Biomarker Letter of Support for two essential kidney safety biomarkers identified and evaluated by the Predictive Safety Testing Consortium (PSTC)’s Nephrotoxicity Working Group.

The kidney safety biomarkers, osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL), are proteins that can be measured in urine. Higher levels of OPN and NGAL could indicate that the kidneys are being damaged, which may result in a loss of kidney function. The Letter of Support intends to encourage scientists to collect data from nonclinical and exploratory clinical studies, which may lead to qualification of these biomarkers.

“We are pleased to continue working collaboratively with the EMA, academia, and industry to identify tools, processes, and methods to improve the drug development process,” said Martha Brumfield, Ph.D., president and chief executive officer of C-Path. “With this Letter of Support, the EMA has opened doors that encourage the generation of necessary, rigorous clinical data to determine if these biomarkers hold clinical utility.”

The EMA’s Letter of Support indicates that these biomarkers have strong potential for use in humans and warrant additional exploration and data gathering. The EMA granted the Letter of Support for OPN and NGAL to encourage their use in both nonclinical and exploratory clinical studies as markers of proximal renal tubule degeneration/necrosis. With this milestone, work will continue in earnest on the qualification of OPN and NGAL for use in clinical trials.

“We are all incredibly excited about our collaborative interactions with EMA and the creation of the Letter of Support, enabling us to further define the path to clinical biomarker qualification,” said John Michael Sauer, Ph.D., Executive Director, Predictive Safety Testing Consortium, Critical Path Institute.

The Letter of Support is posted on the EMA website and can also be accessed via the C-Path PSTC website under the Regulatory Successes tab, along with a summary data package describing the studies that support the use of these kidney safety biomarkers.

About the Critical Path Institute

The Critical Path Institute (C-Path) is an independent, non-profit organization established in 2005 with public and private philanthropic support from the Arizona community, Science Foundation Arizona, and the U.S. Food and Drug Administration (FDA). C-Path’s mission is to catalyze the development of new approaches that advance medical innovation and regulatory science, accelerating the path to a healthier world. An international leader in forming collaborations, C-Path has established seven global, public-private partnerships that currently include over 1,000 scientists from government and regulatory agencies, academia, patient advocacy organizations, and dozens of major pharmaceutical companies. C-Path is headquartered in Tucson, Arizona. For more information, visit http://www.c-path.org.