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Report from Washington D.C. Metro Area No.8 June 2011

Nobuo UEMURA        6/30/2011


  In mid-February, 2010, I moved to the United States Pharmacopeia (USP) secretariat office as a visiting scientist of USP General Chapter team from Japan and a liaison official of MHLW/PMDA ("Ministry of Health, Labour and Welfare" and "Pharmaceuticals and Medical Devices Agency").

  This is the eighth report on the USP and FDA issues. However this report is my personal views and opinions, and it does not necessarily represent the formal position of MHLW, PMDA, FDA and USP.


1. Collaboration with EDQM (EP Secretariat)

  The European Directorate for the Quality of Medicines & HealthCare (EDQM) was created in 1996 as a leading organization for developing quality standards for safe medicines and their safe use. The European Pharmacopoeia Department of EDQM is a secretariat of the European Pharmacopoeia which started in 1964.
  European Pharmacopoeia (EP) is legally binding in EU Member States, and the EDQM is establishing and providing official standards which apply to the manufacture and quality control of medicines in all signatory States of the "Convention on the Elaboration of a European Pharmacopoeia".
  EDQM is also ensuring the application of these official standards to substances used in the production of medicines, coordinating a network of Official Medicines Control Laboratories (OMCL), collaborating with national, European and international organizations in efforts to combat counterfeiting of medical products and similar crimes, and providing policies and model approaches for the safe use of medicines in Europe.
  In 1991 the commission of the European Communities and the Council of Europe signed a Memo of Understanding to put EP secretariat in charge of biological standardization program. In 2006 the EDQM became responsible for blood transfusion and organ transplantation activities, and took over responsibility for World Health Organization (WHO) International Standards for Antibiotics (ISA). In 2010 the EDQM also took over responsibility for the establishment, preparation, storage and distribution of WHO International Chemical Reference Substances (ICRS).

  European Pharmacopoeia currently has 36 Member States and European Union as members who participate in EP Commission session. Other 8 countries in Europe, 14 non-European countries and WHO are observers who may participate in the scientific work of the EP Commission. United States of America, Canada, Australia, Russian Federation and China etc. are observers.
  In 1990 the Pharmacopoeial Discussion Group (PDG) started International Harmonization activities among EP, JP, and USP. The EDQM has participated in the International Conference on Harmonization (ICH) which started in 1991. The EDQM represents the European Pharmacopoeia, and all the relevant EP experts are involved in the international harmonization activities.
  In 2009 Memorandums of Understanding (MOU) on the exchange of information relating to the manufacturing of active pharmaceutical ingredients (APIs) and excipients used in medicinal products are signed with the United States Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA).
  Based on common initiative of 2 manufacturers, EP and USP in 2008, a pilot project for developing 4 monographs and reference standards started between EP and USP. Identical data packages were submitted to EDQM and USP, a common list of questions was sent to the manufacturer after paper review. EDQM reviews the replies of manufacturer and prepare a draft to a joint EDQM-P4/USP expert group. The draft is verified in parallel in laboratories of EDQM, USP, Official Medicine Control Laboratories (OMCLs), or FDA, and all laboratories' reports are exchanged. A consensus draft is published in "Pharmaeuropa" of EDQM and "Pharmacopeial Forum" of USP for requesting public comments. The P-4 Rapporteur coordinate a review of public comments in consultation with the joint expert group. Common version of the final draft is sent for adoption by EP Commission and USP Expert Committee.
  Besides above pilot project, many experts of EP and EDQM are cooperating in the USP standard setting procedure through the Expert Committee, Expert Panel, Work-shop etc.


2. Recent USP activities

  After the USP Convention in April 2010, USP conducted several activities to implement the resolutions for the period of 2010-2015 which was adopted by the USP Convention membership on April 2010.
  Followings are the items USP has conducted or launched during the USP's fiscal year 2011 which are classified by the clauses of the resolutions.

  Bold titles are 2010-2015 RESOLUTIONS adopted by the USP Convention membership on April 24, 2010.)

RESOLUTION 1 : Grandfather Constitutionally-Named Organizations
  • USP notified all grandfathered organizations in November 2010 of their continuing member status in the USP Convention. Appointment or reappointment of a delegate by November 2011 is required.


RESOLUTION 2 : Strengthen Focus on Core Compendial Activities
  • USP is introducing redesigned monographs in a more methodical, phased way.
  • USP has increased the involvement of its Quality Assurance group in its documentary standards activities.
  • USP is continuing to increase opportunities for stakeholder involvement through workshops, webinars, Expert Panels, website and compendia notices services.
  • USP has responded to the FDA's request for monograph modernization.


