Module 4

History of Good Clinical Practice Regulations Barbara Novak

US Food and Drug Law Chronology 1848 Congress banned importation of adulterated drugs after a bad batch of quinine was imported for U.S. Army. (Did not affect domestic issues of adulteration) 1879 Congress began investigating incidents involving contamination of food and drugs through the USDA BAN/CDR

US Food and Drug Law Chronology 1902 Biologics Control Act Required licensing of serums and vaccines 1906 Pure Food and Drug Act Congress began investigating incidents involving contamination of food and drugs through the USDA BAN/CDR

1906 Pure Food and Drugs Act AKA Wiley or Heyburn Act Dr. Wiley’s lunch crew Upton Sinclair’s The Jungle Prohibited interstate transportation of adulterated and misbranded foods and drugs BAN/CDR

US Food and Drug Law Chronology 1912 Sherley Amendment Prohibited false and fraudulent curative claims or therapeutic claims on labels (snake venom, elixirs, wonder cures) 1938 Food, Drug and Cosmetic Act Added cosmetics to the 1906 Act BAN/CDR

1938 Food, Drug and Cosmetic Act Elixir of Sulfanilamide - 1937 Required pre-market approval of new drugs for safety Sulfanilamide, a new liquid dosage form of a leading anti-infective drug was mixed w/the diethylene glycol (antifreeze) as a delivery vehicle, resulting in death of about 106 children. Congress passed the 1938 act to mandate premarket review of new drugs for safety, giving the FDA authority to inspect drug manufacturing plants and strengthening the enforcement powers of the FDA BAN/CDR

Food, Drug and Cosmetic Act Authorizes FDA to inspect at reasonable times Authorizes FDA to promulgate and enforce regulations BAN/CDR

US Food and Drug Law Chronology 1962 Kefauver Act Amendments to the 1938 ACT that set up a mandatory reporting system for drug safety Led to the Spontaneous Reporting System which catalogues ADR reports for marketed drugs BAN/CDR

1962 Kafauver Act Thalidomide tragedy BAN/CDR Thalidomide was a widely used sedative available w/o Rx in Europe. It was found to cause limb deformations in infacts born to women who used the drug during pregnancy. In the USA, a delayed review process prevented the drug from being marketed before this toxicity was identified. The Food, Drug and Cosmetic Act was then amended, requirieng drug companies to demonstrate the efficacy AND SAFETY of a drug in adequate and controlled studies before marketing. BAN/CDR

1987 IND Rewrite 21 CFR Part 312 Introduced Laid out the responsibilities of sponsors, monitors and investigators BAN/CDR

Prescription Drug User Fee Act (PDUFA) 1992 & 1997 FY2001 Fees Application fee - $309,647 Establishment Fee - $145,987 Annual product fee - $21,892 FY 2005 Fees Application fee - $672,000/ 336,00 (SNDA) Establishment Fee - $262,000 Annual product fee - $41,710 BAN/CDR

Good Clinical Practices (GCPs) Phrase coined by industry Includes Regulations, Guidelines and Industry practices which address responsibilities of: the Sponsor the Investigator Institutional Review Boards and requirement for Informed Consent. BAN/CDR

Regulations vs Guidelines Regulations = LAW Guideline = Clarification BAN/CDR

Purpose of GCP’s To protect the rights and safety of subjects To assure the quality and integrity of the clinical research data BAN/CDR

GCP Regulations 21 CFR Part 312 – IND Regulations 21 CFR Part 312.50 to 312.59 Sponsor/monitor responsibilities 21 CFR Part 312.60 to 312.69 Investigator responsibilities 21 CFR Part 50 Informed consent regulations BAN/CDR

GCP Regulations 21 CFR Part 56 - IRB regulations 21 CFR Part 11 – Electronic signatures 21 CFR Part 54 – Financial disclosure BAN/CDR

GCP Guidelines FDA Information Sheets Guidelines for Monitoring, Investigators, etc ICH GCP Guideline BAN/CDR

