Regulatory Aspects of Human Subjects Research Lecture 4 PDF

Regulatory aspects of human subjects research Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School Overview –Part I Human Subjects Recap –Belmont Report Good Clinical Practice (GCP) Overview of applicable federal regulat...

Regulatory aspects of human subjects research Robert Wieder, MD, PhD Division of Medical Oncology/Hematology Rutgers New Jersey Medical School Overview –Part I Human Subjects Recap –Belmont Report Good Clinical Practice (GCP) Overview of applicable federal regulations: 45 CFR 46 and 21 CFR ICH-GCP 2 Overview –Part 2 IRB review process Writing an IRB application Informed Consent Essential Documents Source documentation Audits 3 Human Subjects Protection: Re-cap BELMONT REPORT  Past injustices, including Tuskegee syphilis experiments lead to the Belmont Report of 1979 Belmont report led to establishment of US Federal Regulations governing the conduct of clinical research Three guiding principles of Belmont Report: 1. Respect for persons Informed consent Protection of Vulnerable populations 2. Beneficence 3. Justice 6 Belmont Report 1. Respect for persons Individuals must be treated as autonomous persons –they must enter research voluntarily and with adequate information –Informed Consent Persons with diminished autonomy are entitled to additional protections (e.g. children, people with developmental disorders or those with dementia, persons who are incarcerated) Informed Consent Process Information –a reasonable person should have enough information to decide whether or not to participate Comprehension–use understandable language; allow for questions Voluntariness –decision must be made free of coercion Vulnerable Populations Defined as “Groups that may contain individuals who have limited autonomy, i.e. cannot fully appreciate or freely participate in the informed consent process.” Children Individuals who are mentally disabled; those with dementia or other cognitive disorders Prisoners Require additional protections Belmont Report 2. Beneficence Do no harm Maximize possible benefits and minimize possible harms Belmont Report 3. Justice Individuals and groups must be treated fairly and equitably in terms of bearing the burdens and receiving the benefits of research Include diverse populations in research Concept of Justice requires Equitable Selection of Subjects Individual level: Inclusion/exclusion criteria must be fair Societal level: Selection of subjects must be equitable –research should not unduly involve persons from groups unlikely to benefit from the findings of the research Belmont report –lead to establishment of two sets of US Federal Regulations 45 CFR 46 –covers research funded or supported by the HHS 21 CFR (multiple parts) –covers FDA regulated research Recognized as the standard for how research must be conducted in the US –institutions generally apply these regulations to all research regardless of whether it technically falls under these regulations 45 CFR 46 US DEPARTMENT OF HEALTH AND HUMAN SERVICES (DHHS) REGULATIONS US Department of Health and Human Services (DHHS) 45 CFR 46 Subpart A–describes required protections for all Federally conducted or supported human subjects research Subpart B–additional protections for women, fetuses and neonates Subpart C–additional protections for prisoners Subpart D–additional protections for children Subpart E–Registration of IRBs 45 CFR 46: Subpart A (aka “The Common Rule”) Defines a “Human Subject” as “a living individual about whom an investigator conducting research obtains: Data through intervention or interaction with the individual Identifiable private information Defines “research” as “a systematic investigation designed to develop or contribute to generalizable knowledge.” 18 45 CFR 46: Protective Mechanisms Established by the Common Rule Review of research by an Institutional Review Board Informed Consent of subjects Institutional assurances of compliance 45 CFR 46 Common Rule: Review by Institutional Review Board 1. Independent ethical (not necessarily scientific) review 2. IRB must consider: Risk to subjects Anticipated benefits to subjects and others Importance of the knowledge to be gained The informed consent process 3. IRB must report to the appropriate federal agencies (i.e. OHRP, FDA, NIH, etc.) Injuries to human subjects or other unanticipated problems Serious or continuing noncompliance with regulations or IRB requirements Suspension or termination of IRB approval 45 CRF 46 Common Rule: Review by Institutional Review Board (cont.) 4. Initial and continuing review and approval (minimally –annual) following receipt of appropriate progress report from the investigator, including study-wide findings when available 5. Investigator may not implement changes to the research without prior approval of the IRB (except in case of eliminating apparent immediate hazard to subjects) 21 45 CRF 46 Common Rule: Informed Consent As per Belmont report, consent must be informed, understood and voluntary 45 CRF 46 Common Rule: Institutional Assurances of Compliance Before a federal grant or contract is awarded –institution must have an “Assurance of Compliance” or Federal-Wide Assurance (FWA) Under terms of the FWA –institution agrees to apply the federal regulations Office for Human Research Protection (OHRP)-oversees Assurances –US institutions as well as international institutions receiving DHHS funds for research 45 CFR 46 Common Rule: Violations of Assurance OHRP has the authority to terminate or suspend an institution’s assurance upon evidence that the institution has failed to comply with the regulations –this means no federally funded research can be conducted until the assurance is re-instated 25 U.S. halts Hopkins research Seven weeks after the death of a young woman in an asthma study, the federal government suspended human medical experiments at the Johns Hopkins University yesterday because of what regulators characterized as widespread lapses in safety procedures. By Jonathan Borand Tom Pelton, The Baltimore Sun July 20, 2001  Could her death have been prevented? Healthy volunteer inhaled hexamethonium bromide in a study in a study of how the lungs of healthy people protect against asthma attacks Investigator did not submit protocol to FDA for review and request for IND Ellen Roche asphyxiated after participating in a clinical trial for a proposed asthma treatment at Johns Hopkins University in 2001. 45 CFR 46 Common Rule OHRP continued OHRP can also temporarily suspend new enrollments into existing protocols OHRP can also sanction individual researchers: Worst case: bar researcher from receiving federal funds to conduct research Require OHRP approval for each study Require remedial training Place other restrictions on the investigator, such as requiring supervision 45 CFR 46: “Vulnerable Populations” Groups that may contain individuals who have limited autonomy, i.e. cannot fully appreciate or freely participate in the informed consent process 45 CFR 46 Subpart B: Pregnant women, human fetuses and neonates Additional burden on IRB to assure extra protections for pregnant women, fetuses and neonates –assures risk is minimized 45 CFR 46 Subpart C –Prisoners Recognizes that prison is a unique situation & prisoners could more easily be subject to coercion Research conducted in a prison setting must be approved by DHHS –prisoners cannot be a convenient population –the research must be applicable to health concerns in the prison setting IRB must not be comprised of a majority of persons affiliated with the prison At least one member must be a prisoner advocate 45 CFR 46 Subpart D –Children Additional burden on the IRB to minimize risk Requirement for parental consent and “Assent” of children Age for assent is left to the IRB –generally aged 7 and older; separate form for adolescents Good Clinical Practice (GCP) “An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects” Goal of GCP is to protect research participants as well as to assure good quality of data so that future patient populations are protected  GCP (in the US) FDA 21 CFR OHRP (DHHS) International Council for Electronic 45 CFR 46 Harmonisation of documents (A) IRBs & Informed Technical Requirements Informed consent for Pharmaceuticals for consent (B) Pregnant Human Use (ICH) Financial Women, fetuses, Disclosure International Guidelines neonates IRBs (C) Prisoners IND & NDA Glossary Principles IRBs (D) Children Biologics Investigator Sponsor (E) Registration of Devices Essential Documents IRBs Department of Health and Human Services  Food and Drug Administration Branch of the Department of Health and Human Services (DHHS) Administers laws concerned with pharmaceutical industry Power to seize offending goods or prosecute responsible persons Office of Human Research Protections (OHRP) Responsible for the conduct of clinical research that is sponsored or conducted by DHHS agencies National Institutes of Health (NIH) Agency of DHHS Composed of 20 institutes and 7 centers National Cancer Institute (NCI) Institute of NIH Funds cooperative clinical trial groups which conduct many large cancer clinical trials  National Cancer Institute (NCI) Composed of divisions involved with the conduct of clinical trials Division of Cancer Treatment and Diagnosis Cancer Therapy Evaluation Program – http://ctep.info.nih.gov Pharmaceutical Management Branch (PMB) Cancer Trials Support Unit (CTSU) – www.ctsu.org Central IRB (CIRB) Clinical Trials Cooperative Group Program State & Local Regulations Regulations that affect conduct of clinical trials is very diverse at the state level Most states do not have specific clinical trial regulations (i.e., MD, VA, CA) General Rule: State laws and regulations MUST be followed if they are stricter than federal regulations International Conference on Harmonization (ICH) Provide a unified standard for the European Union (EU), Japan, and the US to facilitate the mutual acceptance of clinical data by the regulatory authorities of these jurisdictions Developed with consideration of current GCP of the European Union, Japan, and the US, Australia, Canada, the Nordic countries, and the World Health Organization 21 CFR FDA-REGULATED RESEARCH Overview of FDA Regulations Covers most of what is covered in DHHS regs, but far broader in scope: 21 CFR 11: Electronic documents 21 CFR 50: Protection of Human Subjects (informed consent, additional