Strengthen USP's Relationship with the U.S. Food and Drug
  • USP and FDA/CDER agreed to form a staff-driven steering committee to monitor progress on joint activities between USP and CDER.
  • FDA continues to be involved in USP standards-setting activities with over 88 liaisons currently participating in the USP Expert Committee and Expert Panel meetings.
  • FDA has formed a Monograph Modernization Task Group which provides input to USP on priorities for modernization.
  • FDA and USP have signed a new Cooperative Research and Development Agreement (new CRADA) that supports development of USP reference standards for quality, identity, purity, and strength of medicines. Provisions call for: collaborative testing between USP and FDA laboratories of chemical reference standards including controlled substances; modernization of tests and assays; developing test methods for hand-held devices that FDA inspectors can use to screen drugs in the field for adulteration or contamination.


RESOLUTION 4 : Support and Advance Global Public Health Initiatives
  • USP is building a replacement site in Hyderabad, India that will house over 100 staff.
  • USP is launching the Medicines Compendium (MC), a new online-free compendium comprising quality standards for medicines moving in global commerce.
  • USP is exploring expansion of its site in China.
  • USP conducted a USP-Chinese Pharmacopeia Commission meeting, a meeting with ASEAN at Bangkok, meetings in India, Egypt, Jordan, and Turkey.
  • USP launched a Technical Assistance Program (TAP) in Sub-Saharan Africa in support of official medicines control laboratories in five countries; Ethiopia, Ghana, Kenya, Senegal, and Sierra Leone..
  • USP continues to expand the Promoting the Quality of Medicines (PQM) Program in Ethiopia, funded by U.S. Agency for International Development (USAID).


RESOLUTION 5 : Strengthen and Expand Harmonization Efforts
  • The Pharmacopeial Discussion Group (PDG) with EP, JP and USP will consider ways to improve and strengthen PDG collaboration.
  • USP has been working with EP on a harmonization pilot project for developing monographs and reference standards for 4 drug substances.
  • USP and British Pharmacopoeia Commission (BP) have been exchanging information on 2 drug product monographs.
  • USP has entered into adopt/adapt agreements with pharmacopeias in Ukraine and Kazakhstan, that allow these pharmacopeias to freely incorporate USP-NF standards into their own compendia.
  • USP's new Medicines Compendium, science and standards symposia, joint agreement for international visiting scientists increase the exchange of information to harmonizing the quality standards-related work of pharmacopeias and regulatory authorities.
  • USP is assisting the ASEAN Reference Standards Working Group with its efforts to provide certified reference materials (CRMs) to that region.


Continue and Expand Commitment to Quality Standards
for Food Ingredients
  • USP has petitioned the FDA to update its references to FCC standards in the Code of Federal Regulations.
  • USP has begun Memorandum of Understanding (MOU) work with the National Institute for Nutrition and Food Safety in Beijing. Translation of USP's FCC into Chinese is proceeding.


Promote Availability, Use and Recognition of Quality
Standards for Dietary Supplements
  • The second edition of the Dietary Supplements Compendium in 2012 will contain redesigned versions of the current and new dietary supplement monographs including excipients, and expanded color plates and a photographic section with new plant materials.
  • USP is working in China and India to build better links between monographs and reference materials for dietary supplements, which frequently correspond to natural products of traditional Chinese medicines (TCM) in China and of Ayurvedic medicines in India.


Develop, Maintain and Promote Adoption of Quality
Standards for Compounded Medicines
  • USP is exchanging information and views with the FDA regarding compounded medicines standards. USP and FDA are collaborating on a study to test compounded preparations using USP monograph methods.
  • USP continues to support the Pharmacy Compounding Accreditation Board (PCAB), which is a site accrediting activity, led by the American Pharmacists Association and other key pharmacy practitioner bodies.


Explore Development of Quality Standards of Value to
Practitioners and the Public
  • USP released General Chapter >17< Prescription Container Labeling, a standard that optimize label content to help ensure patient compliance and medication use safety.
  • USP hosted a Consumer-Patient Summit in April 2011 to better understand health-related challenges facing consumer stakeholders and where USP standards for drugs and dietary supplements could help.
  • USP formed a Monograph Naming Advisory Group to develop a plan for educating practitioners about the implications of USP's new monograph naming policy.
  • USP"s CEO has visited several schools of pharmacy.


3. CDER's Education and Training Programs

  CDER has several education and training programs for CDER staff. The Division of Training and Development (DTD) offers a range of educational activities for CDER throughout the year, primarily on a semester basis, Fall and Spring.

