AMP’d Up Search for Biomarkers

By Kathy A. Grako, Ph.D., PMP, CCRP, Senior Clinical Strategy Scientist

In February the United States government announced a unique triad brought together to “accelerate the development of life saving drugs and to help identify new treatments and cures for diseases” under the Accelerated Medicine Partnership (AMP).  FDA and NIH have teamed up with 10 industry heavy weights (AbbVie, Biogen Idec, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Lilly, Merck, Pfizer, Sanofi, and Takeda) and 8 non-profits (Alzheimer’s Association, American Diabetes Association, Lupus Foundation of America, Foundation for the NIH, Geoffrey Beene Foundation, PhRMA, Rheumatology Research Foundation, and USAgainstAlzheimer’s) to identify biological processes and molecules related to Alzheimer’s, Type 2 Diabetes, and two autoimmune disorders:  rheumatoid arthritis and lupus.  Everyone wants to find the perfect biomarker for their indication; however, the sponsors I’ve spoken with do not want to take the time nor bear the cost alone to find that biomarker.  Clinical trials are expensive enough without adding on detection and validation of a biomarker.  The FDA has made improving the clinical trial process a priority for both sponsors and most importantly for the subjects enrolled in the clinical studies.  Over a 3‑5 year period $230 million in possible grant funding will be managed by the Foundation for the NIH for pilot projects in the 3 chosen disease indications.  Most importantly, all of the AMP data and analyses will be publicly accessible.

According to the NIH website (www.NIH.gov/AMP) AMP members will develop partnerships and will share costs, expertise, and resources to identify and validate new biological targets for diagnostics and drugs.  Research highlights for each of the pilot diseases include:

Alzheimer’s disease

(Total project funds $129.5 million:  NIH = $67.6 million and Industry = $61.9 million)

  • Identify an expanded set of biomarkers to predict clinical outcomes and incorporate them into 4 major NIH-funded clinical trials.
  • Conduct large-scale, system biology analysis of human Alzheimer’s patient brain tissue samples to validate biological targets with key roles in disease progression, and increase understanding of molecular networks involved and identify new potential therapeutic targets.

 

Type 2 Diabetes

(Total project funds $58.4 million:  NIH = $30.4 million and Industry = $28 million)

  • Build a knowledge portal of DNA sequence, functional genomic and epigenomic information, and clinical data from studies on type 2 diabetes including heart and kidney complications.  The portal will include existing and new data from 100,000-150,000 individuals and provide an opportunity to identify promising new therapeutic targets for diabetes.
  • Focus on DNA regions thought critical for development or progression of the disease and search for natural variations for possible use in predicting drug development successes in targeted populations

 

Rheumatoid Arthritis and Lupus

(Total project funds $41.6 million:  NIH = $20.9 million and Industry = $20.7 million)

  • Collect and analyze tissue and blood samples from people with rheumatoid arthritis and lupus to focus on biological changes at the single cell level, to allow comparisons across diseases, and determine insights into key aspects of the disease process.
  • Identify differences between rheumatoid arthritis patients who respond to current therapies and those who do not, and find a better systems-level understanding of disease mechanisms in rheumatoid arthritis and lupus.

The outcome for this unique open collaboration to identify and validate clinically relevant biomarkers are planned to be (1) an increased efficiency leading to shorter development time and improved rates of success leading to lower costs; (2) improving the process by identifying and understanding targets and biomarkers resulting in improved clinical trials; and (3) an increased number of more targeted therapies with improved efficacy because of a better understanding of disease biological pathways which in turn will decrease the number of failed Phase 2 and Phase 3 clinical trials and ultimately a more rational drug design with better targeted therapies.

If all goes as projected, the AMP program will be of great benefit and translate across multiple indications.  We should all watch their progress and particularly the amount and quality of the publicly available data and the impact it should have on both research and development and clinical trial conduct over the upcoming years.

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New FDA Guidances for March 2014

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in March, are posted.  In addition, upcoming Advisory committee meetings, other public meetings hosted by FDA, as well as CDRH’s 2014 Strategic Priorities are listed below with links to more information on each.

