1.
Legislative Views on Risk Management in Healthcare Products and Services Tri-Division Conference Regulations and Regulators Joseph Curtis MS, PhD March 27, 2008

2.
Global Risk Management Infrastructure Healthcare Products and Services FDA 3 2007 China-US Food Safety 2007 China-US Safety of Drugs & Medical Devices 2007 IMI Joint Undertaking Australia - US Cooperative Agreement 2007 Advanced Therapy Medicinal Products & Amending Directive Post-Market Surveillance Study 2008

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Risk Management Legislation Healthcare Products <ul><ul><li>Food & Drug Administration Amendments Act of 2007 (FDA 3 ) </li></ul></ul><ul><ul><ul><li>Title l – Prescription Drug User Fee Amendments of 2007 </li></ul></ul></ul><ul><ul><ul><ul><li>SEC 102 Postmarket Safety Activities For Drugs Approved With Human Drug Applications & Supplements </li></ul></ul></ul></ul><ul><ul><ul><li>Title II – Medical Device User Fee Amendments of 2007 </li></ul></ul></ul><ul><ul><ul><ul><li>SEC 215 Additional Authorization of Appropriations for Postmarket Safety Information </li></ul></ul></ul></ul><ul><ul><ul><ul><li>SEC 226 Unique Device Identification System </li></ul></ul></ul></ul><ul><ul><ul><li>Title III – Pediatric Medical Device Safety And Improvement Act 2007 </li></ul></ul></ul><ul><ul><ul><ul><li>SEC 307 Postmarket Surveillance </li></ul></ul></ul></ul><ul><ul><ul><li>Title IV/V – Pediatric Research Act 2007 / Best Pharmaceutical Act for Children 2007 </li></ul></ul></ul><ul><ul><ul><li>Title VI – Reagan-Udall Foundation </li></ul></ul></ul><ul><ul><ul><ul><li>SEC 603 Critical path public-private partnerships </li></ul></ul></ul></ul><ul><ul><ul><li>Title VIII – Clinical Trial Databases </li></ul></ul></ul><ul><ul><ul><ul><li>SEC 801. Expanded clinical trial registry data bank. </li></ul></ul></ul></ul><ul><ul><ul><li>Title IX – Enhanced Postmarket Safety Authorities: Effective 3/24/2008 </li></ul></ul></ul><ul><ul><ul><li> Subtitle A – Postmarket Studies and Surveillance </li></ul></ul></ul><ul><ul><ul><ul><li>SEC 901 Postmarket Studies & Clinical Trials For Human Drugs; Risk Evaluation & Mitigation Strategies . </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Subtitle B—Other Provisions to Ensure Drug Safety and Surveillance </li></ul></ul></ul></ul><ul><ul><ul><ul><li>SEC. 912 - 921 </li></ul></ul></ul></ul><ul><ul><ul><li>Title X – Food Safety </li></ul></ul></ul>

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International Risk Management Legislation Initiatives <ul><li>China Legislation </li></ul><ul><ul><li>Safety of Drugs and Medical Devices 2007 </li></ul></ul><ul><ul><li>Food Safety </li></ul></ul><ul><li>European Union </li></ul><ul><ul><li>Council Regulation (EC) No 73/2008 – The Joint Technology Initiative on Innovative Medicines </li></ul></ul><ul><ul><li>Advanced Therapy Medicinal Products And Amending Directive 2001/83/EC and Regulation (EC) No 726/2004 </li></ul></ul><ul><li>Canada </li></ul><ul><ul><li>Post Market Surveillance </li></ul></ul><ul><li>Australia </li></ul><ul><ul><li>Current Good Manufacturing Practices Inspections Of Human Pharmaceutical Products </li></ul></ul>

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US Legislation Initiatives Healthcare Product Risk Management Legislative Approach to Managing Risks to Consumers of Medical Technology The United States continues to expand its risk management infrastructure by integrating postmarket surveillance with eHealth tools for consumer safety, and apply science-based approaches to minimizing potential risks associated with medical technology. Additional efforts have been initiated to innovate across the risk continuum and introduce advanced technology into the marketplace at reduced risk to the consumer. Efforts to harmonize regulatory practice and extend the best practice in consumer safety into markets across the global medical product supply chain will also be examined.

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US Legislative Framework for Risk Management <ul><ul><li>H.R. 3580 became Public Law 110-85 </li></ul></ul><ul><ul><ul><li>Passed by House on September 19, 2007 by a vote of 407 to 5 </li></ul></ul></ul><ul><ul><ul><li>Passed by Senate on September 20, 2007 by unanimous consent </li></ul></ul></ul><ul><ul><ul><li>President Bush signed FDA 3 into law on September 27, 2007 </li></ul></ul></ul><ul><ul><li>Purpose of FDA 3 is to amend the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act to: </li></ul></ul><ul><ul><ul><li>Revise and extend the user-fee programs for prescription drugs and medical devices </li></ul></ul></ul><ul><ul><ul><li>Enhance the postmarket authorities of the Food and Drug Administration with respect to the safety of drugs, and information transparency. </li></ul></ul></ul><ul><ul><ul><li>Provide new authorities to assist the agency in quickly and effectively responding to potential safety issues, including making labeling changes and requiring post-market studies to more fully examine potential risks. </li></ul></ul></ul><ul><ul><ul><li>http://www.fda.gov/oc/initiatives/advance/fdaaa.html </li></ul></ul></ul><ul><ul><li>Food & Drug Administration Amendments Act of 2007 (FDA 3 ) </li></ul></ul>

