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Sandra Maddock & Brandy Smith BioEnterprise Presentation 9.6.12

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Sandra Maddock & Brandy Smith BioEnterprise Presentation 9.6.12

  1. 1. The Difference is in the Details Drugs vs. Devices Presented by: Brandy Smith Sandra MaddockWe have studied clinical research and regulatory compliance issues since 1999.
  2. 2. AgendaAn Overview of Drugs and Devices Determining the Need for a Clinical Trial Regulatory Overview Clinical Trial Similarities Clinical Trial DifferencesFAIR Shake™- The Regulations
  3. 3. AgendaAn Overview of Drugs and Devices Determining the Need for a Clinical Trial Regulatory Overview Clinical Trial Similarities Clinical Trial DifferencesFAIR Shake™- The Regulations
  4. 4. Overview of Drugs and Devices DrugsArticles recognized in the official USPharmacopoeia, official HomoeopathicPharmacopoeia of the US, or official NationalFormulary • intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease • intended to affect the structure of any function of the body (FDC Act, Section 201)
  5. 5. Overview of Drugs and Devices DevicesAninstrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or relatedarticle… which is – • intended for use in the diagnosis of disease… in cure, mitigation, treatment, or prevention of disease • intended to affect the structure of any function of the body… not achieved through chemical action… or being metabolized (FDC Act, Section 201)
  6. 6. Overview of Drugs and Devices Device classificationsClass DescriptionClass I Least risky, general controls adequate; no clinical trial neededClass II Intermediate risk, special controls needed (510k)Class III Substantial risk devices, pre-market approval needed (IDE)
  7. 7. Drugs Devices Chemical/ metabolic action Not metabolized Distributed systemically Acts locallyMay impact metabolism of other Effects structure drugsLarger number of study subjects Smaller number of study subjects needed to identify side effects needed Clinical trial needs are based onClinical Trial Always Required risk classification of device
  8. 8. AgendaAn Overview of Drugs and Devices Determining the Need for a Clinical Trial Regulatory Overview Clinical Trial Similarities Clinical Trial DifferencesFAIR Shake™- The Regulations
  9. 9. Determining the Need for a Clinical Trial• In situations of a drug, a clinical trial will always be required• However, not all devices will need to undergo a clinical trial• The determination of whether or not a device clinical trial is required is based on a risk stratification
  10. 10. Determining the Need for a Clinical Trial Drugs DevicesAll Drugs require Assess Risk Clinical Trials Classification 21 CFR 312 Intermediate Risk Substantial Risk “IND” Clinical trial MAY be Clinical Trial required Required
  11. 11. Determining the Need for a Clinical Trial Devices Assess Risk Classification Intermediate Risk Substantial Risk Clinical trial MAY be Clinical Trial required Required
  12. 12. Determining the Need for a Clinical Trial Risk StratificationClass Description Risk ClassificationClass I Least risky, general controls Minima Intermediat Substantial } adequate; no clinical trial needed l Risk e Risk RiskClass II Intermediate risk, special controls needed (510k)Class III Substantial risk devices, pre-market No MAY REQUIRES approval needed (IDE) Clinical Require Clinical Trial Clinical Trial Required Trial
  13. 13. Determining the Need for a Clinical Trial Risk StratificationClass Description Risk ClassificationClass I Least risky, general controls Minima Intermediat Substantial } adequate; no clinical trial needed l Risk e Risk RiskClass II Intermediate risk, special controls needed (510k)Class III Substantial risk devices, pre-market No MAY REQUIRES approval needed (IDE) Clinical Require Clinical Trial Clinical Trial Required Trial
  14. 14. Determining the Need for a Clinical Trial Risk Stratification Devices Drugs Assess Risk ClassificationAll Drugs require Clinical Trials Intermediate Risk Substantial Risk 21 CFR 312 “IND” Clinical trial MAY Clinical Trial be required Required
  15. 15. Determining the Need for a Clinical Trial Risk Stratification DrugsAll Drugs require *Clinical Trials Always Clinical Trials Required for New Drugs* 21 CFR 312 “IND”