FDA Organization FDA is 1 agency within the Dept. of Health and Human Services (HHS) Reports to Secretary of HHS Funding is through the HHS budget (FDA has a separate budget) Small agency – frequent visit to Capitol Hill BAN/CDR

FDA FDA is comprised of 8 Centers/Offices CDER – Center for Drug Evaluation and Research (most therapeutic biologics recently transferred to CDER) CBER- Center for Biologics Evaluation and Research) CDRH – Center for Devices and Radiological Health Remaining in CBER: cellular products (incl products composed of human, bacterial or animal cells or parts of cells vaccines allergenic extracts used for the diagnosis and treatment ofallergic diseases antitoxins, venoms blood, blood components, plasma derived products, blood substitutes, human or animal polyclonal antibody preparations and some fibrinolytics. There is some overlap between CDER and CBER- BAN/CDR

FDA CFSAN – Center for Food Safety and Applied Nutrition CVM – Center for Veterinary Medicine NCTR – Nat’l Center for Toxicological Research OC - Office of Commissioner (head of FDA) ORA – Office of Regulatory Affairs BAN/CDR

Office of Medical Policy Reports to CDER Director Division of Scientific Investigations Select sites for inspection Assist on inspections Review inspection reports Final classification of reports/regulatory action BAN/CDR

Office of Regulatory Affairs (ORA) Associate Commissioner for Regulatory Affairs Office of Resource Management Office of Regional Operations Office of Enforcement Office of Criminal Investigations BAN/CDR

Field Set-Up Report to Office of Regional Operations 5 Regions Northeast Region Regional office in New England & NY District offices in NE, NYC, Buffalo Central Region Regional office in Phila, Baltimore & Chicago District offices in Philadelphia, Baltimore, Chicago, NJ, Cincinnati, Detroit, Minneapolis BAN/CDR

Field Set-Up Southeast Region Southwest Region Regional office in Atlanta District offices in Atlanta, New Orleans, Florida, San Juan Southwest Region Regional office in Dallas, Denver, KC District offices in Dallas, Denver, Kansas City, and a Southwest Import District BAN/CDR

Field Set-Up Pacific Region Regional office in San Francisco & Seattle District offices in Los Angeles, San Francisco & Seattle BAN/CDR

Submissions Drugs IND: Investigational New Drug Application NDA: New Drug Application Biologics BB-IND: Biologics Investigational Drug Application BLA: Biologics License Application BAN/CDR

FDA Website www.fda.gov Each center is represented Can access guidelines, regulations, speeches Warning letters are posted, and investigator disqualifications BAN/CDR

Module 9

International Conference on Harmonization (ICH) US, EU, Japan Industry, trade organizations and regulatory representatives 5 step process, with Step 5 being FINALIZATION of the individual guideline i.e., acceptance of the guideline by each country BAN/CDR

Purpose of ICH Harmonize standards Improve quality and reliability of data Protect rights & welfare of subjects Minimize human new drug exposure Speed up marketing of new drugs Decrease cost BAN/CDR

ICH GCP Guideline Published as guideline in US Includes requirements for Sponsors Investigators IRB/IEC Informed consent Essential documents BAN/CDR

ICH GCP Guideline Similar to FDA regulations FDA very involved in ICH process More detailed in most places BAN/CDR

FDA Bioresearch Monitoring Program Kefauver Harris amendments Field survey 1972 – 1974 Sponsors, Investigators, Contract research Organizations (CROs), IRBs, Toxicology Laboratories Drugs, Devices, Biologics, Foods, Veterinary Medicine BAN/CDR

Why GCPs? Mandated by regulatory authorities History indicates need Uniform way of conducting research Drug/biologic/device development is expensive – DO IT RIGHT THE FIRST TIME BAN/CDR

Office for Good Clinical Practice (OGCP) Within the Office of the Commissioner Agency-side coordinating functions Work with OHRP Improve conduct and oversight of clinical research Ensure protection of participants in FDA-regulated clinical research BAN/CDR

Responsibilities Promote protection of human research participants Support quality and integrity of clinical trials and applications Support global harmonization and implementation of GCP standards BAN/CDR