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Medical Device User Fee Amendments of 2007 <ul><li>SEC. 226 Unique Device Identification System Requirements </li></ul><ul><li>The label of a device to bear a unique identifier that </li></ul><ul><ul><li>Confirmation the identify of the device through distribution and use </li></ul></ul><ul><ul><li>The unique identifier may include the lot or serial number </li></ul></ul>Subtitle B —Amendments Regulating Medical Devices <ul><li>SEC. 228 Inspection By Accredited Persons </li></ul><ul><li>FD&C Sec 704 Factory Inspection By Accredited Persons </li></ul><ul><li>Accredited person will notify Secretary of non-conformance with quality system standard </li></ul><ul><li>Conduct audits of a device establishment to establish conformance with the quality systems standard </li></ul><ul><li>Establishes eligibility criteria for device establishment inspection by accredited person where most recent inspection results indicated “no action indicated” or “voluntary action indicated”. </li></ul><ul><li>Requires the owner or operator to submit a notice to Secretary certifying that at least1 of the devices manufactured in the establishment are marketed in the US and </li></ul><ul><li>At least 1 of such devices is intended to be marketed in 1 or more foreign countries, 1 of which countries certifies, accredits or recognizes the person accredited as a person authorized to conduct inspections of device establishments. </li></ul>

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Medical Device User Fee Amendments of 2007 <ul><li>SEC. 228 Inspection By Accredited Persons </li></ul><ul><li>Participation In The Accredited Persons Program - Deadlines </li></ul><ul><li>A device establishment is deemed to have clearance to participate in the program and to use the accredited person identified in the notice unless the Secretary has not later than 30 days after receiving such notice, issues a response that— </li></ul><ul><ul><li>Denies clearance to participate </li></ul></ul><ul><ul><li>Makes a request from the owner or operator of a device establishment or from the accredited person for </li></ul></ul><ul><ul><ul><li>Compliance data for the establishment </li></ul></ul></ul><ul><ul><ul><li>information concerning the relationship between the owner or operator of the establishment and the accredited person identified in the notice </li></ul></ul></ul><ul><ul><li>Owner -operator of the establishment, or the accredited person, not later than 60 days to provide the requested information. </li></ul></ul><ul><ul><li>Secretary Can Deny Clearance to Participate in the Accredited Persons Program Within 60 Days of receiving and reviewing the information. </li></ul></ul><ul><ul><ul><li>Evidence that the certification is untrue </li></ul></ul></ul><ul><ul><ul><li>Determined that the establishment has failed to demonstrate consistent compliance with Quality System standards </li></ul></ul></ul><ul><ul><ul><li>Reject the selection of the accredited person </li></ul></ul></ul><ul><ul><li>Owner or operator can request a review of the evidence within 30 days of decision </li></ul></ul>

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Title III -Pediatric Medical Device Safety and Improvement Act 2007 <ul><li>The Secretary by order may require a manufacturer to conduct postmarket surveillance for any class II or class III device where: </li></ul><ul><li>(i) the failure of which would be reasonably likely to have serious adverse health consequences; </li></ul><ul><li>(ii) that is expected to have significant use in pediatric populations; or </li></ul><ul><li>(iii) that is intended to be: </li></ul><ul><ul><li>( I) implanted in the human body for more than 1 year; or </li></ul></ul><ul><ul><li>(II) a life-sustaining or life-supporting device used outside a device user facility. </li></ul></ul>SEC. 307. Postmarket Surveillance Surveillance Approval- Longer Surveillance For Pediatric Devices >36 months Dispute Resolution- A manufacturer may request review under section 562

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Titles IV/V Pediatric Drug Legislation 2007 <ul><li>Pediatric Laws </li></ul><ul><ul><li>the Best Pharmaceuticals for Children Act (BCPA) and the Pediatric Research Equity Act (PREA), two laws that encourage and require drug companies to study their products in children. </li></ul></ul><ul><ul><li>Together BPCA and PREA have generated a wealth of pediatric drug information for physicians and parents. </li></ul></ul><ul><ul><li>The reauthorization strengthened the transparency and accountability of BPCA and PREA and increased the authority of FDA to require studies. </li></ul></ul><ul><ul><li>Other improvements included i ncreasing the speed, accuracy, and dissemination of label changes and enhancing the role of the National Institutes of Health (NIH) in meeting pediatric drug research needs . </li></ul></ul><ul><ul><ul><li>Reauthorization </li></ul></ul></ul><ul><ul><ul><li>Title IV. Pediatric Research Equity Act (PREA) </li></ul></ul></ul><ul><ul><ul><li>Title V Best Pharmaceuticals for Children Act (BCPA) </li></ul></ul></ul>

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Title VIII – Expanded Clinical Trial Registry Data Bank <ul><li>SEC 801. Expanded Clinical Trial Registry Data Bank </li></ul><ul><li>Defines data submission requirements for applicable clinical trials to begin 90 days post enactment of FDA 3 2007 for inclusion into the clinical trials registry </li></ul><ul><li>Responsible party submits data according to the following schedule: </li></ul><ul><ul><li>90 days post enactment date </li></ul></ul><ul><ul><li>21 days after first patient is enrolled in the clinical trial </li></ul></ul><ul><ul><li>1 year post enactment date for a clinical trial that is not for a serious or life-threatening disease or condition and that is ongoing on such enactment date. </li></ul></ul><ul><li>The Director of NIH shall ensure that clinical trial information trial is posted in the registry data bank for a </li></ul><ul><ul><li>drug clinical trail not later than 30 days after submission to NIH. </li></ul></ul><ul><ul><li>device clinical trial submitted to the Director will be posted publicly in the registry data bank </li></ul></ul><ul><ul><ul><li>not earlier than the date of clearance under section 510(k) or approval under section 515 or 520(m), for a device that was not previously cleared or approved, and not later than 30 days after such date; or </li></ul></ul></ul><ul><ul><ul><li>for a device that was previously cleared or approved, not later than 30 days after the clinical trial information is required to be posted by the Secretary. </li></ul></ul></ul>