  16. 16. Clinical Trials DrugsPhase PurposePhase I Normal healthy volunteers Determine metabolism and pharmacologic actions Aim= safety and tolerancePhase II Patients with the disease or condition Small Sample Aim= safety and effectivenessPhase III Patients with the disease or condition LARGER population Aim= safety and effectivenessPhase IV Post approval studies Obtain additional information regarding risks, benefits, and optimal use
  17. 17. Clinical Trials DevicesStudy PurposeAlthough there are “phases” in device research, they are not as delineated asdrugsPilot May conduct pilot study (strategic decision or FDA request) Single-center or small number of multi-center sites Small number of subjects Safety and tolerancePivotal Larger number of subjects Larger number of sites Safety and effectivenessContinued During PMA review of pivotal data, the FDA may grantAccess continued use of the device and allow more subjects to be enrolledPost Market Strategic decision or FDA’s request Method to collect long-term data
  18. 18. Clinical Trials Drugs and DevicesFeature Drug DeviceRate of technology change Low HighInfluence of physician technique Low HighPopulation size Large SmallAble to visualize performance Low HighAbility to blind treatments Easy DifficultUse of randomization High LowPhases Clear Less Clear (pilot/pivot al)
  19. 19. AgendaAn Overview of Drugs and Devices Determining the Need for a Clinical Trial Regulatory Overview Clinical Trial Similarities Clinical Trial DifferencesFAIR Shake™- The Regulations
  20. 20. Regulatory Overview What you need to know21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs;AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR Sponsor Good Internal Requirements CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRBSOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 Clinical PoliciesSOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFRPractice CFR 11; 21 CFR 50; 21 CFR 812; 21 812; 21CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; 21 CFR 812; 21 CFR 11; 21CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; FDAPROTOCOL; 21 CFR 812; IRB CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB Regulations 21 SOPs; SPONSOR SOPs; SITESOPs; AGREEMENTS; Requirements 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR PROTOCOL; Research CRO/54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 Monitor Sponsor SiteCFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS;PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRBSOPs; SPONSOR SOPs; NIH SOPs; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SITE ICHSPONSOR SOPs; SITEGuidelinesAGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR SOPs; Guidelines56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR11; 21 CFR 50; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 21CFR 56; ICH; IRB SOPs; SPONSORISO14155SITE SOPs;Investigator SOPs; Protocol AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; RequirementsSPONSOR AND SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;IRB SOPs; It’s Complicated! Agreements
  21. 21. Regulatory Overview Our Focus FDA Regulations CRO/ Research Monitor Sponsor Site • Investigator(s) • Research Coordinator(s) • Other Research Administration • Institutional Review Board (IRBs)
  22. 22. Regulatory Overview Code of Federal Regulations• Requirements for conducting clinical studies• Outlines responsibilities of the sponsors, investigators, and IRBs for conducting trials involving human subjects
  23. 23. Regulatory Overview Code of Federal Regulations Titles Chapters PartsSections Subparts Paragraphs
  24. 24. Regulatory Overview Code of Federal RegulationsTitle: CRF Title 21 Chapter: Food and Drugs Part: 50 Protection of Human Subjects Subpart: B Informed Consent of Human Subjects Section: (a) – Basic Elements of Informed Consent Section Paragraph: (1) Statement that the study involves research…
  25. 25. Regulatory Overview Code of Federal RegulationsTitle: CRF Title 21 Chapter: Food and Drugs Part: 312 Drugs Part: 812 Devices Part: 50 Protection of Human Subjects Part: 56 Institutional Review Boards (IRBs) Part: 54 Financial Disclosures Part: 11 Electronic Records/Electronic Signatures
  26. 26. Minute to Win It!
  27. 27. Fill in the blanks….Regarding record maintenance, an investigator mustmaintain accurate, complete and currentrecords, including:21 CFR 812.140 (1)All _____________ with another____________, an _______, thesponsor, a monitor, or ______, includingrequired ________________.