HHS OHRP – Office of Human Research Protections More inspections of IRBs Required training for sites Loss of funding BAN/CDR

Module 8

Obligations of Sponsors 21CFR 312.50 to 312.59 DEFINITION Sponsor: An individual, company, institution or organization that takes responsibility for and initiates (and/or finances per ICH) a clinical investigation BAN/CDR

Obligations of Sponsors 21CFR 312.50 to 312.59 KEY POINTS: Select and Update Investigators Study Monitoring Recordkeeping Drug Distribution Maintain the Regulatory Submissions BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 SPECIFIC OBLIGATIONS: Sponsor commits to: Obtain a signed FDA form 1572 and Curriculum Vitae from each investigator Ensure investigator understands his/her obligations per the regulations Provide investigator with a current Investigator Brochure BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 SPECIFIC OBLIGATIONS: Sponsor commits to: Obtain sufficient, accurate financial information to submit the required certification or disclosure statements, and obtain commitment from investigator to update this information if relevant changes occur BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 Continued... Keep investigator informed of new observations discovered or reported, particularly with respect to adverse effects and safety Monitor study by on-site visits BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 Continued... Ensure that investigator and staff are following approved protocol and ensure that case report forms are being adequately completed Assure that qualified IRB will be involved Assure investigator will inform IRB of any protocol changes except to eliminate an immediate hazard to subjects BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 Continued... Evaluate evidence relating to safety and efficacy as it is received from the investigator Discontinue study if it is determined that the study drug presents an unreasonable and significant risk to subjects. Notify FDA, all IRBs and all investigators of a discontinuation for such reasons BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 Continued... Submit to FDA annual progress reports, updated Investigator Brochure, and IND safety reports as required Maintain records showing any financial payments to clinical investigators Maintain records of drug shipment, receipt, and disposition, including date, quantity, and batch BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 Continued... Assure the return or disposition of unused supplies Retain all records for 2 years after NDA is approved or study is discontinued Allow for FDA inspections of records and reports of clinical investigations BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 Continued... Discontinue drug shipment or secure compliance from any investigator who has not maintained or made available his/her records to FDA for inspection Assure compliance with storage and record-keeping requirements BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 Continued... Notify FDA and all participating investigators of any serious and unexpected adverse experience associated with the use of the study drug BAN/CDR

Obligations Of Sponsors 21CFR 312.50 to 312.59 Continued... Notify FDA and all participating investigators of any preclinical findings that suggest a significant risk for human subjects (e.g., mutagenicity, teratogenicity, or carcinogenicity findings) BAN/CDR

Obligations Of Clinical Investigators DEFINITION Investigator: An individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispense to a subject). If conducted by a team, the inv. is the responsible leader of the team. ICH: A person responsible for the conduct of the clinical trial at a site 21CFR 312.60 to 312.70 BAN/CDR

Obligations Of Clinical Investigators REGULATION: 21CFR 312.60 to 312.70 KEY POINTS: Conduct Clinical Study Protection of Patients Control of Drug Compliance with IRB requirements Recordkeeping Reporting BAN/CDR

Obligations Of Clinical Investigators Specific Obligations: The Investigator commits to: Personally conduct or supervise the described investigation Provide a list of the names of subinvestigators who will be assisting in the conduct of the investigation BAN/CDR

Obligations Of Clinical Investigators Continued… Ensure that all associates, colleagues, and employees assisting in the conduct of the study are informed about their study obligations. Such associates, colleagues, and employees must be listed on the FDA form 1572 BAN/CDR

Obligations Of Clinical Investigators Continued… Assure that study is conducted in accordance with the protocol, and only make changes after notifying the sponsor Obtain informed consent from all patients prior to their participation in the study BAN/CDR

Obligations Of Clinical Investigators Continued… Prepare and maintain adequate and accurate case histories that record all observations relevant to the study. Case histories include study CRFs, informed consent forms, and medical records including progress notes, hospital charts, nurses notes, and lab records BAN/CDR