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Global Clinical Trial Registry Network ICTRP CTRI CLINICAL TRIALS REGISTRY INDIA

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Title IX – Enhanced Authorities Postmarket Safety of Drugs <ul><li>Subtitle A - Postmarket Studies and Surveillance </li></ul><ul><li>SEC. 901. Postmarket Studies & Clinical Trials Regarding Human Drugs; </li></ul><ul><li>Risk Evaluation And Mitigation Strategies </li></ul><ul><li>Amendments to section 505 of the Federal FD&C Act (21 U.S.C. 355): </li></ul><ul><li>(o) Postmarket Studies and Clinical Trials; Labeling </li></ul><ul><ul><li>( o)(3) Studies and Clinical Trials </li></ul></ul><ul><ul><li>(o)(4) Safety Labeling Changes </li></ul></ul><ul><li>(p) Risk evaluation and mitigation strategy </li></ul><ul><li>(k)(3) Active postmarket risk identification </li></ul><ul><li>(k)(4) Advanced analysis of drug safety data </li></ul>

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Section 505 (k)(3) Active Postmarket Risk Identification <ul><li>Establishment of the Postmarket Risk Identification & Analysis System </li></ul><ul><li>The Secretary shall, not later than 1 year after the development of the risk identification and analysis methods, establish and maintain procedures for- </li></ul><ul><ul><li>(I) Risk Identification and Analysis based on electronic health data in compliance with Health Insurance Portability Accountability Act 1996 </li></ul></ul><ul><ul><li>(Il) The reporting of data on all serious adverse drug experiences and those adverse events submitted by patients, providers, and drug sponsors, when appropriate;. </li></ul></ul><ul><ul><li>III) Provide for active adverse event surveillance using the following data sources available: </li></ul></ul><ul><ul><ul><li>Federal health-related electronic data (such as data from the Medicare program and the health systems of the Department of Veterans Affairs); </li></ul></ul></ul><ul><ul><ul><li>Private sector health-related electronic data (such as pharmaceutical purchase data and health insurance claims data); and </li></ul></ul></ul><ul><ul><ul><li>Other data as the Secretary deems necessary to create a robust system to identify adverse events and potential drug safety signals; </li></ul></ul></ul>

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Section 505 (k)(4) Advanced Analysis of Drug Safety Data <ul><li>Establishment Of Collaborations For </li></ul><ul><li>Advanced Analysis of Drug Safety Data </li></ul><ul><ul><li>(I) improve the quality and efficiency of postmarket drug safety risk-benefit analysis ; </li></ul></ul><ul><ul><li>(Il) provide the Secretary with routine access to outside expertise to study advanced drug safety questions ; </li></ul></ul><ul><ul><li>III) enhance the Secretary’s ability to make timely assessments based on drug safety data . </li></ul></ul><ul><ul><li>Public process for priority questions: </li></ul></ul><ul><ul><ul><li>At least biannually, the Secretary shall seek recommendations from the Drug Safety and Risk Management Advisory Committee and other advisory committees on: </li></ul></ul></ul><ul><ul><ul><li>(i) priority drug safety questions ; and </li></ul></ul></ul><ul><ul><ul><li>(ii) mechanisms for answering drug safety questions , through-- </li></ul></ul></ul><ul><ul><ul><ul><li>(I) active risk identification under the Postmarket Risk Identification & Analysis System; and </li></ul></ul></ul></ul><ul><ul><ul><ul><li>(II) when risk identification is not sufficient, postapproval studies and clinical trials </li></ul></ul></ul></ul>The Secretary shall establish collaborations with public, academic, and private entities, including the Centers for Education and Research to provide for advanced analysis of drug safety data described in the Postmarket Risk Identification & Analysis System, in order to—

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Section 505 (k)(5) and 505(l) Adverse Event Reporting System and Public Disclosure of Safety Data <ul><li>Adverse Event Reporting System. </li></ul><ul><li>The Secretary will conduct regular bi-weekly screening of the Adverse Event Reporting System database and post a quarterly report to the AERS Web site of any new safety information or potential signal of a serious risk identified by the AERS within the last quarter. </li></ul><ul><li>Office of Surveillance and Epidemiology (OSE) </li></ul><ul><li>Report to Congress not later than 2 years after the date of the enactment of the FDAAA 2007 on procedures and processes of the FDA for addressing ongoing post market safety issues identified by the Office of Surveillance and Epidemiology and how recommendations of the OSE are handled within the agency . </li></ul><ul><li>Annual Review of Postmarket Safety Commitments </li></ul><ul><li>Public Disclosure of Safety and Effectiveness Data </li></ul><ul><ul><li>Safety and effectiveness data not previously disclosed to the public made available upon request </li></ul></ul><ul><ul><li>Action package for approval published on FDA web site < 30 days after approval date </li></ul></ul><ul><ul><li>Summary review published not later than 48 hrs after approval date </li></ul></ul>