  28. 28. Regulatory Overview Code of Federal RegulationsTitle: CRF Title 21 Chapter: Food and Drugs Part: 312 Drugs Part: 812 Devices Part: 50 Protection of Human Subjects Part: 56 Institutional Review Boards (IRBs) Part: 54 Financial Disclosures Part: 11 Electronic Records/Electronic Signatures
  29. 29. Regulatory Overview Code of Federal RegulationsTitle: CRF Title 21 Chapter: Food and Drugs Part: 312 Drugs Part: 812 Devices Part: 50 Protection of Human Subjects Part: 56 Institutional Review Boards (IRBs) Part: 54 Financial Disclosures Part: 11 Electronic Records/Electronic Signatures
  30. 30. Regulatory Overview Global Perspective• ISO 14155 has been designed for medical devices• ICH GCP has origins in the pharmaceutical industry• ISO 14115 and ICH GCP complement one another as they are based on the same principles: – Patient protection – Documentations – Risk-benefit assessments – Ensuring data validity
  31. 31. AgendaAn Overview of Drugs and Devices Determining the Need for a Clinical Trial Regulatory Overview Clinical Trial Similarities Clinical Trial DifferencesFAIR Shake™- The Regulations
  32. 32. Clinical Trial Similarities Regulations• Regulations that drugs and devices have in common: – 21 CFR 11 (electronic records) – 21 CFR 50 (protection of human subjects) – 21 CFR 54 (financial disclosure) – 21 CFR 56 (institutional review board)
  33. 33. Clinical Trial Similarities Regulations• Within 21 CFR 312 and 21 CFR 812 are many similarities: – Submit to FDA before beginning an investigation – Update annually – Amendments required when changes are made – Promotion and charging for the product – Labeling – Waivers – Product accountability
  34. 34. Clinical Trial Similarities Sponsor ResponsibilitiesDRUGS DEVICES•Select qualified investigators •Selecting qualified investigators•Provide info to investigators •Provide info to investigators•Ensure proper monitoring •Ensure proper monitoring•Ensure trial is conducted in •Ensure trial is conducted in accordance with the general investigational plan and protocols accordance with the general•Maintain an effective IND with investigational plan, protocol, respect to the investigations agreement, IRB•Ensure the FDA and investigators are •Ensure IRB review and approval promptly informed of significant •Ensure IRB and FDA are promptly new adverse effects or risks with informed of significant new respect to the drug information
  35. 35. Clinical Trial Similarities Sponsor ResponsibilitiesDRUGS DEVICES312.56: ….(paraphrased) Ensuring that 812.46: (paraphrased) Ensuringthe investigation(s) is conducted in compliance with signed agreement,compliance with the investigational plan, investigational plan, applicable FDAthe signed agreement, and the applicable regulations, and IRB requirements....regulations….
  36. 36. Clinical Trial Similarities Investigator ResponsibilitiesDRUGS DEVICES312.60: ….Ensuring that an investigation 812.110: An investigator shall conduct anis conducted according to the signed investigation in accordance with theinvestigator statement, the signed agreement with the sponsor, theinvestigational plan, and applicable investigational plan, this part and otherregulations.... applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA.
  37. 37. Clinical Trial Similarities Trials organized differently (defined phases Sponsor v. pilot/pivotal), responsibiliti but many of the es similar same requirements apply Investigator responsibilitie s similar Lots of Similarities!
  38. 38. AgendaAn Overview of Drugs and Devices Determining the Need for a Clinical Trial Regulatory Overview Clinical Trial Similarities Clinical Trial DifferencesFAIR Shake™- The Regulations
  39. 39. Clinical Trial DifferencesDifferences are in the Details Agreements Training Payments Adverse Events
  40. 40. Clinical Trial Differences AgreementsIn both drug studies and device studies, the FDArequires that the investigator comply with theagreements (21 CFR 312.56 and 21 CFR812.46), however the agreements are notidentical.
  41. 41. Clinical Trial Differences Agreements - Drugs• The FDA Form 1572 is the agreement mandated by the FDA to be completed by all investigators involved in a drug trial.• The agreement describes an investigator’s qualifications and specifies his or her commitment to adhering to applicable FDA regulations.
