CiPA Update December 2018

Dear CiPA Community,
Welcome to the CiPA Quarterly Update!

We are happy to share news from the recent ICH face-to-face meeting held in November 2018. The ICH S7B/E14 Q&A concept paper and work plan have been approved! The ICH Assembly endorsed the establishment of an Implementation Working Group (IWG) to begin the process of developing a Q&A document. This IWG will build on work done by the former E14/S7B Discussion Group (DG) including work on the CiPA initiative.

The purpose of the IWG will be to provide guidance around the proposed nonclinical assays (in vitro, in silico, and in vivo). The current plan calls for a two-staged Q&A approach starting with S7B and then E14 guidance with the goal to have this be a more efficient process. Read more online including the concept paper and work plan:

E14/S7B Questions & Answers: Clinical and non-Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential

Concept Paper

Work Plan

Recent Publications:

  • Vicente J, Zusterzeel R, Johannesen L, Ochoa-Jimenez R, Mason JW, Sanabria C, Kemp S, Sager PT, Patel V, Matta MK, Liu J, Florian J, Garnett C, Stockbridge N, Strauss DG. (2018.) Assessment of Multi-Ion Channel Block in a Phase-1 Randomized Study Design: Results of the CiPA Phase 1 ECG Biomarker Validation Study. Clin Pharmacol Ther. 2018 Nov 17. doi: 10.1002/cpt.1303.
  • Li Z., Ridder B. J., Han X., Wu W. W., Sheng J., Tran P. N., Wu M., Randolph A., Johnstone R. H., Mirams G. R., Kuryshev Y., Kramer J., Wu C., Crumb W. J., Strauss,
    D. G. (2018). Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the CiPA Initiative. Clinical Pharmacology and Therapuetics. Available online August 27, 2018. doi:10.1002/cpt.1184
  • Blinova K., Dang Q., Millard D., Smith G., Pierson J., Liang G., Brock M., Lu H.R., Kraushaar U., Zeng H., Shi H., Zhang X., Sawada K., Osada T., Kanda Y., Sekino Y., Pang L., Feaster T.K., Kettenhofen R., Stockbridge N., Strauss D.G., Gintant G. (2018). (2018). International Multisite Study of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment. Cell Reports. Available online September 25, 2018. https://doi.org/10.1016/j.celrep.2018.08.079.

If you’re interested in finding past Quarterly Updates, they are available online.

Regards,


____________________________
Jennifer Pierson, MPH
Senior Scientific Program Manager
Health and Environmental Sciences Institute (HESI)
jpierson@hesiglobal.org

CSRC Think Tank: Defining the Clinical and Regulatory Landscape for Cardiogenic Shock

September 7, 2018

8:00am – 8:15am Introduction and Purpose of Think Tank Mitchell Krucoff, MD (Duke)

  • Introduction to CSRC
  • Anatomy of a Think Tank

8:15am – 8:45am Session I: Overview of shock

Session I Objectives:

8:45am – 9:00am BREAK

9:00am – 10:30am Session II: Defining unmet needs, clinical study barriers, and targets for drug and device therapy for shock: Part I Moderator: Joseph Rogers, MD (Duke)

Session II Objectives:

  • Define a population of intended use for drug and device therapies in cardiogenic shock.
  • Discuss and identify comparator cohorts for cardiogenic shock trials.
  • Discuss and identify primary and secondary outcomes for cardiogenic shock trials.

9:00am – 9:10am Cohorts to study: defining a “population of intended use”

9:10am – 9:20am Comparators for drug and device trials in shock patients

  • Clinical/best practice perspective Judith Hochman, MD (NYU Langone)

9:20am – 9:30am Outcome endpoints: mortality plus?

9:30am – 9:40am FDA Perspective Ileana Pina, MD
9:40am – 9:50am Health Canada Perspective Roy Masters, MD
9:50am – 10:30am Discussion

  • Lead Discussant: Ron Waksman, MD (Medstar Health)

10:30am – 10:45am BREAK

10:45am -12:15pm Session III: Defining unmet needs, clinical study barriers, and targets for drug and device therapy for shock: Part II | Moderator: David Morrow, MD MPH (Harvard)

Session III Objectives:

  • Discuss enrollment of patients who may not be capable of providing informed consent.
  • Discuss and identify novel evidence structures for future shock trials.
  • Discuss and identify novel statistical approaches for trials of shock therapies.