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Section 505 (o)(3) Postmarket studies and clinical trials <ul><li>Postmarket Clinical Trial Requirements </li></ul><ul><li>The Secretary may require a responsible person for a drug to conduct a postapproval study or studies of the drug, or a postapproval clinical trial or trials of the drug, on the basis of scientific data deemed appropriate by the Secretary, including information regarding chemically-related or pharmacologically-related drugs . </li></ul><ul><li>Purposes of study or clinical trial </li></ul><ul><ul><li>(i) To assess a known serious risk related to the use of the drug involved. </li></ul></ul><ul><ul><li>(ii) To assess signals of serious risk related to the use of the drug. </li></ul></ul><ul><ul><li>(iii) To identify an unexpected serious risk when available data indicates the potential for a serious risk. </li></ul></ul><ul><li>Establish of requirement after approval of covered application </li></ul><ul><ul><li>The Secretary may require a postapproval study or studies or postapproval clinical trial or trials for a drug for which an approved covered application is in effect as of the date on which the Secretary becomes aware of new safety information </li></ul></ul>

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FD&C Section 505 (k)(3) Active postmarket risk identification <ul><li>Develop Postmarket Risk Identification & Analysis Methods </li></ul><ul><li>The Secretary shall, not later than 2 years after the date of the enactment of the Food and Drug Administration Amendments Act of 2007 [enacted Sept. 27, 2007], in collaboration with public, academic, and private entities— </li></ul><ul><ul><li>(i) develop methods to obtain access to disparate data sources including the data sources specified in the establishment of the postmarket risk identification and analysis system. </li></ul></ul><ul><ul><li>(ii) develop validated methods for the establishment of a postmarket risk identification and analysis system to link and analyze safety data from multiple sources, with the goals of including, in aggregate-- </li></ul></ul><ul><ul><ul><li>(I) at least 25,000,000 patients by July 1, 2010; and </li></ul></ul></ul><ul><ul><ul><li>(II) at least 100,000,000 patients by July 1, 2012; and </li></ul></ul></ul><ul><ul><ul><li>(iii) convene a committee of experts to make recommendations on the development of tools and methods for the ethical and scientific uses for, and communication of, postmarketing data specified under the postmarket risk identification and analysis system, including recommendations on the development of effective research methods for the study of drug safety questions. </li></ul></ul></ul>

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Section 505 (o)(4) Safety Labeling Changes <ul><li>New Safety Information </li></ul><ul><li>If the Secretary becomes aware of new safety information that the he believes should be included in the labeling of the drug, the Secretary shall promptly notify the responsible person </li></ul><ul><li>Response to Notification </li></ul><ul><li>Following notification, the holder of an approved application will </li></ul><ul><ul><li>(i) submit a supplement proposing changes to the approved labeling within 30 days or </li></ul></ul><ul><ul><li>(ii) notify the Secretary that the holder of the approved application does not believe a labeling change is warranted and submit a statement detailing the reasons why such a change is not warranted </li></ul></ul><ul><ul><li>(iii) To identify an unexpected serious risk when available data indicates the potential for a serious risk. </li></ul></ul><ul><li>Review and Discussion </li></ul><ul><li>Upon receipt of such supplement, the promptly review and act upon such supplement. </li></ul><ul><li>If the Secretary disagrees with the proposed changes in the supplement the Secretary shall initiate discussions to reach agreement on whether the labeling for the drug should be modified to reflect the new safety information, and the contents of the labeling changes. </li></ul><ul><li>Discussions shall not extend for > 30 days </li></ul><ul><li>Order and Dispute Resolution: (15:5) </li></ul><ul><li>Within 15 days the Secretary may issue an order directing the holder of an approved application to change the labeling addressing the new safety information. </li></ul>

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Section 505 (p) Risk Evaluation & Mitigation Strategy (REMS) <ul><li>Risk Evaluation And Mitigation Strategies </li></ul><ul><li>Section 505(p) is amended with 505-1 Risk Evaluation And Mitigation Strategies </li></ul><ul><li>Initial Approval: Upon the determination of the Secretary , the office responsible for reviewing the drug, and the office responsible for postapproval safety, determines that a risk evaluation and mitigation strategy is necessary to ensure that the benefits of the drug outweigh the risks of the drug, then the applicant is required to propose and submit a risk evaluation and mitigation strategy . </li></ul><ul><li>Postapproval Requirement: if the Secretary becomes aware of new safety information on an approved application and makes a determination that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks of the drug, then the applicant is required to submit a risk evaluation and mitigation strategy not later than 120 days post notification by the Secretary . </li></ul><ul><li>Definitions: </li></ul><ul><li>Adverse Drug Experience; New Safety Information; Serious Adverse Drug Experience; Signal of A Serious Risk; Responsible Person; Unexpected Serious Risk; </li></ul><ul><li>Abbreviated New Drug Applications </li></ul><ul><li>Drug Safety Oversight Board </li></ul>

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Postmarket Safety of Drugs Serious Risk Identification & Mitigation <ul><li>Drug Risk Evaluation and Mitigation Strategy </li></ul><ul><li>Provide a schedule of assessments at 18 months, 3 years and </li></ul><ul><li> 7 years post initial approval (defined in strategy). </li></ul><ul><ul><li>Can be eliminated after 3yr-period, if serious risks identified + managed </li></ul></ul><ul><li>Elements of strategy may require 1 or more of the following: </li></ul><ul><ul><li>A medication guide for distribution to patients (FDA approved) </li></ul></ul><ul><ul><li>A patient package insert to mitigate serious risks </li></ul></ul><ul><ul><li>Communication plan to health care providers </li></ul></ul><ul><li>Allowing Safe Access to Drugs With Known Serious Risks </li></ul><ul><li>The Secretary, in consultation with the offices for drug review and postapproval safety may require that the risk evaluation and mitigation strategy for a drug include elements necessary to assure safe use of the drug, because of its inherent toxicity or potential harmfulness, including </li></ul><ul><ul><li>drugs which have been shown to be effective, and associated with a serious adverse drug experience to gain approval or be withdrawn must include elements as part of their strategy to mitigate a specific serious risk listed in the labeling of the drug ; </li></ul></ul><ul><ul><li>a drug initially approved without elements to assure safe use, other elements defined under risk evaluation and mitigation strategy are not sufficient to mitigate such serious risk (opens the door for customized risk evaluation and research into risk) </li></ul></ul>