protections for children) 21 CFR 54: Financial Disclosure 21 CFR 56: Institutional Review Boards 21 CFR 312: Investigational New Drug Application 21 CFR 314:New Drug Application (NDA) 21 CFR 600, 601:Biologics 21 CFR 812, 814, 860:Investigational Devices 34 ICH Principles of GCP Trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki & that are consistent with GCP. Before a trial is initiated, foreseeable risks and inconven should be weighed against the anticipated benefit for the subject and society. A trial should be initiated/continued only if benefits justify the risks. Rights, safety and well-being of subjects are most important and should prevail over science and society. Available non-clinical and clinical info on a product should be adequate to support proposed trial. Trials should be scientifically sound, and described in a clear detailed protocol. Trial should be conducted in compliance with protocol that has received IRB approval.  ICH Principles of GCP (cont.) Medical care given to and decisions should always be responsibility of a qualified practitioner. Each individual involved in conducting a trial should be qualified by education, training and experience to perform his/her tasks. Freely given informed consent should be obtained from every subject prior to trial participation. All trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification. Confidentiality of records that could identify subjects should be protected, respecting privacy and confidentiality rules. Investigational products should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP). Systems with procedures that ensure the quality of every aspect of the trial should be implemented. FDA-Regulated Research KEY ASPECTS  FDA:Investigational New Drug (IND) Application Required before human testing of any drug Application includes summary of pre-clinical testing Investigator’s Brochure –summarizes pre-clinical data; updated continually with results of early phase data 36  FDA:Package Insert Drug “Labeling” and indication Prior to granting marketing approval to a new drug, sponsor and FDA agree on language Summarizes what FDA agrees is safe & effective use of the drug Further research use with the drug, when used in accordance with package insert, is exempted from IND regulations (but not IRB review) 37 FDA:IND Filing required post market approval when: New indication Change in the approvedroute of administration or dosage Change in the approved patientpopulation (e.g. children) Significant change in the promotion of an approved drug  FDA Form 1572 or “statement of the investigator” Legal document required of any investigator conducting a trial subject to IND regulations Requires submission of investigator credentials showing capability to conduct the trial (i.e. CV) Lists co-investigators, laboratories, physical location where the trial will be conducted, IRB to be used  Investigator Responsibilities delineated on the FDA 1572 Conduct the study in accordance with the protocol Supervise co-investigators and study staff Abide by FDA regulations in regard to obtaining IRB initial and continuing review and approval and obtaining informed consent Not make changes to the protocol without IRB approval Report adverse experiences to the sponsor 40  FDA:Sponsor Responsibilities “Sponsor” is an individual, company, institution or organization that takes responsibility for the initiation, management and financial of a research study  FDA:Sponsor Responsibilities 1. Select qualified investigators to conduct the trial; provide training and required documents (i.e. Investigator’s Brochure) 2. Monitor the conduct of the study to assure data are accurate and that the trial is conducted in accordance with regulations and guidelines 3. Complete regulatory filings (IND safety reports) 4. Control of study product shipment and disposition Additional Requirements of conducting FDA-Regulated research –site perspective 1. Handling of investigational product maintain drug accountability logs; account for all product received at end of trial Store drug securely, in accordance with manufacturer’s guidelines 2. Maintain adequate source documentation 3. Complete & accurate case report forms 4. Retain all study records for a minimum of two years after FDA approval, or discontinuation Sampling of differences between DHHS and FDA regulations No FDA requirement for Federal Wide Assurance FDA regulations allow for emergency use (no such provision in DHHS regs) Informed Consent –FDA regsrequire that consent form states that FDA is allowed to review records; no such DHHS requirement) DHHS guidelines don’t address monitoring Sampling of differences between DHHS and FDA regulations (cont.) FDA regs require subject to signs and date the consent form ICF and receive copy; DHHS regsrequire subject to sign and receive a copy (no requirement to date the signature) DHHS regs require retention of records for at least 3 yrsafter completion of study; FDA–retain records for 2 yrs after marketing application approved or investigation discontinued Similarities: FDA and DHHS Elements of informed consent are identical International Conference on Harmonization GCP (ICH-GCP) Written in 1995, with periodic