10:45am – 10:55am Informed consent

  • Clinical/best practice perspective Timothy Henry, MD (Cedars-Sinai)

10:55am – 11:05am Avenues for real world evidence, pragmatic trials, or novel infrastructure for shock trials

  • Clinical/best practice perspective Holger Thiele, MD (University of Leipzig)

11:05am – 11:15am Novel statistical approaches for shock studies

11:15am – 11:20am Improving Patient Outcomes in Cardiogenic Shock as a core mission of clinical development programs Seth Bilazarian, MD (Abiomed)

11:20am-11:30am FDA Perspective John Sapirstein, MD

11:30am – 12:10pm Discussion

  • Lead Discussant: Roseann White, MA (Duke)

12:10pm – 1:00pm LUNCH

1:00pm – 2:00pm Session IV: Future directions for device and drug development in shock. Moderator: Sunil Rao, MD (Duke)

Session IV Objectives:

  • Identify global collaborators for trials of shock therapies.
  • Discuss trial designs incorporating both drug and device therapies for patients with cardiogenic shock.
  • Discuss and define “-ARC” definitions of shock (SHARC).

1:00pm – 1:10pm Global collaboration: is it possible? Is it desirable? Clinical/best practice perspective William Abraham, MD (Ohio State)

1:10pm – 1:20pm Factorial device and drug study designs

  • Clinical/best practice perspective Roxana Mehran, MD (Mount Sinai)

1:20pm – 1:30pm Definitions: Shock-ARC (SHARC)

  • Clinical/best practice perspective George Dangas, MD (Mount Sinai)

1:30pm-1:40pm FDA Perspective Fortunato Senatore, MD, PhD
1:40pm – 2:30pm Discussion
2:30pm – Closing Remarks

Scientific Programs Committee Chair Attends CEC Summit

CSRC Executive Committee member and Scientific Programs Committee Chair Jonathan Seltzer, MD, MBA, MA, attended the inaugural 2018 CEC Summit on September 26-27, 2018. This event, cohosted by the Duke Clinical Research Institute and Stanford Center for Clinical Research, brought together thought leaders from academia, industry, and government to establish consistent standards globally for clinical events classification (CEC) and adjudication in clinical trials.

“This meeting was special as it examined both the scientific justification for endpoint adjudication as well as operational best practices. It is likely that future meetings with this group will deliver innovative solutions to issues whereby adjudication strategies can be more broadly applied, but in an intelligent, cost-effective manner,” said Seltzer, who also serves as the president and CEO of ACI Clinical.

Event panelists and speakers represented various organizations including the U.S. Food and Drug Administration (FDA), Harvard University, Cleveland Clinic, George Clinical, the Cardiovascular Research Foundation, Cardialysis, and more.

Hear what others had to say about the event in this recap.

CiPA Update October 2018


Dear CiPA Community,
Welcome to the CiPA Quarterly Update!

Recent publications from the CiPA workstreams are listed below. Visit the CiPA website to see all publications: http://cipaproject.org/publications/:

  • Strauss D.G., Gintant G, Li Z, Wu W, Blinova K, Vicente J, Turner J.R., Sager P.T. (2018). Comprehensive In Vitro Proarrhythmia Assay (CiPA) Update from a Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA Meeting. Therapeutic Innovation & Regulatory Science. First Published August 29, 2018. doi.org/10.1177/2168479018795117
  • Li Z., Ridder B. J., Han X., Wu W. W., Sheng J., Tran P. N., Wu M., Randolph A., Johnstone R. H., Mirams G. R., Kuryshev Y., Kramer J., Wu C., Crumb W. J., Strauss, D. G. (2018). Assessment of an In Silico Mechanistic Model for Proarrhythmia Risk Prediction Under the CiPA Initiative. Clinical Pharmacology and Therapuetics. Available online August 27, 2018. doi:10.1002/cpt.1184
  • Blinova K., Dang Q., Millard D., Smith G., Pierson J., Liang G., Brock M., Lu H.R., Kraushaar U., Zeng H., Shi H., Zhang X., Sawada K., Osada T., Kanda Y., Sekino Y., Pang L., Feaster T.K., Kettenhofen R., Stockbridge N., Strauss D.G., Gintant G. (2018). (2018). International Multisite Study of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes for Drug Proarrhythmic Potential Assessment. Cell Reports. Available online September 25, 2018. https://doi.org/10.1016/j.celrep.2018.08.079.