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Postmarket Safety of Drugs Patient Access to Drugs with Serious Risks <ul><li>Safe Access to Drugs With Known Serious Risks </li></ul><ul><li>Be commensurate with the specific serious risk listed in the labeling; </li></ul><ul><li>Not be unduly burdensome on patient access to the drug, considering patients: </li></ul><ul><ul><li>with serious or life-threatening diseases or conditions </li></ul></ul><ul><ul><li>who have difficulty accessing health care </li></ul></ul><ul><li>Minimize the burden on the health care delivery system </li></ul><ul><ul><li>assure safe use for other drugs with similar, serious risks; </li></ul></ul><ul><ul><li>be designed to be compatible with established distribution, procurement, and dispensing systems for drugs. </li></ul></ul><ul><li>Expanded access to unapproved therapies and diagnostics </li></ul><ul><li>Waiver in Public Health Emergencies </li></ul><ul><li>Elements To Assure Safe Use </li></ul><ul><li>Shall include 1 or more goals to mitigate a specific serious risk listed in the labeling of the drug Including: </li></ul><ul><ul><li>Health care providers who prescribe the drug and pharmacies, practitioners, or health care settings that dispense the drug have particular training , experience and certification . </li></ul></ul><ul><ul><li>the drug be dispensed only to patients in certain healthcare settings </li></ul></ul><ul><ul><li>with evidence or other documentation of safe-use conditions , i.e.,lab test results </li></ul></ul><ul><ul><li>each patient using the drug be subject to certain monitoring and registry enrollment </li></ul></ul>

23.
Postmarket Safety of Drugs Implementation System & Assurance Evaluation <ul><li>Monitor and Evaluate Implementation </li></ul><ul><li>The applicant is required deploy a system to ensure safe use of their drug by </li></ul><ul><ul><li>monitoring and evaluating implementation of their safe use provisions by </li></ul></ul><ul><ul><ul><li>healthcare providers, </li></ul></ul></ul><ul><ul><ul><li>pharmacists and </li></ul></ul></ul><ul><ul><ul><li>other parties within the healthcare system responsible for implementation. </li></ul></ul></ul><ul><ul><li>Work to improve implementation of safety elements </li></ul></ul><ul><li>Drug Safety and Risk Management Advisory Committee </li></ul><ul><li>Secretary and this committee will seek input from patients, physicians, pharmacists and other health care providers on how to standardize without restricting patient access to the drug or burdening the healthcare delivery system. </li></ul><ul><li>Annually evaluate 1 or more drugs and their safety assurance elements to assess whether the elements assure safety of the drug and minimize impact on healthcare system. </li></ul>

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(g) Assessment And Modification of Approved Risk Evaluation & Mitigation Strategy <ul><li>Voluntary Assessments </li></ul><ul><li>After the approval of a risk evaluation and mitigation strategy the responsible person may submit to the Secretary an assessment of, and propose a modification to the approved strategy at any time. </li></ul><ul><li>Required Assessments </li></ul><ul><li>when submitting a supplemental application for a new indication for use </li></ul><ul><li>when required by the strategy, as provided for in a drug assessment schedule </li></ul><ul><li>Within a time period determined by the Secretary </li></ul><ul><li>Within 15days when ordered by the Secretary* </li></ul><ul><li>Requirements for Assessments </li></ul><ul><li>An assessment of the capacity of the assurance elements to meet their goals and ensure safe use </li></ul><ul><li>For postapproval clinical trials required under 505(o) to investigate safety issues where difficulties completing the study have been encountered </li></ul><ul><li>Status of clinical trial including </li></ul><ul><ul><li>Date enrollment begins and # of participants enrolled </li></ul></ul><ul><ul><li>Whether difficulties completing the study have been encountered </li></ul></ul><ul><ul><li>Required registration information </li></ul></ul>

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(h) Review of Proposed Strategies <ul><li>Review of Assessments of Approved Strategies </li></ul><ul><li>The Secretary, in consultation with the office responsible for reviewing the drug and the office responsible for postapproval safety shall promptly review each </li></ul><ul><ul><li>proposed risk evaluation and mitigation strategy for a drug and </li></ul></ul><ul><ul><li>each assessment of an approved risk evaluation and mitigation strategy for a drug </li></ul></ul><ul><li>The Secretary and the responsible person will determine a strategy </li></ul><ul><ul><li>not later than 60 days after assessment submission or </li></ul></ul><ul><ul><li>not later than 30 days after assessment submission when the Secretary has withdrawn approval; grounds; immediate suspension upon finding imminent hazard to public health. </li></ul></ul><ul><li>The Secretary, in consultation with the office responsible for reviewing the drug and the office responsible for postapproval safety shall </li></ul><ul><ul><li>Issue an Action Letter to describe any required risk evaluation and mitigation strategy or modification to any required strategy </li></ul></ul><ul><ul><li>Issue an Order not later than 90 days after discussion date </li></ul></ul>