  CDER Courses recommended for New Reviewer provides essential information to perform quality and timely reviews. New reviewers should complete courses in the recommended sequence to optimize their learning experience. The courses in the reviewer curriculum (0-18 months +) include;

  • New Employee Orientation
  • New Reviewer Workshop
  • IND Regulations and Policies
  • NDA Regulations and Policies
  • Successful Negotiations
  • Basic Drug Law
  • Current Good Manufacturing Practices
  • Introduction to Generic Drug
  • Biologics Law


  The courses for Clinical Reviewer include in addition;

  • Basic Statistics
  • Introduction to Design, Conduct and Review: Clinical Trials in Drug Development
  • Topics in Clinical Trials
  • Tools and Methods of the Office of Surveillance and Epidemiology
  • Lean the "Safety Dance": a Practical Approach to Pre-market Safety Review


  Project Managers takes a course;

  • Successful Meeting and Minutes


  The following courses are timing optional (as needed) ;

  • Time Management
  • Presentation Skills
  • English as Second Language
  • Technical Writing for Reviewers
  • Grammar Refresher


  CDER also have following courses;

  • Active-Controlled Trial Course
  • CDER Scientific Rounds
  • CDER Seminar
  • Chemistry for Non-Chemists
  • Editing the Work for Others
  • FDA review of Biologic Products
  • Genomics Review Course
  • New Managers Seminar
  • Potential Supervisors
  • Regulatory and Safety Overview of Non-Prescription Products
  • Technical Writing for Non-Reviewers
  • Writing for Publication
  • DARRTS - Safety Application
  • Decision Support System (DSS)
  • Division File System (DFS)
  • Electronic Submission Data Analysis Training (eDAT)
  • Enterprise Search (ES)
  • GSReview
  • JMP
  • JMP Clinic I - Joining Table
  • JMP Clinic II - Calculating a Difference from Baseline Value
  • JMP Clinic III - Transforming Data from a Vertical to Horizontal Display
  • JMP Clinic IV - Converting Dates from Character to Date format
  • JMP Clinic V - Comparing Lab Value to Normal Range

  CDER has other kind training programs;

  • CDERearch for Better Health
  • CDER Nurses Network
  • Committee for Advanced Scientific Education (CASE)
  • Clinical Reviewers Education Program
  • Facilitation Program
  • Georgetown university Public Health Certificate CDER Program
  • Journal Clubs
  • Leadership and Management Development Program
  • Office of Business Process Support (OBPS) Training Courses
  • Preceptorship Program
  • Pharmacology/Toxicology Education Subcommittee
  • Support Staff Education Program
  • University of Southern California Certificate in Patients and Product Safety Regulatory Science CDER Program
  • Visiting professor Lecture Series (VPLS)


4. Current  Update of FDA's Critical Path Initiative

  In March 2004, FDA launched the Critical Path Initiative with the report that noted the need to transform the sciences of medical product development including new in vitro tests and assays, computer modeling, qualified biomarkers, and innovative trial designs. FDA created the Office of Critical Path Programs, and opened a public docket to collect the views of stakeholders on the pressing scientific hurdles in product development. The Critical Path Report and Opportunities List were published in March 2006, and it listed 76 specific activities organized into six key areas. Thereafter the Projects were tracked based on the 76 specific activities.
The contents of 76 activities are;

  Biologics (Vaccine/Blood)

  • To improve vaccine safety
  • To promote development of innovative therapies in the area of cancer and regenerative therapies
  • To ensure blood safety
  • To support the development of treatments for allergic diseases

  Drugs and Therapeutic Proteins

  • To evaluate the safety of inhaled and intravenous anesthetic drugs in children (SAFEKIDS Project)
  • To assess drug-related cardiac toxicity
  • To address kidney, liver, and muscle injury
  • To facilitate development and review of drugs to treat hepatitis C and multiple sclerosis\
  • To stimulate development of new safe and effective pain killers
  • To spur use of modern manufacturing techniques

  Clinical Trial Modernization

  • To improve the monitoring process and the process for reporting of serious adverse events
  • The second annual clinical investigator course

  Device-Related Work

  • To assess disk replacement devices
  • To assess blood damage in medical devices
  • To encourage the development of bio-absorbable implants
  • To facilitate development of pediatric cardiovascular devices
  • To develop regulatory approaches for integrating nanotechnologies into medical diagnostic and devices
  • To evaluate the medical imaging and simulation-based technologies for their use in device design and evaluation
  • To develop autonomous drug administration devices to improve personalized dosing and safety
  • To standardize the use of brain functional Magnetic Resonance Imaging (fMRI) as a biomarker for clinical trials
  • To develop a model to assess the effect of breast pump use on infant health