Open Data Formatting:
A subteam including volunteers from industry and FDA is currently working on an open data format specification for manual and automated patch clamp data. The open format will be manufacturer independent and will meet CiPA in vitro and in silico needs. The format will be also eCTD compliant.

Best Practices Papers:
The CiPA Work Streams continue to make progress on additional manuscripts including one from each group that will detail some of the discussions and recommendations that came out of the recent May 2018 CiPA Meeting. These publications will cover topics such as quality standards necessary for regulatory submissions to best practices and recommendations. The hope is to help provide some further clarity around expectations around the differences in early drug development screening tools and data that will be submitted as part of a regulatory submission package.

If you’re interested in finding past Quarterly Updates, they are available online: http://cipaproject.org/latest-news/.

Jennifer Pierson, MPH
Senior Scientific Program Manager
Health and Environmental Sciences Institute (HESI) jpierson@hesiglobal.org

Over the Edge for Cardiac Safety

October 4, 2018

Salim Idriss, MD, PhD, principal investigator for CSRC’s Sudden Cardiac Death in the Young initiative, is going Over the Edge for cardiac safety. What does this mean? Dr. Idriss is participating in the 2018 Over the Edge fundraiser on behalf of sudden cardiac death in the young initiatives. On Saturday, October 13, Dr. Idriss and Clare Matti, assistant director of Regulatory Services at the Duke Clinical Research Institute, will rappel 17 stories down the side of the historic 21c Museum Hotel in downtown Durham.

This event, sponsored by Duke Children’s Hospital, helps support patient care, medical research, and physician training at Duke Children’s.

Through your 100% tax-deductible donation, you can help support efforts to end sudden cardiac death in the young. Hear what Dr. Idriss has to say about the event.

DONATE HERE.

CSRC forms partnership with ACCP

August 1, 2018

In July 2018, the American College of Clinical Pharmacology (ACCP) and Cardiac Safety Research Consortim announced the signing of a collaborative Memorandum of Understanding (MOA). CSRC and ACCP will work together to develop, plan and conduct various educational events and programs. The partnership will also develop and produce research and policy statements/position papers relevant to the fields of clinical pharmacology and the cardiac and vascular safety of medical products.

Two collaborative activities defined in the agreement are already underway. First, a group of coauthors from both organizations is preparing a joint position paper on the use of the heart rate-corrected J-Tpeak interval as seen on the human electrocardiogram for purposes of evaluating a new drug’s potential to induce Torsade de Pointes, a rare polymorphic ventricular arrhythmia that typically occurs in self-limiting bursts and can lead to symptoms of dizziness, palpitations, syncope, and seizures. Torsade de Pointes can occasionally progress to ventricular fibrillation and sudden cardiac death.

Second, a CSRC/ACCP sponsored symposium will be held September 25th at the 2018 ACCP Annual Meeting in Bethesda, MD. At the symposium, titled “The Challenging World of Cardiac Evaluation & Utilization of Concentration-QT Analyses of Phase I Data to Waive the Thorough QT/QTc Study Requirement,” Chairs and Faculty Speakers will present industry, academia and regulatory agency viewpoints. ACCP will provide CME & CPE credits for the course.

CSRC and ACCP look forward to the continued opportunities that will arise from this new collaboration. If you are interested in becoming involved in these activities, please contact us at info@cardiac-safety.org.

CSRC Committee Chair to Moderate at CEC Summit

July 18, 2018

On September 26-27, 2018 the Duke Clinical Research Institute and the Stanford Center for Clinical Research will cohost a CEC Summit, an exciting new educational event at the Chicago Hilton O’Hare. Thought leaders from academia, industry, and government will be in attendance including CSRC Executive Committee member and Scientific Programs Committee Chair Jonathan Seltzer, MD, MBA, MA, who will serve as a moderator.