26.
(h) Review of Proposed Strategies Dispute Resolution <ul><li>Dispute Resolution At Initial Approval </li></ul><ul><li>the responsible person is directed to use the major dispute resolution procedures described in section 101(c) of FDA 3 2007 </li></ul><ul><li>Dispute Resolution In All Other Cases </li></ul><ul><li>Not earlier than 15 days, and not later than 35 days, after discussions have begun, the responsible submits a written request for review by the Drug Safety Oversight Board (5 days) </li></ul><ul><li>Disagreement After Discussion or Administrative Appeals </li></ul><ul><li>A request for review shall not preclude further discussions to reach agreement on the risk evaluation and mitigation strategy, or preclude the use of administrative appeals , and appeals for procedural or scientific matters involving the review of human drug applications and supplemental applications that cannot be resolved at the divisional level. </li></ul><ul><li>Action Letter/ Order </li></ul><ul><li>The Secretary shall issue an action letter/order not later than 7 days after receiving recommendation of the Drug Safety Oversight Board </li></ul><ul><li>International Coordination </li></ul><ul><li>The Secretary, may coordinate the timetable for submission of assessments with efforts to identify and assess the serious risks with efforts from other countries whose drug approval and risk management processes are comparable to those of the United States </li></ul>

27.
Section 503B Preview of Television Advertisements <ul><li>Prereview of Television Advertisements </li></ul><ul><ul><li>The Secretary may review the script, story board, rough, or a completed video production of the television advertisement 45 days before dissemination of the television advertisement and make recommendations on label information – </li></ul></ul><ul><ul><ul><li>changes necessary to protect the consumer good and well-being </li></ul></ul></ul><ul><ul><ul><li>provide inclusion statements for the advertisement to address the specific efficacy of the drug as it relates to specific population groups, including </li></ul></ul></ul><ul><ul><ul><ul><li>elderly populations </li></ul></ul></ul></ul><ul><ul><ul><ul><li>children </li></ul></ul></ul></ul><ul><ul><ul><ul><li>racial and ethnic minorities </li></ul></ul></ul></ul><ul><ul><li>if the Secretary determines that the advertisement would be false or misleading without a specific disclosure about a serious risk listed in the labeling , then the Secretary may require that the advertisement include a disclosure . </li></ul></ul>

28.
Section 503B Direct to Consumer Advertisements <ul><li>Direct to Consumer Advertisements </li></ul><ul><li>In the case of an advertisement for a drug subject to section 503(b)(1) presented directly to consumers in television or radio format and stating the name of the drug and its conditions of use , the major statement relating to side effects and contraindications shall be presented in a clear, conspicuous, and neutral manner .’’ </li></ul><ul><ul><li>Not later than 30 months after the date of the enactment of the FDA 3 of 2007, the Secretary shall establish standards for determining if a major statement relating to side effects and contraindications meet the requirements . </li></ul></ul><ul><ul><li>Sec 906. In the case of published direct-to-consumer advertisements the following statement printed in conspicuous text: </li></ul></ul><ul><ul><ul><li>‘ You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1–800- FDA-1088 </li></ul></ul></ul><ul><li>Civil Penalties </li></ul><ul><li>Any person who disseminates or causes another party to disseminate a direct-to-consumer advertisement that is false or misleading shall be liable to the United States for a civil penalty in an amount not to exceed $250,000 for the first such violation in any 3-year period, and not to exceed $500,000 for each subsequent violation in any 3-year period . </li></ul>

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Section 902 Enforcement Misbranding & Civil Penalties <ul><li>Misbranding </li></ul><ul><li>If the responsible person fails to comply with a requirement of an approved risk evaluation and mitigation strategy for a drug, and is in violation of a requirement relating to postmarket studies and clinical trials or relating to labeling with respect to such drug, and </li></ul><ul><li>Any responsible person (as such term is used in section 505–1) that violates a requirement of section 505(o), 505(p), or 505–1 shall be subject to a civil monetary penalty of </li></ul><ul><ul><li>Not more than $250,000 per violation, and not to exceed $1,000,000 for all such violations adjudicated in a single proceeding; or </li></ul></ul><ul><ul><li>In the case of a violation that continues after the Secretary provides written notice the responsible person shall be subject to a civil monetary penalty of $250,000 for the first 30-day period and </li></ul></ul><ul><ul><li>The amount doubles for every 30-day period thereafter that the violation continues , not to exceed $1,000,000 for any 30-day period , and not to exceed $10,000,000 for all such violations adjudicated in a single proceeding . </li></ul></ul>

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Section 913 Assuring Pharmaceutical Safety <ul><li>SEC 505D. Pharmaceutical Security </li></ul><ul><li>The Secretary shall develop standards and identify and validate effective technologies for the purpose of securing the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs. </li></ul><ul><li>Not later than 30 months after the date of the enactment of the Food and Drug Administration Amendments Act of 2007, the Secretary shall develop a standardized numerical identifier </li></ul><ul><ul><li>which, to the extent practicable, shall be harmonized with international consensus standards for such an identifier </li></ul></ul><ul><ul><li>to be applied to a prescription drug at the point of manufacturing and repackaging at the package or pallet level, sufficient to facilitate the identification, validation, authentication, and tracking and tracing of the prescription drug. </li></ul></ul><ul><li>Interagency collaboration with Federal Health Security Agencies </li></ul><ul><ul><li>Department of Justice; the Department of Homeland Security; the Department of Commerce; and other appropriate Federal and State agencies . </li></ul></ul>