  Food Safety

  • To analyze Salmonella enteric
  • To study factors that affect the antioxidant activities of dietary supplements
  • To detect organism by means relevant to epidemiological studies
  • To develop a microarray for the genetic discovery of enteric pathogens and analysis of gastrointestinal issues

  Veterinary Medicine

  • To develop regulatory tools to ensure the public health by protecting the food supply with regard to genetically engineered animals
  • To obtain data from a Salmonella study that can help with risk-based decision making regarding human and animal use of antimicrobials
  • To improve methods for controlling unexpected toxic reactions to drugs in dogs

  Pharmacogenomic / Toxicology Project

  • To support evaluation of complex pharmacogenomic data being submitted to FDA in marketing applications
  • To develop and maintain a liver toxicity knowledge base to support research into relationships among diseases, genes, proteins, and drugs

  The Critical Path Initiative projects which received funding during FY 2010 ($18.35 million) and the outcome of which were reported in the FY2010 Report on Projects Receiving Critical Path Support are mainly as follows;

  • Biomarkers/Other Tools to Facilitate Personalize Medicine
  • Modernizing Clinical Trials
  • Using Health Information Systems to Improve Safety Evaluation and Surveillance

  And the followings are the example of the outcome of the CPI projects in FY 2010.

Biomarkers/Other Tools to Facilitate Personalize Medicine

  • The International Serious Adverse Events Consortium announced the release to the public of data on the genetics of adverse events-negative side effects- for drug-induced liver injury and drug-related serious skin reaction.
  • The Predictive Safety Testing Consortium facilitates industry's data sharing to receive, review, and approve new tools as qualified for use in drug development. Seven new biomarkers can be analyzed through laboratory tests on urine, and these new tests can be used in laboratory research to detect acute drug-induced kidney toxicity.
  • The Critical Path Initiative funded a research project to develop genetically based instructions for warfarin dosing, facilitated planning for a clinical trial that will study warfarin dosing based on genetic test information, and is helping to pay for another clinical study that will derive personalized warfarin dosing algorithms for patients new to the drug. These collaborative researches with Universities and Institutes into the genetics of people using warfarin led to the addition of supplementary dosing information to warfarin labels.


Modernizing Clinical Trials

  • In February 2010, FDA issued two draft guidances making recommendations on innovative trial designs ? adaptive and non-inferiority designs.
  • FDA and the Clinical Trials Transformation Initiative (CTTI) which was launched by Duke University and FDA in 2008, sponsored the CPI's annual training courses for clinical investigators.


Using Health Information Systems to Improve Safety Evaluation and Surveillance

  • In 2010, quicker review of new drugs for chronic hepatitis C became possible through the Anti-viral Information Management System, an Oracle database used by FDA staff to speed the review of hepatitis C protocols.
  • In late fiscal year 2009, FDA competed and awarded a contract to Harvard Pilgrim Health to create a pilot program for the Sentinel System (Mini-Sentinel) for electronic monitoring of post-market safety.
  • Collaboration with the Centers for Medicare and Medicaid Services (CMS) and Assistant Security Planning and Evaluation (ASPE) is a pilot project aimed to inform and facilitate development of a fully operational active surveillance system for monitoring the safety of the medical products, and cooperative efforts have been expanded to include other federal agencies; the U.S. Department of Veterans Affairs (VA) and the Department of Defense (DoD).
  • The collaboration (SafeRx) among Centers for Medicare and Medicaid Services(CMS), FDA, and Assistant Security Planning and Evaluation (ASPE) is enhancing FDA's existing safety surveillance capacity and providing close to real-time, electronic vaccine safety monitoring of seasonal and H1N1 influenza vaccines.
  • A collaboration of private- and academic-sector partners and FDA created the ECG Warehouse, a repository of digital electrocardiograms (ECGs) that is being used to study the cardiac toxicity of drugs. This allows the FDA to electronically search abnormal ECGs and determine if they were linked to a drug.


  The FY2010 Report of CPI also describes the five competitive awards against Tropical Diseases, especially Tuberculosis (TB);

  • For the discovery of biological and immunological biomarkers for TB vaccines
  • To develop a repository of clinical trial specimens and to qualify new preclinical models for the development of TB drug combinations
  • To develop a diagnostic for latent TB
  • To qualify small molecule biomarkers of TB treatment, relapse, and cure
  • To develop and validate point-of-care tests for TB.

The updated situation of Critical Path Activities is reported to the FDA Science Board.

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Report from Washington D.C. Metro Area No.8 June 2011