  42. 42. Clinical Trial Differences Agreements - Drugs Read the SMALL PRINT of the 1572 Supervise Maintain Records Adhere to protocol Learn investigator brochure Let FDA inspect rePort adverse events Retain records Inform subjects Notify IRBRead the SMALL PRINT of the 1572, The Essential GCP Document;http://www.wlap.org/filearchive/cacr/CACR_CRE_ 2.ppt#256,1,Readthe SMALL PRINT of the 1572 staff Train
  43. 43. Clinical Trial Differences Agreements - Drugs Read the SMALL PRINT of the 1572 Supervise Maintain Records Adhere to protocol Learn investigator brochure Let FDA inspect rePort adverse events Retain records Inform subjects Notify IRBRead the SMALL PRINT of the 1572, The Essential GCP Document; Train staffhttp://www.wlap.org/filearchive/cacr/CACR_CRE_ 2.ppt#256,1,Readthe SMALL PRINT of the 1572
  44. 44. Clinical Trial Differences Agreements - Devices• No standard format or specific form required• Direction provided as to what should be included in the agreements (21 CFR 812.43) – Investigator qualifications – Commitment to conduct the study in accordance with regulations – Commitment to supervise device use – Statement regarding involvement in research that was terminated (if applicable)
  45. 45. Clinical Trial Differences TrainingTraining should be approached differently whenbeginning a drug study versus beginning adevice study.
  46. 46. Clinical Trial Differences TrainingDrugs • Training on dispensing of product not likely to be needed • Burden of responsibility to comply with drug regimen lies with patient/patient’s caregiver • A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug. 21 CFR 312.53Devices • Training could be significant and might require the assistance of engineers, product development, nurses, other physicians, etc. • Influence of physician technique can be very high depending on the complexity of device study • A sponsor shall select investigators qualified by training and experience to investigate the device. 21 CFR 812.43
  47. 47. Clinical Trial Differences PaymentsProduct reimbursement varies quite a bitfrom drugs to devices.
  48. 48. Clinical Trial Differences Payments• Drugs are often provided free of charge to clinical sites and patients in clinical trials• Devices expensive to produce• Having to provide it free could cause a significant barrier to development• For some studies, investigator could be charged for the device (then reimbursed by Medicare or private insurance) – “Category B Investigational Devices”
  49. 49. Clinical Trial Differences Adverse EventsDue to the systemic nature of drugs, all adverseevents will need to be captured and analyzed aspotentially related to the drug. Devices have a localaffect, and the likelihood of an adverse event beingrelated to the device is easier to determine. For thisreason, not all negative occurrences in a devicestudy are reportable.
  50. 50. Clinical Trial Differences Adverse events • AE: Adverse Effect • SAE: Serious Adverse Effect ADEs • ADE: Adverse Device Effect UADEs AEs • SADE: Serious Adverse FDA Device Effect UADEs SADEs • UADE: Unanticipated Adverse Device Effect • FDA UADE: Unanticipated Adverse Device Effect that isSource: also SERIOUSMichaels, MB, AppliedClinical Trials, August2011, pages 36.
  51. 51. Clinical Trial Differences Adverse Events• UADEs- report to Sponsor and IRB no later than 10 days after learning of the event
  52. 52. Clinical Trial Differences Adverse Events• Immediately conduct investigation• If UADE presents unreasonable risks to subjects, sponsor shall terminate all investigations within 5 working days of making that decision
  53. 53. Key Points• Devices have local affect, drugs systemic• Follow different regulatory pathways• Clinical trials very similar in requirements Agreements• Differences lie in the details: Training Payments Adverse Events
  54. 54. AgendaAn Overview of Drugs and Devices Determining the Need for a Clinical Trial Regulatory Overview Clinical Trial Similarities Clinical Trial DifferencesFAIR Shake™- The Regulations
  55. 55. Let’s Shake Things Up
  56. 56. “You can fool all of the people some of the time, andsome of the people all of the time, but you cannotfool all of the people all of the time.”- Abraham Lincoln
  57. 57. You Need To Bring It!