updates ICH is an international board that sets standards for the pharmaceutical industry Guidelines developed primarily to respond to the demands of increased globalization and the need to have a unified set of standards so that data from studies done in one country can be used in support of a regulatory application in another Written with consideration of research regulations in EU, US, Japan, Australia, Canada, Nordic countries and the WHO47 ICH-GCP Content Glossary IRB/Independent Ethics Committee –Responsibilities, composition, procedures, records Investigator Responsibilities –care of the trial subject, compliance with the protocol, record keeping SponsorResponsibilities –investigator selection, trial management, investigational product, Adverse drug reaction reporting, monitoring, etc. ICH-GCP Content (cont.) Clinical Trial protocol –outlines essential elements of protocol design, data handling, record keeping, publication Investigator’s Brochure –contents Essential Documents –filed with sponsor and/or investigator –i.e. protocol, signed original consent, investigator’s brochure, etc. ICH GCP vs. US federal regulations CH-GCP –based largely on US regulations 21 CFR –addresses US process for IND/NDA US regulations –have the force of law; ICH-GCP are guidelines Some minor differences: Additional informed consent elements with ICH-GCP “GCP” US regulations vs. ICH GCP can be confusing In reality –IRBs impose one standard for all clinical research and that is “GCP” which encompasses all, where applicable Covers the gaps where US regulations do not have the force of law (non DHHS-funded, non-FDA clinical research) Part 2 Overview: Putting it all together IRB review process Writing an IRB application Informed Consent Essential Documents Source documentation Audits 53 IRB REVIEW PROCESS Re-cap: Definition of Human Subjects Research (45 CFR 46) A “Human Subject” is “a living individual about whom an investigator conducting research obtains: Data through intervention or interaction with the individual Identifiable private information” “Research” is “a systematic investigation designed to develop or contribute to generalizable knowledge” (OR -is the intent to publish?) If the research meets this definition of Human Subjects Research –IRB review is required 55 WRITING AN IRB APPLICATION IRB Application:Protocol Start with a protocol –as an independent document from the application Refer to ICH-GCP guidelines, RBHS IRB website or NIH website for protocol templates IRB Application: Protocol Include: Background: Knowledge to date Rationale –why this study will answer a key gap in the knowledge Objectives/Endpoints Study population Inclusion/Exclusion criteria Research plan –what will be done and when Toxicity management if applicable Statistical analysis Human Subjects protection issues References68 IRB Application: Informed Consent Form –Mandatory Elements Elements of IRB and Consent form covered in Lecture Week 2 of this course Confidentiality Certificate Information about subjects that can be protected with a Certificate of Confidentiality includes: Genetic information Their psychological well-being Their sexual attitudes, preferences or practices Substance abuse or other illegal risk behaviors Their involvement in litigation related to exposures under study (e.g., breast implants, environmental or occupational exposures). Levels of IRB Review Exempt Expedited Full-Board Levels of IRB Review: Exempt Most common category for biomedical research: “Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigators in such a manner that subjects cannot be identified,directly or through identifiers linked to the subjects” Levels of IRB Review: Exempt Review (cont.) Research using commonly used educational tests, educational settings Quality assurance projects Taste tests, customer acceptance studies The investigator does not determine whether the study is exempt –the IRB does. 58 Levels of IRB Review: Expedited Review Research must entail “Minimal Risk”: “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.” 45 CRF 46 59 Categories of Minimal Risk Research eligible for Expedited review Blood collection so long as less than 550 ml is collected over an 8 week period in a healthy adult Prospective collection of biological samples obtained by non- invasive means: sputum, saliva, nail clippings, etc. Collection of data obtained through non-invasive means if used routinely in a clinic setting (other than x-ray or microwave) –such as ultrasound, weight, EEG Categories of Minimal Risk Research eligible for Expedited review (cont.) Research involving materials (data, documents, records, or specimens) that have collected or will be collected, solely for non- research purposes Continuing review of research previously approved by the convened IRB if the study is closed to enrollment; subjects are in follow up only; or the remaining research activities are limited to data analysis Expedited Review May NOT be allowed if identification of the subjects would place him/her at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, insurability, reputation, or be stigmatizing Expedited Review –does not mean that consent is not required Expedited Review does not