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Title X – Food Safety Reportable Food Registry <ul><li>SEC 417. Reportable Food Registry </li></ul><ul><li>FDA 3 Amends Chapter IV of the FD&C Act and Establishes an Early Warning System to protect the Public Health from Adulterated Food. </li></ul><ul><ul><li>Establish Reportable Food Registry within 1 year of enactment </li></ul></ul><ul><li>Food Safety Reports </li></ul><ul><ul><li>Requires the responsible party to report as soon as possible, no later than 24hr within discovery that a reportable food is adulterated </li></ul></ul><ul><ul><ul><li>Submit a report using an electronic portal established by the FDA </li></ul></ul></ul><ul><ul><ul><li>Investigate the cause of the adulteration if the adulteration of the article of food may have originated with the responsible party. </li></ul></ul></ul><ul><ul><li>No Report is required if </li></ul></ul><ul><ul><ul><li>The adulteration originated with the responsible party </li></ul></ul></ul><ul><ul><ul><li>The responsible party detected the adulteration prior to any transfer to another person of such article of food; and the responsible party </li></ul></ul></ul><ul><ul><ul><ul><li>corrected such adulteration; or </li></ul></ul></ul></ul><ul><ul><ul><ul><li>destroyed or caused the destruction of such article of food. </li></ul></ul></ul></ul><ul><ul><li>Public Health Officials may submit a report about a reportable food </li></ul></ul><ul><ul><ul><li>Service agreements Fed, State, or local agencies for coordination, homeland security </li></ul></ul></ul>

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Food Safety Reports Data Elements <ul><li>Maintenance And Inspection </li></ul><ul><ul><li>The responsible party shall </li></ul></ul><ul><ul><ul><li>maintain records related to each report received, notification made, and report submitted to the FDA for 2 years. </li></ul></ul></ul><ul><ul><ul><li>At the request of the Secretary, permit inspection of such records as provided for section 414. </li></ul></ul></ul><ul><li>Food Safety Reports Data Elements </li></ul><ul><ul><li>Facility registration numbers </li></ul></ul><ul><ul><li>Date on which an article of food was determined to be a reportable food </li></ul></ul><ul><ul><li>A description of the article of food including the quantity or amount. </li></ul></ul><ul><ul><li>The extent and nature of the adulteration. </li></ul></ul><ul><ul><li>If the adulteration of the article of food may have originated with the responsible party, the results of the investigation </li></ul></ul><ul><ul><li>The disposition of the article of food, when known. </li></ul></ul><ul><ul><li>Product information including product codes, use-by dates, and names of manufacturers, packers, or distributors sufficient to identify the article of food. </li></ul></ul><ul><ul><li>Contact information for the responsible party </li></ul></ul><ul><ul><li>The contact information for parties directly linked in the supply chain </li></ul></ul>

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International Legislation for Risk Management Global Legislative Tools for Risk Management The global international community has responded to the direction of the World Health Organization and the United States to harmonize regulatory practice and extend the best practice in consumer safety into markets across the globe. Australia China Canada European Union

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The Third U.S. - China Strategic Economic Dialogue 2007: MOAs <ul><ul><li>Drugs and medical products : Agreement between the U.S. Department of Health and Human Services (HHS) and China's State Food and Drug Administration (SFDA), signed on December 11, 2007 </li></ul></ul><ul><ul><li>Food and feed : Memorandum of agreement between the U.S. Department of Health and Human Services (HHS) and China's General Administration of Quality Supervision, Inspection, and Quarantine (AQSIQ), signed on December 11, 2007 </li></ul></ul><ul><ul><li>Food safety : The U.S. Department of Agriculture (USDA) and China's AQSIQ agree to upgrade their food safety memorandum of cooperation to a ministerial-level </li></ul></ul>Healthcare Products & Services 2007 On December 11, 2007, the U.S. Department of Health and Human Services and the State Food and Drug Administration of the People's Republic of China signed memorandum of agreements in eight areas intended to improve the safety of exports. Three of these support consumer health product quality and risk management:

35.
China and US Sign Agreement Safety of Drugs and Medical Devices 2007 <ul><li>Safety of Drugs and Medical Devices 2007 </li></ul><ul><li>Purpose: To ensure the quality control and safety of drugs and medical devices used by the public in China and the United States. Prioritized the cooperation for import and export control of drugs, including: </li></ul><ul><ul><li>active pharmaceutical ingredients </li></ul></ul><ul><ul><li>excipients and finished dosages </li></ul></ul><ul><ul><li>medical devices </li></ul></ul><ul><li>Cooperation in the five following areas : </li></ul><ul><ul><li>High-level meetings - establish a meeting mechanism for high-level leaders of drug regulatory authorities of both countries; </li></ul></ul><ul><ul><li>Exchange information – exchange information concerning companies subject to respective regulation, and the quality and safety of their products; </li></ul></ul><ul><ul><li>Legislative harmonization – harmonization of laws and regulations </li></ul></ul><ul><ul><li>Technical cooperation – exchange innovative drug technologies, and to set up a platform for training of inspectors </li></ul></ul><ul><ul><li>Combat counterfeiting – joint investigation and tracing of counterfeited products that might pose threats to consumer health </li></ul></ul>

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European Union Council Regulation (EC) No 73/2008 <ul><ul><li>The seat of the IMI Joint Undertaking shall be located in Brussels, Belgium and should operate until December 31, 2017. </li></ul></ul><ul><ul><li>be a public-private partnership aiming at increasing the research investment in the biopharmaceutical sector in the Members States and countries associated to the Seventh Framework Program by pooling resources and fostering collaboration between the public and private sectors; </li></ul></ul><ul><ul><li>The Joint Technology Initiative on Innovative Medicines replies to </li></ul></ul><ul><ul><ul><li>The Report &quot;Creating an Innovative Europe&quot; of January 2006 which identifies pharmaceuticals as a key strategic area and it stresses the need for the Joint Technology Initiative on Innovative Medicines at European level. </li></ul></ul></ul><ul><ul><ul><li>The Commission Communication of 1 July 2003&quot;A Stronger European-based Pharmaceutical Industry for the Benefit of the Patient — A Call for Action&quot; </li></ul></ul></ul>Joint Technology Initiative on Innovative 2007 The Joint Technology Initiative on Innovative Medicines establishes a coordinated approach to overcome identified research bottlenecks in the drug development process, and to support pre-competitive pharmaceutical research and development, in order to accelerate the development of safe and more effective medicines for patients.