  58. 58. What You Need to Know21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs;AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFRSponsor CFR 50; 21 Good 54; 21 CFR 56; ICH; IRB SOPs; 11; 21 CFR InternalSPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; Requirements 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 Clinical PoliciesCFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; Practice21 CFR 50; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITESOPs; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITESOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; FDASPONSOR SOPs; SITEIRB SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;Regulations 50; 21 CFR 54; 21 21 CFRCFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; Requirements21 CFR 50; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE CRO/ ResearchSOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21Sponsor21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; CFR 11; Site MonitorSPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;21 CFR 50; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE NIHSOPs; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE Guidelines ICH GuidelinesSOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs;SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;21 CFR 50; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS;Protocol ISO14155 PROTOCOL; 21 CFR 812; 21 CFR 21 Investigator RequirementsCFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; AgreementsSPONSOR AND SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;IRB SOPs; It’s Complicated!
  59. 59. Adding To The Mix… Fixed versus Variable A decision about regulatory compliance made at one site forone study may not be the right decision at another site for the same study or at the same site for another study….
  60. 60. 21 CFR 812 - IDEs • 812.110: An investigator shall conduct an investigation in accordance with the signed agreement with theInvestigator sponsor, the investigational plan, this part and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA. • 812.46: (paraphrased) Ensuring compliance with Sponsor signed agreement, investigational plan, applicable FDA regulations, and IRB requirements....
  61. 61. Working through the chaos Federal Regulations Agreements Investigational Plan Requirements of IRB
  62. 62. Federal Regulations• Requirements for conducting clinical studies• Outlines responsibilities of the sponsors, investigators, and IRBs for conducting trials involving human subjects
  63. 63. Federal Regulations FDA Regulations to Know812 IDEs (Investigational Device Exemptions)50 Protection of Human Subjects56 IRBs (Institutional Review Boards)54 Financial Disclosures11 Electronic Records/Signatures
  64. 64. Federal Regulations21 CFR 812 - IDEs • Describes the procedures for the conduct of clinical investigations of devices • Sponsor responsibilities • Investigator responsibilities
  65. 65. Federal Regulations 21 CFR 812 - IDEs • 812.110: An investigator shall conduct an investigation in accordance with the signed agreement with theInvestigator sponsor, the investigational plan, this part and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA. • 812.46: (paraphrased) Ensuring compliance with Sponsor signed agreement, investigational plan, applicable FDA regulations, and IRB requirements....
  66. 66. Federal Regulations 21 CFR 812 - IDEs• Overall conduct of a study: – Labeling – Promotion – Selection of Investigators – Monitoring (securing compliance) – Record keeping – IRB approval….. DOCUMENT IT!
  67. 67. Federal Regulations 21 CFR 50 – Human Subject Protection• The rights, safety, and well-being of the trial subjects should prevail over interests of science and society.• Freely given Informed Consent should be obtained from every subject prior to clinical trial participation.• The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality
  68. 68. Federal Regulations21 CFR 50 – Human Subject Protection • Specifies: – Consenting procedures – Elements to include in an informed consent – Documentation of informed consent – Exceptions of informed consent – Safeguards for children/wards
  69. 69. Federal Regulations 21 CFR 50 – Human Subject Protection• Sponsor obligations: – Ensure informed consent process at site level is compliant with regulatory requirements DOCUMENT IT!
  70. 70. Federal Regulations 21 CFR 56 - IRBs• IRBs – Institutional Review Boards (Ethics Committees) Review and approve research studies involving human subjects• 21 CFR part 56 contains general standards for the composition, operation, and responsibility of an IRB that reviews clinical investigations regulated by the FDA
  71. 71. Federal Regulations 21 CFR 56 - IRBsAn IRB has the authority to: • Approve research • Require modifications in research • Disapprove research • Require additional elements of informed consent are provided • Waive the requirement for a signed informed consent
  72. 72. Federal Regulations 21 CFR 56 - IRBs• Sponsor’s obligations: – Ensure IRB is operating in compliance with 21 CFR 56 – Ensure site is following IRB procedures DOCUMENT IT!