Obligations Of Clinical Investigators Continued… Promptly report to the sponsor all adverse effects that may reasonably be suspected to have been caused by the study drug. If the adverse effect is serious and unexpected, it should be reported to the sponsor immediately BAN/CDR

Obligations Of Clinical Investigators Continued… Assure that study drug is administered only to subjects under the investigator’s personal supervision or the supervision of a subinvestigator in his/her study Return or otherwise dispose of all unused study medication in accordance with the sponsor’s instructions BAN/CDR

Obligations Of Clinical Investigators Continued… Maintain accurate and adequate records of drug disposition and drug accountability Assure that an IRB that complies with the IRB regulations will be responsible for the initial and continuing review and approval of the proposed protocol BAN/CDR

Obligations Of Clinical Investigators Continued… Assure that the study informed consent form is approved by an IRB prior to initiation of the study Assure that all changes in the protocol are reported to an IRB, and assure that no changes will be made to the protocol without prior IRB approval, except where necessary to eliminate apparent, immediate hazards to human subjects BAN/CDR

Obligations Of Clinical Investigators Continued… Submit annual progress reports to an IRB Submit progress reports of study findings to the sponsor Provide sponsor with a final study report shortly after completion of participation in the clinical investigation BAN/CDR

Obligations Of Clinical Investigators Continued… Maintain study records for 2 years after NDA approval or 2 years after discontinuation of study Provide sponsor with sufficient, accurate financial information to submit the required certification or disclosure statements, and obtain commitment from investigator to update this information if relevant changes occur BAN/CDR

Obligations Of Clinical Investigators Continued… Permit access to, including copying of study records and reports by FDA, sponsor, or sponsor-designated individual(s) BAN/CDR

Obligations Of Clinical Investigators Laboratory Records Form 1572 lists laboratory and its location Lab accreditation stored with investigator Lab normals retained Label lab samples with patient ID, study number and date BAN/CDR

Module 6

Obligations of IRBs DEFINITION: Institutional Review Board (IRB): any board, committee or group formally designated by an institution to review, approve and conduct periodic review of biomedical research involving human subjects. ICH definition: An independent body constituted of medical, scientific and nonscientific members whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial. Information on composition, functions, and operations of IRB can be found in CFR 56, Subpart B, Section 56.107 BAN/CDR

Obligations of IRBs REGULATION: 21CFR 56 Purpose: Protect the rights and welfare of research subjects both before and during their study participation Determine: Should the study be approved (do benefits outweigh the risks)? What constitutes adequate informed consent? Information on composition, functions, and operations of IRB can be found in CFR 56, Subpart B, Section 56.107 BAN/CDR

IRB Membership & Organization At least five members with appropriate qualifications to review the research At least one member whose primary area of interest is in a nonscientific area At least one member who is independent of the institution/trial site Should not consist entirely of men or women A list of IRB members should be maintained Information on composition, functions, and operations of IRB can be found in 21CFR 56, Subpart B, Section 56.107 Members must have diverse backgrounds to consider scientific, medical, legal and ethical implications, and should have knowledge of the community in which the research is being done (especially for vulnerable populations). BAN/CDR

IRB Functions Reviews protocols, consents, and ads Reviews amendments Provides expedited review—i.e. minor changes to a protocol that don’t increase risk Provides continuing review of trials (at least annually) Reviews qualifications of investigators Has the authority to suspend research Reviews all adverse drug reactions both serious and unexpected Additional information on IRBs can be found in CFR 56, Subpart B, Section 56.107 BAN/CDR

IRB Records Copies of research proposals/protocol (and accompanying documentation) Minutes of meetings Correspondence List of members Written operating procedures (SOPs) for IRB Kept for 3 years after completion of research Copies of research proposals/protocol (and accompanying documentation) Including Investigator Brochure, Informed Consent Information provided to subjects, including advertisements, significant new findings Minutes of meetings including record of votes Correspondence Approval letter to Investigator/ Annual progress reports or Safety Reports from Inv Significant new findings provided to subjects List of members with current CVs documenting qualifications for IRB membership With annual changes BAN/CDR