 

Special Interest Guidances/Information

Date Posted

Fees for Human Drug Compounding Outsourcing Facilities Under Sections 503B and 744K of the FD&C Act – Draft Guidance

31 Mar 2014

Medical Device Tracking - Final Guidance; supersedes 25 Jan 2010 guidance

27 Mar 2014

Premarket Assessment of Pediatric Medical Devices- Final Guidance; supersedes 14 May 2004 guidance

24 Mar 2014

Labeling for Human Prescription Drug and Biological Products Approved Under the Accelerated Approval Regulatory Pathway - Draft Guidance

24 Mar 2014

Premarket Notification [510(k)] Submissions for Bipolar Electrosurgical Vessel Sealers for General Surgery – Draft Guidance

24 Mar 2014

Premarket Notification [510(k)] Submissions for Electrosurgical Devices for General Surgery - Draft Guidance

24 Mar 2014

Humanitarian Device Exemption (HDE): Questions and Answers - Draft Guidance

18 Mar 2014

Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs — General Considerations – Draft Guidance

17 Mar 2014

Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products – Draft Guidance

13 Mar 2014

Administrative Procedures for CLIA Categorization - Final Guidance, supersedes 7 May 2008 guidance

12 Mar 2014

Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Developing Drug Products for Treatment - Draft Guidance

10 Mar 2014

BLA for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System – Final Guidance

5 Mar 2014

IND Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System – Final Guidance

5 Mar 2014

CDRH 2014 Strategic Priorities

5 Feb 2014

Upcoming Meetings (* = New)

* Endocrinologic and Metabolic Drugs Advisory Committee Meeting; 1Apr 2014, Hyattsville, MD
* Anesthetic and Analgesic Drug Products Advisory Committee Meeting Announcement; 22Apr 2014, Silver Spring, MD
* Neurological Devices Panel of the Medical Devices Advisory Committee Meeting; 24Apr2014, Gaithersburg, MD
* May 5, 2014: Risk Communication Advisory Committee Meeting Announcement; 5May2014, Silver Spring, MD
* Public Hearing on the Food and Drug Administration Safety and Innovation Act (FDASIA) Section 907; 1Apr2014, Silver Spring, MD
* Public Meeting on Pulmonary Arterial Hypertension Patient-Focused Drug Development, 13May  2014, Silver Spring, MD
* Public Workshop – Advancing Regulatory Science for High Throughput Sequencing Devices for Microbial Identification and Detection of Antimicrobial Resistance Markers; 1Apr2014, Silver Spring, MD
* Public Workshop – Methods for Thrombogenicity Testing; 14Apr2014, Silver Spring, MD
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The Clinical Trial Management System: A Recipe for Operational Success

By the CTMS Team at Cato Research

A Clinical Trial Management System (CTMS) is a one-stop shop for managing and tracking global, study-related operational information such as study monitoring visits, site contact information, subject enrollment status, the study decision log, issues resolutions, project milestones, investigator and vendor payments, and study documents.  Without efficient clinical trial operations business practices, however, the CTMS simply serves as a storage space for accessing study information.  To realize the full capabilities and benefits of a CTMS, the organization must design well-defined processes which are well-integrated with CTMS functionality and its full capabilities.  These business practices enable trial managers and project stakeholders to manage and analyze the study information that is being acquired on a daily basis and ensure that meaningful trial operations data are obtained.  CTMS data should provide the study team with both a macro-understanding and a micro-understanding of the current study status. Whether for validation, risk mitigation, or goal assessment, these insights should effectively guide the study teams through the study life cycle and provide the executive team with study-level, cross-study, and program-level matrices for decision-making and planning purposes.

Integration with other critical systems, such as electronic data capture (EDC) and/or interactive web response systems (IWRS), are important as well in order to avoid data redundancy and to thereby ensure trial operations data integrity and process efficiency.  Systems of data authority should be defined, and automated integration points should be implemented.  A fully integrated CTMS, aligned with automated and efficient business processes, can provide study managers and project stakeholders with a dependable recipe for successful study management.

 

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New FDA Guidances for February 2014

By Sheila R. Plant, Ph.D., R.A.C., Regulatory Scientist at Cato Research

FDA draft and final guidances, released from CDER, CBER, and CDRH in February, are posted.  In addition, the upcoming Advisory committee meetings and other public meetings hosted by FDA are listed below with links to more information.