mean “fast” –the procedure involves a subcommittee and not the full-board Waiver of consent Separate part of IRB application –will need to demonstrate that: The Protected Health Information (PHI) collected is necessary for the study No PHI will be removed from Rutgers premises Risks are minimized; a plan is in place to protect the identity of subjects The research cannot be practicably conducted without the waiver of consent Exempt and Expedited Review considerations IRB reviewer will focus on privacy protections Security of data Retrospective chart reviews: will need to specify period of time. All data must be “on the shelf” at the time the IRB application is written. Levels of IRB Review: Full-Board Review Required for research involving “greater than minimal risk” or research that otherwise does not meet the criteria for exempt or expedited Possible outcomes of IRB Review Approved Approved with stipulations Re-review by IRB chair or designee Re-review by subcommittee Tabled (Re-review by full-board) Disapproved (can only be disapproved by full-board) 76  Review Criteria Subject Selection Justice Safeguards for Vulnerable Populations Fed regs for the protection of human subjects (45 CFR 46) provide additional protections for the use of pregnant women (Subpart B), prisoners (Subpart C), and children (Subpart D). Points to Consider Number of subjects Subject Populations Eligibility Criteria Components Evidence of a specific cancer Level of overall health Age limit / life expectancy Major organ system function Prior medical history Eligibility Criteria Components Prior treatments for cancer Baseline disease state Concomitant illness/medications Protection for offspring of patients of childbearing age Study compliance Strategies for Recruitment Plan Development ICH 4.2 states that the investigator should “be able to demonstrate a potential for recruiting the required number of suitable subjects” Stages develop a plan development of a referral base estimate the rate of enrollment Informed Consent Review Informed Consent Review Element of an Informed Consent Foreseeable risks Purpose of research Benefits of the research Disclosure of alternative procedures Confidentiality of patient and records Compensation, if any exists Who to contact with questions Statement that participation is voluntary Investigator’s Brochure Clinical and nonclinical data on the investigational product relevant to the study Physical, chemical, & pharmaceutical properties & formulation Pharmacokinetics, product metabolism, & toxicology in animals Effects in humans Safety and efficacy Marketing experience Investigational New Drug (IND) Applications New drug - limited by federal law to investigational use Application process which takes a minimum of 30 days Application must indicate results of previous experiments IND Submissions Required forms for IND submission located on the FDA CDER website at www.fda.gov/opacom/morechoices/fdaforms/cder.html Forms required include: 1572 – Statement of Investigator 1571 3455 – Disclosure: Financial Interest and Arrangements for Clinical Investigator Does this Study Need an IND?  To Provide Initial Approval: Risks to subjects are minimized Risks to subjects are reasonable in relation to anticipated benefits Selection of subjects is equitable Informed consent will be sought from each prospective subject or the subject's legally authorized representative Informed consent will be appropriately documented When appropriate, the research plan makes adequate provisions for monitoring data collection to ensure the safety of subjects When appropriate there are adequate provisions to protect the privacy of subjects and the confidentiality of data When some or all of the subjects are likely to be vulnerable to coercion or undue influence such as children or people with mental disabilities, additional safeguards have been included in the study to protect the rights and welfare of these subjects Continuation or Annual Review The number of subjects enrolled Summary of patient reaction and experiences Withdrawals from study and why Any results concluded at the time of the review Current risk-benefit ratio Any new information that IRB should be made aware of in accordance with the conduct of the study  Protocol Revisions & Modifications Vary Administrative Changing the pagination, telephone number changes Therapeutic Dosing changes Statistical analysis changes Revisions should not be implemented until IRB approval unless patients safety is affected Full board or Expedited review Protocol Deviations Departure from the protocol Major deviation protocol variance that results in questionable data Minor deviation protocol variance that does not affect the outcome or interpretation of the study Major Deviations Failure to meet all eligibility criteria Use of old or expired informed consent Failure to assess disease response according to protocol Failure to modify doses according to protocol Failure to report SAEs Adverse Event Reporting: NCI Cancer Therapy Evaluation Program Definition: “any unforeseeable and unintended sign (including abnormal lab values) symptom of disease temporally associated with the use of a medical treatment or procedure