  73. 73. Federal Regulations 21 CFR 54 – Financial Disclosure• Protect the integrity and reliability of clinical data• FDA considers whether adequate steps are taken in the design, conduct, reporting and analysis of studies to minimize bias• The FDA works with the applicant/sponsor to minimize potential bias
  74. 74. Federal Regulations 21 CFR 54 – Financial Disclosure Investigator to Sponsor to FDA SponsorIf financial interests raise questions about data integritythe FDA may: • Initiate audits of the data from that investigator • Request further analyses of data • Request applicant to conduct additional studies • Refuse the data
  75. 75. Federal Regulations 21 CFR 54 – Financial Disclosure• Sponsor’s obligations: • Collect accurate investigator financial information before study participation (21 CFR 812.43) • Report COI to FDA at time of application • Obtain updates throughout the study and for one year after all study data is submitted DOCUMENT IT!
  76. 76. Federal Regulations21 CFR 11 – Electronic Records • Describes How: – Electronic records, electronic signatures, and handwritten signatures executed to electronic records are considered trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper.
  77. 77. Federal Regulations 21 CFR 11 – Electronic Records• To ensure the authenticity, integrity and confidentiality of electronic records, controls include: – Tracking of data entry with an audit trail (paper or electronic) – Documented verification of data entry accuracy – Unique electronic signatures
  78. 78. Federal Regulations 21 CFR 11 – Electronic Records• Sponsor’s obligation: – Know the requirements of 21 CFR 11 – Ensure site and internal (sponsor) compliance DOCUMENT IT!
  79. 79. Working through the chaos Federal Regulations Agreements Investigational Plan Requirements of IRB
  80. 80. Agreements• Statement of investigator’s commitment to: – Conduct the investigation in compliance with FAIR – Supervise device use – Obtain informed consent – Other items as agreed upon with sponsor… DOCUMENT IT!
  81. 81. Working through the chaos Federal Regulations Agreements Investigational Plan Requirements of IRB
  82. 82. Investigational Plan • Inclusion / Exclusion • Required Testing • Procedural Requirements • Randomization Processes • Follow-up Requirements DOCUMENT IT!
  83. 83. Working through the chaos Federal Regulations Agreements Investigational Plan Requirements of IRB
  84. 84. Requirements of IRB • Informed consent procedures • Adverse event reporting requirements • Renewal timelines • Etc.
  85. 85. Case Study #1You are monitoring a site when younotice that an investigator routinelysigns the consent forms days after thepatients sign them. You’re not surewhat to do. The manager of the brandnew research coordinator tells you thatthis is no big deal and there is nothingto address.She said “It’s not in the regs…..” Is sheright?
  86. 86. Federal RegulationsAgreementsInvestigational PlanRequirements of IRB Could be specified by the IRB
  87. 87. Case Study #2 A monitor notes that all of the IRB approvals were on file at a site, but some of the correspondence back and forth regarding the approvals was missing. The RC refused to locate the missing documentation. The monitor insists “It’s in the Regs….” Is the monitor correct?
  88. 88. Federal Regulations FDA requires that all correspondence with an IRB be maintained (21 CFR 812.140) Agreements Investigational Plan Requirements of IRB
  89. 89. Case Study #3 You have a site that routinely takes case report forms (CRFs) into the exam room while seeing patients. While much of the information you need for the study is included in the patient’s regular assessment, they write the other data directly onto the CRF. You think they need a separate source, but you’re not sure. You dig into the regulations and find what???
  90. 90. Federal RegulationsAgreements  Could be in an agreement  Could be in anInvestigational Plan investigational planRequirements of IRB
  91. 91. Sandra Maddock Brandy Smith CEO and President Director of Clinical Monitoring Services Meet Our Team John Lehman Mary LewisDirector of Business Development Clinical Auditor
  92. 92. More Information for You Download our WhitepapersDrugs vs. Devices
  93. 93. References• FDA’s official website: • www.fda.gov• GCP Guidances and Information Sheets • http://www.fda.gov/oc/gcp/guidance.html• Informed Consent • A Guide To Informed Consent: • http://www.fda.gov/oc/ohrt/irbs/informedconsent.html • Protection of Subjects: • http://www.fda.gov/cdrh/devadvice/ide/informed_consent.shtml• Running clinical trials • http://1.usa.gov/ILt1tc

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