Special Interest Guidances/Information

Date Posted

Distributing Scientific and Medical Publications on Unapproved New Uses — Recommended Practices - Revised Draft Guidance

28 Feb 2014

Antiviral Product Development — Conducting and Submitting Virology Studies to the Agency: Guidance for Submitting HIV-1 Resistance Data: Attachment to the Guidance - Draft Guidance

27 Feb 2014

E2B(R3) Electronic Transmission of Individual Case Safety Reports Implementation Guide — Data Elements and Message Specification; and Appendix to the Implementation Guide — Backwards and Forwards Compatibility – Final Guidance

21 Feb 2014

New Chemical Entity Exclusivity Determinations for Certain Fixed-Combination Drug Products - Draft Guidance

21 Feb 2014

Analytical Procedures and Methods Validation for Drugs and Biologics - Draft Guidance

19 Feb 2014

Providing Regulatory Submissions in Electronic Format–Receipt Date - Final Guidance

10 Feb 2014

Analgesic Indications: Developing Drug and Biological Products – Draft Guidance

5 Feb 2014

Providing Regulatory Submissions in Electronic Format — Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act- Draft Guidance

5 Feb 2014

Providing Submissions in Electronic Format — Standardized Study Data -Draft Guidance

5 Feb 2014

Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff – Final Guidance

18 Feb 2014

Annual Reports for Approved Premarket Approval Applications (PMA) – Final Guidance

10 Feb 2014

Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies – Draft Guidance

March 2014

Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff - Final Guidance

18 Feb 2014

Questions and Answers about eMDR – Electronic Medical Device Reporting - Final Guidance

13 Feb 2014

Upcoming Meetings (* = New)

* Pediatric Advisory Committee Meeting; 3Mar 2014; Bethesda, MD
* Public Workshop: Advancing the Development of Pediatric Therapeutics (ADEPT): Pediatric Bone Health; 4 Mar 2014, Bethesda, MD
Over-the-Counter Ophthalmic Drug Products – Emergency Use Eyewash Products; 7 Mar 2014; Silver Spring, MD.
* Microbiology Devices Panel of the Medical Devices Advisory Committee Meeting; 12Mar 2014; College Park MD
Blood Products Advisory Committee Meeting; 18-19 Mar 2014; Silver Spring, MD
* Food and Drug Administration/Xavier University PharmaLink Conference—Leadership in a Global Supply Chain; 19 Mar & 21 Mar 2014, Xavier University, Cincinnati, OH
* Vaccines and Related Biological Products Advisory Committee Meeting; 20 Mar 2014; Rockville, MD
* Regulatory Science and Sustainable Implementation of National and International Medical Device Registries; 24 Mar 2014; San Francisco, CA
* Over-The-Counter Drug Monograph System — Past, Present and Future; Public Hearing; 25-26 Mar 2014; Silver Spring, MD
* International Medical Device Regulators Forum (IMDRF) – Stakeholders Meeting; 26 Mar 2014; San Francisco, CA
Rescheduled Public Meeting on Fibromyalgia Patient-Focused Drug Development; 26 Mar 2014; Silver Spring, MD
Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee Meeting; 26-27 Mar 2014;  Gaithersburg, MD
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Will Social Media Kill the Placebo Trial?

By David Gee, Strategic Business Developer at Cato Research

In the past, patients participating on drug trials had very little chance to communicate with other participants. With the increasing use of social media, not only between people all over the world with common disease interests, but now also between participants on specific trials comparing notes, we see increasing cases where trials are effectively “unblinded” by the patients themselves. In such cases, comparison of experiences can often reveal effects of the active drug (such as inflammation, injection site reactions, diarrhea, nausea etc.) not seen with the placebo and, patients motivated to be on the active arm of the study, decipher which arm they are likely to be on, with those on placebo dropping out to move onto another trial. This has significant statistical impact on the original study.

In the past, doctors were the experts, they held all the knowledge and information and the patient trusted in their ability to process this information and interpret it as treatment and care . Patients were mostly passive volunteers on trials again trusting in the advice of the medical profession and accepting the risks of the placebo design trial. Today, the health systems positively encourage the patient to access this information for themselves – including their own patient records. The internet provides the patient and their families with access to the most detailed advice on any disease, including trials and the very latest medical findings and opinions. Patient advocacy groups provide enriched sources of information to further guide the patient.  Motivated patients become experts with knowledge about their specific disease that can frequently exceed that of the medical generalist or even the specialist. This appetite for the very latest information empowers the patient and allows them to become critically aware of the options.These patients communicate with others in similar circumstances, to gain any advantages from shared experiences.

So what of the future? Whatever the plans and intentions of the pharmaceutical companies, investigators or regulators, social media will continue to have a bigger and bigger impact on trial design and what is feasible and what is not according to the experiences shared between patients. Strategies to minimize the impact of this effect such as modification of trial design and endpoints to accommodate losses in the numbers on placebo arm, altering placebos to emulate some of the most obvious effects of the active (this being equivalent to designing in side effects which will be a problematic concept for all) or simply increasing the size of the placebo arm have limitations. One outcome is likely to be the diminishing feasibility of the placebo controlled trial as social media continues to become more pervasive.

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