regardless of whether it is considered related to the medical treatment or procedure” In Other Words: An adverse event may be described as any deterioration in health status associated with the use of a drug, whether or not considered drug related by the investigator. An adverse drug reaction is considered to be any response to a drug which is noxious, unintended, and which occurs at doses used in man for prophylaxis, diagnosis and treatment. Adverse Events Can Be: A symptom A finding during a physical exam A syndrome or disease An abnormal lab value An overdose A significant failure of expected pharmacological action Unexpected Adverse Events: Any adverse drug experience which is not consistent with the risk information described in the sponsor protocol or investigator brochure. Serious Adverse Events A serious adverse event is defined as any adverse drug experience occurring at any dose that results in any of the following outcomes: death a life threatening adverse drug experience an inpatient hospitalization or prolongation of an existing hospitalization a congenital anomaly/birth defect Serious Adverse Events (cont’d) A persistent or significant disability/incapacity Important medical events that may not result in one of the above descriptions may be considered a serious adverse drug experience when they jeopardize the patient or subject and may require intervention to prevent one of the outcomes listed in this definition. Assessment of AE includes: Grade Was the event anticipated? Attribution or association to the protocol therapy Unrelated, unlikely, possible, probable, or definite Reporting an Adverse Event Reaction Types of reactions Acute - within hours Subacute - days after Delayed - weeks after Chronic - months or years after What is included in the report? What was done? Why was it done? When was it done? Timing of treatment? How was it done? What was the outcome? Who did it? Provide and supporting documentation Toxicity Grading Common Toxicity Criteria Known vs. unknown reactions Phase of study Is the event related to the drug and is it investigational? CTC Grading Example: Stomatitis Grade 0 None Grade 1 Painless ulcers, erythema, or mild soreness in the absence of lesions Grade 2 Painful erythema, edema, or ulcers but can eat Grade 3 Painful erythema, edema, or ulcers requiring IV hydration Grade 4 Severe ulceration or requires parenteral or enteral nutritional support or prophylactic intubation SAE Reporting Refer to protocol Expected vs. Unexpected event Attribution to investigational agent Telephone notification within 24 hours sponsored protocols Initial report within 10 days www.fda.gov/medwatch SAE Reporting Follow-up report as additional information obtained MedWatch form to sponsor to FDA Sponsor form AdEERS Adverse Drug Event Expedited Reporting System computerized CTEP form When do you report an Adverse Event? If and adverse reaction or adverse event occurs within 30 days of last dose of drug, you must report it. Failing to report the event can result in discontinuation of the study and suspension of the investigator’s privilege to do clinical research. Data Monitoring Safety Board DSMB Review of interim data Implications regarding safety, early termination, greater treatment efficacy Objectives Ensure that risks are minimized as much as possible Ensure the integrity of data Stop trial if safety concerns arise or if trial objectives are met ESSENTIAL DOCUMENTS 77 Regulatory documentation required for conducting clinical trials CV’s or Curriculum Vitaes for all pertinent staff 1572’s 1571’s Financial Disclosures Investigator Brochure Signed Protocol and Amendments Regulatory Documentation (cont’d) Insurance Statement from Sponsor Contract to document the financial agreement between investigator/institution and sponsor Normal lab values Lab certification/accreditation (CLIA/CAPA) ALL IRB correspondence Essential Document Keeping: Part of Investigators obligations according to regulations and GCP Protocol (all versions) All original signed informed consents (including those for subjects who failed screening) Copy of fully-executed contract with budget IRB approvals (initial, continuing review, modification requests, and IRB correspondence) 78 Essential Documents (cont.) Investigator’s Brochure or product insert and any updates Laboratory certifications Screening logs Enrollment logs Delegation of authority log Source documents Case Report forms Essential Documents: Source Documents Defined as the FIRST place that data is recorded Necessary for re-construction of trial data Generally separate from case report forms Examples: Chart notes, History and Physical, Vital Signs Medication records EKG, diagnostic testing Laboratory test results Essential Documents:Source Documents (cont.) All research procedures must be documented (e.g. administration of questionnaires, blood sampling, medication adherence, etc.) Address adverse events, study drug toxicities as required by protocol Source documents must be signed and dated by the person making the assessment No white out or obliterations Initial/date any corrections to show audit trail Essential Documents: Informed consent documentation considerations Document process in