Join Dr. Seltzer and other experts from around the country for provocative and challenging discussions on various topics including CEC audit readiness, emerging trends in safety and efficacy, new technologies, and data quality and standards.

Visit the event website for more information.

CiPA Update

June 18, 2018

Dear CiPA Community,

On behalf of the CiPA Steering Team, I would like to share some exciting updates.

We are pleased to share materials from the recent May CiPA Update meeting, “The Future of the Assessment of Drug-Induced Arrhythmias and CiPA.” Presentations and a meeting synopsis are now available on the CiPA and CSRC websites: http://cipaproject.org/meetings-webinars/ and https://cardiac-safety.org/. Feel free to share these links with your colleagues!

In addition to the meeting materials, the recommended cardiac ion channel protocols are now available on the CiPA website: http://cipaproject.org/data-resources/. Protocols included are for hERG, CaV1.2 and NaV1.5. As more data is generated, the protocols may evolve and updates will be posted to the website. Should you have any questions, feel free to contact me.

Finally, the Myocyte Pilot Study MEA results were recently published in Toxicological Sciences and are available online ahead of print: http://cipaproject.org/publications/.

Look forward to regular, quarterly communications or check the CiPA website for more updates soon!

Jennifer Pierson, MPH
Senior Scientific Program Manager
Health and Environmental Sciences Institute (HESI) jpierson@hesiglobal.org

Announcement of Interest in the Domain of Drug Cardiovascular Safety

On May 31, 2018 the US Food and Drug Administration (FDA) released a draft Guidance for Industry entitled “Assessment of Pressor Effects of Drugs.” The purpose of the guidance is to advise sponsors with regard to their premarketing assessment of a drug’s off-target effect on blood pressure. Given that elevated blood pressure is known to increase the risk of stroke, heart attack, and death, a drug’s effect on blood pressure can be an important consideration in benefit-risk assessment. The guidance therefore recommends systematic characterization of a drug candidate’s effect on blood pressure during drug development.

This draft guidance is of particular interest to many members of CSRC since we held a think tank on this topic in 2012 and published a meeting report in the American Heart Journal the following year (Am Heart J. 2013;165:477-488). For 60 days after the draft guidance’s release, comments and suggestions regarding the document can be submitted to the FDA. All interested parties are encouraged to read the document and consider submitting comments and suggestions. The draft guidance is available here.

We are currently in the planning stages for a follow-up think tank that will be held after the 60-day open comment period has finished. More details will follow in due course.

 


 

New Advances in the Assessment of Drug-Induced Arrhythmias and the Comprehensive In Vitro Proarrhythmia Assay (CiPA)

An FDA/CSRC/HESI-sponsored think tank meeting was convened in Washington, D.C., on May 21- 22, 2018, to discuss the latest data from the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative. This synopsis provides a very high level report of results presented.

The four components of CiPA collectively seek to characterize more clearly the torsadogenic risk of drugs by providing a more comprehensive assessment of a drug’s effect on multiple cardiac ionic currents rather than just hERG. In vitro assessment of drug-induced effects on ionic currents focuses primarily on hERG, late sodium, and L‐type calcium (calcium) currents. In silico computer modeling integrates individual ion channel data to predict the clinical risk of Torsade. ECG biomarkers, e.g., the heart rate-corrected J-Tpeak interval (J-Tpeakc), are studied in Phase 1 clinical trials to check for unanticipated effects compared with nonclinical ion channel data and in silico modeling predictions. In vitro drug effects on human induced pluripotent stem cell-derived ventricular cardiomyocytes can be optionally examined for the same purposes.

Click here for the full meeting synopsis.

May 21, 2018 – Day 1

8:00am – Continental Breakfast
Welcome and Introduction
Philip Sager, MD (Stanford University) (15 min)

8:15am-9:45am Session I: Overview
Moderator: Gary Gintant, PhD (AbbVie)

Q&A / Panel Discussion (40 min) Speakers and

  • Krishna Prasad, MD (EMA)
  • Corina Dota, MD (AstraZeneca)
  • Peter Kowey, MD (Lankenau Heart Institute)

9:45am-10:00am Break

10:00am-12:00pm Session II: In Silico Modeling and Ion Channel Approaches
Moderator: Gary Mirams, PhD (University of Nottingham)