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European Union P harmacovigilance of Advanced Therapy Medicinal Products <ul><ul><li>Creates within the European Medicines Agency a Committee for Advanced Therapies , responsible for preparing a draft opinion on the quality, safety and efficacy of each advanced therapy medicinal product for final approval by the Agency’s Committee for Medicinal Products for Human Use. </li></ul></ul><ul><ul><li>Follow-up of Efficacy &Adverse Reactions : applicants detail measures to ensure follow-up </li></ul></ul><ul><ul><li>Risk Management System : Where justified on public health grounds, the holder of the marketing authorization will be required to put in place a suitable risk management system to address risks related to advanced therapy medicinal products. </li></ul></ul><ul><ul><li>Patient & Product Traceability : A system allowing complete traceability of the patient as well as of the product and its starting materials is essential to monitor the safety of advanced therapy medicinal products. </li></ul></ul>Advanced Therapy Medicinal Products And Amending Directive 2001/83/EC and Regulation (EC) No 726/2004 This regulation introduces additional provisions to those laid down in Directive 2001/83/EC. The scope of this regulation is to regulate advanced therapy medicinal products intended to be placed on the market in Member States and either prepared industrially or manufactured by a method involving an industrial process.

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European Union Commission On Pharmacovigilance Pending Legislation Strategy To Strengthen And Rationalize The EU Pharmacovigilance System <ul><li>Proposals for change to the legal framework include: </li></ul><ul><ul><li>Strengthen the rules on transparency relating to pharmacovigilance data, assessment and decision-making and involve stakeholders (e.g. patient and healthcare professional groups) in the processes including reporting (including patient reporting). </li></ul></ul><ul><ul><li>Establish clear standards (‘Good Vigilance Practices - GVP’) for the conduct of pharmacovigilance by both the industry and regulators. And maximum utilization of the EU pharmacovigilance database ‘Eudravigilance’. </li></ul></ul><ul><ul><li>Rationalizing and simplifying the reporting of suspected adverse drug reactions (ADRs), both expedited and periodic reporting, making best use of current information technology (including Eudravigilance) and matching the reporting requirements with the level of knowledge about the safety of a specific product. </li></ul></ul><ul><ul><li>Stimulate innovation by establishing a clear legal requirement to conduct postauthorization safety studies including those in risk management systems. </li></ul></ul><ul><ul><li>Rationalize EU decision-making on drug safety issues to deliver fast, robust decisions that are equally and fully implemented for all relevant products and across all markets. </li></ul></ul>

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Canada Federal Regulatory Post-Market Surveillance Strategy 2007-2012 <ul><li>The focus of the study will be on the federal government’s role with respect to: </li></ul><ul><ul><li>regulatory authority </li></ul></ul><ul><ul><li>capacity for monitoring, surveillance and research </li></ul></ul><ul><ul><li>consumer safety </li></ul></ul><ul><ul><li>compliance and inspection </li></ul></ul><ul><ul><li>public access to information and, </li></ul></ul><ul><ul><li>adverse reaction reporting </li></ul></ul>Study on Post-Market Surveillance Of Pharmaceutical Products, Prescription and Non-Prescription House Of Commons. In January 2008, the Standing Committee on Health will commence a study on the post-market surveillance of pharmaceutical products, prescription and non-prescription. <ul><li>The Post-Market Surveillance Continuum </li></ul><ul><li>comprises three principal phases: </li></ul><ul><ul><li>Information gathering, monitoring and processing; </li></ul></ul><ul><ul><li>Signal detection and assessment; and </li></ul></ul><ul><ul><li>Risk management and intervention </li></ul></ul><ul><li>The Marketed Health Products Directorate (MHPD) within the Health Products and Food Branch has managed post-market surveillance and disseminated health product safety information since 2002 </li></ul>

40.
Australia’s Therapeutic Goods Administration (TGA) and FDA Sign Cooperative Agreement <ul><li>The Exchange Of Information On Current Good Manufacturing Practices Inspections Of Human Pharmaceutical Products </li></ul><ul><li>Purpose: to provide the means by which each administration can obtain information that will enable it to make its own independent facility and/or product regulatory decisions in the assessment of CGMP compliance, public health protection and approval of new drugs: </li></ul><ul><ul><li>sharing Good Manufacturing Practice information from manufacturers located in other countries </li></ul></ul><ul><ul><li>information on firms that potentially counterfeit or substitute Active Pharmaceutical Ingredients. </li></ul></ul><ul><li>Commonwealth of Australia - Standards For Risk Management </li></ul><ul><li>The Standards For Risk Management Order 2007 changes section 41CB of the Therapeutic Goods Act 1989 by revoking Medical device Standards Order No 2 and replaces it with the Standards For Risk Management </li></ul><ul><ul><li>EN ISO 14971:2002 or ISO 14971:2007 Medical Devices – Application of Risk Management to Medical Devices Clauses 1 to 9 inclusive </li></ul></ul>

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Global Risk Management Infrastructure Healthcare Products and Services FDA 3 2007 China-US Food Safety 2007 China-US Safety of Drugs & Medical Devices 2007 IMI Joint Undertaking Australia - US Cooperative Agreement 2007 Advanced Therapy Medicinal Products & Amending Directive Post-Market Surveillance Study 2008

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Discussion Items Joseph Curtis MS, PhD Legislative Views Risk Management in Healthcare Products ASQ Tri-Division Conference 2008 email: [email_address]