research or medical record Be able to prove that consent was obtained prior to any research procedures being conducted Subject must get a copy Re-consent is often required through the course of a clinical trial – must be done at the next study visit & documented Watch to be certain the subject signs their full name and personally dates the correct date All required places are signed or initialed and dated as the form requires Make sure all pages are present Only the current IRB-approved ICF can be used Essential Documents:Case Report Forms Tools to enter the data required by the protocol into the database All data entered onto a CRF must be substantiated by source documentation Retention of Records ALL study records must be retained after the study is completed ICH GCP, OHRP and FDA have varying requirements Check with sponsor prior to destroying any study records Shipment of Research Specimens Subject to federal regulations Hazardous materials 2005 International Air Transport Association (IATA) provides guidance on dangerous goods regulations All study staff responsible for shipping specimens MUST receive IATA training AUDITS Routine Audits Required as per GCP for sponsored trials Generally conducted by a contract research organization under contract with sponsor IRB or other institutional entity may also audit Focus: Is the PI following GCP and conducting the study as per the protocol Will review: Informed consent forms Source documents to compare to CRFs Essential documents IRB correspondence and approvals –to assure all necessary items have been reported to IRB Pharmacy records FDA Audits Can be routine or for-cause Will review same materials as in routine monitoring, but they can also look at other studies conducted at the site Focus: IRB review/approval Whether subjects met inclusion/exclusion criteria Was the protocol followed Were Adverse Events reported 86 Common FDA findings Informed consent problems (60%) Failure to adhere to protocol, including subjects who fail to meet protocol eligibility criteria Missing subject records Over-delegation of study tasks to non-physicians Top 5 Clinical Trial Site FDA Inspection Failures 1. Failure to Follow Investigational Plan (51%) This failure is marked by the code 21 CFR 312.60. It makes up the vast majority of failures at a total of 51% of the failure data from the past five years. These failures include missing consent documents, failure to perform protocol-required procedures, and/or missing documentation of required IRB review of study changes. 2: Inadequate and Inaccurate Records (33%) While part of the investigational plan, this 21 CFR 312.62 failure focuses specifically on record keeping – making up 33% of failures. An example of this failure is a missing or incomplete subject record. 3: Inadequate Drug Accountability (7%) This failure is categorized as 21 CFR 312.62 as well. At 7% of failures, it deals specifically with the record keeping of drugs used in research. A failure of this nature includes absence or inadequacy of records on receipts, preparation, use, and/or disposition of the investigational drug/product 4: Failure to Obtain and/or Document Subject Consent (5%) This 21 CFR 312.62 problem is the fourth most common at 5%, but it deals with the very important clinical trial aspect of subject consent. Obtaining subject consent is extremely important for a multitude of reasons, and keeping consent documentation readily available can help avoid this failure. An example of this aspect of 21 CFR 312.62 is missing consent documents or omission of a description of required elements when obtaining consent. 5: Inadequate Informed Consent Form (4%) Making up the last 4% of recent failures, this 21 CFR 50.25 failure proves that consent-related documentation causes frequent audit failures. We have discussed consent-related failures, but this failure deals more specifically with communication about withdrawal and refusal to participate. Examples include missing documentation showing subject receival of information about their right to refuse to participate in any aspect of the study and missing documentation that shows that subjects were informed of their right to withdraw without penalty Research Misconduct Key Concepts of the “Final Rule” Misconduct in science is defined as fabrication, falsification, or other practices that seriously deviate from those that are commonly accepted within the scientific community for proposing, conducting, or reporting research. It does not include the honest error or honest differences in interpretation or judgments of data SUMMARY Investigator assumes responsibility for the conduct of the study when FDA Form 1572 signed Study personnel have obligation to know the current regulatory and compliance standards Federal government has number of systems in place to ensure safety/wellbeing of participants State governments/local healthcare institutions have developed measures to guide the conduct of clinical trials. Learn and stay FOCUSED on the BASICS of GCP: SIMPLE concepts drive decision-making when implementing clinical trials: any time, every time subject welfare data validity control of investigational product T. Winchell SoCRA SOURCE, Feb. 2006