Q&A / Panel Discussion (45 min) Speakers and

  • Najah Abi Gerges, PhD (AnaBios)
  • Jim Kramer, PhD (Charles River)
  • Takashi Yoshinaga, PhD (Eisai)

12:00pm-12:30pm Working Lunch

12:30pm-2:30pm Session III: IPS-Stem Cells and Phase 1 ECG
Moderators: David Strauss, MD, PhD (US FDA)

Q&A / Panel Discussion (50 min) Speakers and

  • Gary Gintant, PhD (Abbvie)
  • Yasunari Kanda, PhD (Japan NIHS)
  • Charles Benson, MD, PhD (Eli Lilly)

2:30pm-2:45pm Break

2:45pm-4:50pm Session IV: Regulatory Evaluation and Potential Implementation
Moderator: Philip Sager, MD (Stanford University)

Q&A/Panel discussion (60 min) Speakers and

  • Colette Strnadova, PhD (Health Canada)
  • Kaori Shinagawa, MD, PhD (PMDA)
  • Jean-Pierre Valentin, PhD (UCB, EFPIA)
  • Maki Ito MD, PhD (JPMA, Merck)

5:00pm Adjourn


May 22, 2018 – Day 2

7:30am-8:00am Continental Breakfast

8:00am-8:10am General Instructions

8:10am–10:30am Work Stream Breakouts

Breakout 1 – In Silico
Leaders: Zhihua Li, PhD (US FDA); Gary Mirams, PhD (University of Nottingham); Takashi Yoshinaga, PhD (Eisai)

The In Silico Breakout Session discussion will focus the on:

  • Considerations of implementing the proposed CiPA model and qNet metric
  • General principles to qualify any new models and metrics to be used under the CiPA paradigm

Breakout 2 – Ion Channel
Leaders: Wendy Wu, PhD (US FDA); James Kramer, PhD (Charles River); Najah Abi-Gerges, PhD (AnaBios)

The Ion Channel Breakout Session discussion will focus the on:

  • Data quality standards (for consideration of cell integrity and recording quality)
  • Current run-up, run-down, steady state
  • Unified experimental protocol for CiPA
  • Temperature for hERG channel recording
  • Agonist for late NaV1.5 current
  • Charge carrier for CaV1.2 current
  • Where and how drug effects are measured during the voltage protocols

Breakout 3 – Myocyte
Leaders: Gary Gintant, PhD (Abbvie); Ksenia Blinova, PhD (US FDA); Yasunari Kanda, PhD (Japan NIHS)

The Myocyte Breakout Session discussion will focus the on:

  • Brief review of Validation Study results
  • Findings of JiCSA study results
  • Comparison of JiCSA and Validation study results (points of concordance, discordance, models)
  • Comparison of sensitivity of different cell lines (noncore sites study)
  • Setting best practices and calibration standards
  • Roles of myocytes (internal decision-making vs. regulatory perspectives, flow chart examples, benefits vs. current regulatory paradigm)

Breakout 4 – Phase 1 ECG
Leaders: Jose Vicente Ruiz, PhD (US FDA); Christine Garnett, PharmD (US FDA)

The ECG Breakout Session will focus on:

  • Summary of results supporting J-Tpeak use to inform multi-ion channel effects
  • Heart rate dependency of J-Tpeak interval
  • J-Tpeak/RR adaptation and hysteresis
  • Population vs. subject-specific corrections
  • Challenges in concentration-ECG-response models
  • Identifying nonlinear relationships in small sized trials
  • Impact on interpretation of results
  • Role of ECG in a potential implementation of CiPA
  • Integrated risk assessment, context of use and potential thresholds
  • How to handle discrepancies
  • Limitations
  • Are we ready?

10:30am-11:00am Break

11:00am-12:00pm Reports from Work Stream Breakouts

12:00pm-12:30pm Working Lunch

12:30pm-2:30pm Advances in Clinical QTc Assessments and Updates from the FDA QT Interdisciplinary Review Team (IRT)
Moderator: Philip Sager, MD (Stanford University)

Q&A / Panel Discussion (60 min)

  • Christine Garnett, PharmD (US FDA)
  • Borje Darpo, MD, PhD (ERT)
  • Dalong Huang, PhD (US FDA)

2:30 pm Adjourn