IRB: Expedited Review An IRB may use an expedited review procedure to review minor changes in previously approved research during the period (1 year) for which the approval is authorized Expedited review may be carried out by the IRB Chairperson or by one or more experienced reviewers designated by the IRB Chairperson from among the members of the IRB BAN/CDR

IRB: Expedited Review Procedures IRB’s which use expedited review must have a method of keeping all IRB members informed of research proposals which have been approved under this procedure FDA may restrict, suspend, or terminate an IRB’s use of expedited review when necessary to protect the rights of subjects BAN/CDR

Module 5

Informed Consents (IC) IC overview IC audit checklist Class examples of IC showing required elements FDA Warning Letters from IC Handout example of industry IC BAN/CDR

Informed Consent Purpose: Patient protection Patient information REGULATION: 21CFR 50 Purpose: Patient protection Patient information BAN/CDR

Informed Consent Process Exchange of meaningful information Begins with subject first learns of the study Ends when there is no more new relevant information Prior to the performance of study procedures IC is a process whereby a subject foluntarily confirms his or her willingness to participate in a trial after having been informed of all aspects of the trial that are relevant to the decision. Subject must also have enough time to consider the information and ask questions before committing to participate. BAN/CDR

Informed Consent Content Required Elements Additional Elements, as applicable Institution, local, state requirements Language understandable to subject Provide information subject needs to make an informed decision about participation BAN/CDR

Informed Consent Required Elements of Informed Consent: 21CFR 50.25 Purpose, duration and procedures of the research Foreseeable Risks to subject and benefits to subject or others Alternative procedures or courses of treatment Confidentiality of records – must note the possibility of FDA inspection or others BAN/CDR

Informed Consent Required Elements of Informed Consent: Explanation of compensation, if any, for research-related injury Contacts for pertinent questions or reports of research related injuries Statement of voluntary participation -No penalty or loss of benefit upon refusal to participate or withdrawal of consent BAN/CDR

Informed Consent Additional Elements of Informed Consent where applicable (required by ICH): May involve unforeseeable risks to subject (embryo/fetus) Circumstances in which the study may be terminated without subject’s consent Any additional costs to subject from participation BAN/CDR

Informed Consent Additional Elements of Informed Consent where applicable (required by ICH ): Consequences of early withdrawal Significant new findings during study Approximate number of subjects in study BAN/CDR

Informed Consent Problems 50% of FDA inspections at clinical investigator sites identify inadequacies in the informed consent Lack of required elements Lack of proper documentation Not obtained prior to enrollment Improper IRB approval BAN/CDR

HIPAA Health Insurance Portability and Accountability Act (HIPAA) -Enacted in 1996 to protect the security and confidentiality of electronic health information. -Primarily directed at the health care industry, insurers and medical providers. -Original deadline for privacy rule by Congress missed in 1999- finally published in Dec. 2000 , with a compliance date of April 14, 2003. BAN/CDR

HIPAA Law applies to “Covered Entities and Business Associates” that use or disclose protected health information. Requires the “de-identification” of individually identifiable health information, and disclosure of uses of protected health information (PHI). Although no FDA regulation specifically addresses HIPAA, clinical research certainly deals with PHI. BAN/CDR

HIPAA Clinical research now includes HIPAA authorization –either in the IC directly or in a separate document, depending on institutional or IRB policy. must specifically give permission to use PHI for the purpose of research have the right to withdraw permission to use PHI expiration date of the authorization - suspension of access rights to study records until study is completed. Subject initials on CRF may become a thing of the past-since DOB with initials and gender and medical history may conceivably allow identification of subject. BAN/CDR

Issues Noted in Recent Warning Letters and FDA 483’s Informed Consent Study procedures performed prior to signing and dating the IC Failure to obtain appropriate IC (e.g., no signature, incorrect signature/date, not in a language understandable to the subject) Not current/correct version of IC Elements missing from the IC BAN/CDR

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