Good Clinical Practice GCP Key Topics Bridget Foltz

Good Clinical Practice (GCP) Key Topics Bridget Foltz, M. S. , MT(ASCP) Health Scientist Policy Analyst Office of Good Clinical Practice

Topics Good Clinical Practice Overview Investigator Responsibilities Clinical Investigator Financial Disclosure Expanded Access to/Charging for Investigational Products • Resources • • 2

What is Good Clinical Practice (GCP)? • An international standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials. * • Includes freely given informed consent and review/approval by an institutional review board. *ICH E 6 Good Clinical Practice: Consolidated Guidance: http: //www. fda. gov/downloads/Drugs/Guidance. Compliance. Regulatory. Information/Guid ances/UCM 073122. pdf 3

Why is GCP important? • GCP compliance provides public assurance that the rights, safety and wellbeing of human subjects involved in research are protected • Promotes data integrity and reliability Responsibility for GCP is shared by all parties involved in a clinical trial including: sponsors, investigators and site staff, contract research organizations (CROs), institutional review boards (IRBs), FDA, research subjects, etc. 4

What Are the Goals of GCP? • To protect the rights, safety, and welfare of subjects participating in research • To assure the quality, reliability, and integrity of data collected • To provide standards and guidelines for the conduct of clinical research Good Clinical Practice = Ethics + Quality Data 5

How does FDA implement GCP? • • • 21 CFR 11 – Electronic Records & Signatures 21 CFR 50 – Protection of Human Subjects 21 CFR 54 – Financial Disclosure 21 CFR 56 – Institutional Review Boards 21 CFR 312 – Investigational New Drug Applications 21 CFR 812 – Investigational Device Exemptions 6

Investigator Responsibilities • Clinical Investigator (CI) responsible for the conduct of the study at the clinical trial site • Lack of appropriate study oversight by the CI is a common noncompliance cited during a bioresearch monitoring (BIMO) inspection 7

Investigator Responsibilities • FDA Final Guidance – October 2009 • Guidance covers: – Appropriate delegation of study subjects – Appropriate training of study staff – Supervision of staff, including contracted personnel – Subject protections, including necessary medical care 8

Investigator Responsibilities • Appropriate Delegation of Study Tasks: – Individual delegated a study task must be qualified by education, training and experience (and state licensure, where relevant) – Individuals delegated must also meet any protocol specified requirements – Listing of tasks and individuals delegated should be maintained 9

Investigator Responsibilities • Appropriate Training of Study Staff: – Familiarity with protocol and specific tasks – Knowledge of applicable regulations and human subject protection (HSP) and GCP principles – Individuals competent or trained to cover tasks assigned – Updates and additional training provided, as needed 10

Investigator Responsibilities • Supervision of staff, including contracted personnel – Level of supervision should be appropriate to the staff, the nature of the trial, and the subject population – A supervisory plan should include routine meetings with study staff and procedures for determining appropriate completion of delegated tasks – Oversight extends to SMO staff, CI-contracted providers (radiologists, labs), medical engineers, etc. 11

Investigator Responsibilities • Subject protections, including necessary medical care – Reasonable medical care for study-related medical problems – Provision of access to appropriate medical care when specialized care is required – Adherence to the study protocol 12

Clinical Investigator Financial Disclosure 21 CFR 54 • Final regulation issued in 1998 • Investigators and subinvestigators (those who play a significant role in the conduct of the study) are required to report disclosable financial interests – Includes spouse and dependent children • Requires reporting to the study sponsor prior to participation in the study and updates yearly, as needed, until after study completion 13

Clinical Investigator Financial Disclosure 21 CFR 54. 4(b) • Must provide “sufficient accurate financial information to allow the sponsor to submit complete and accurate certification of disclosure statements. . . ” • Must “promptly” update the information if relevant changes occur during the study or 1 year after study completion • Includes investigators and subinvestigators and any spouses and dependent children 14

Clinical Investigator Financial Disclosure 21 CFR 54. 4 • Requires applicant of a marketing application/permit to: – Certify no financial arrangements with each investigator Or – Disclose specific financial arrangements with study investigators and what was done to minimize bias 15

Clinical Investigator Financial Disclosure 21 CFR 54. 4(a)(3) Disclosable Arrangements: 1. Compensation where the value could be affected by the study outcome (e. g. , royalties) 2. Significant Payments of Other Sorts (SPOOS) – i. e. , not including the payments for conducting the study – to either the investigator or the institution (e. g. , grants, equipment, retainers for on-going consultation, honoraria) 16

Clinical Investigator Financial Disclosure 21 CFR 54. 4(a)(3) Disclosable Arrangements (cont. ): 3. Proprietary interest in the product, such as a patent, trademark, copyright, or licensing agreement 4. Equity interest in a publicly traded company whose value >$50, 000 or Equity interest such as ownership interest or stock options whose value cannot be readily determined through reference to public prices 17

Clinical Investigator Financial Disclosure • Final Guidance issued February 2013 • Guidance covers: – Disclosure requirements – Responsibilities of various parties – Further explanation of terms used financial disclosure regulations – How FDA will review financial disclosure information • FDA’s policy to publicly post FDA reviews summarizing financial disclosure information relating to an approved marketing application 18

Expanded Access – Investigational Products • Long history of providing access outside of study participation – Emergency Use – Treatment INDs/IDEs • Food, Drug and Cosmetic Act (FD&C Act) provides for access to investigational products for diagnosis, monitoring or treatment of a serious disease or condition 19

Expanded Access – Investigational Drugs • August 13, 2009 – Final expanded access regulation issued relating to drugs/biologics – 21 CFR 312 Subpart I • Strives to balance competing issues: – Access to unproven therapies for patients with serious or life-threatening diseases/conditions who have no therapeutic alternatives – Potential to impede development and marketing of life-saving therapies – Minimize risk to patients 20

Expanded Access – Investigational Drugs • Regulation recognizes: – Primary Goal is treatment • “Compassionate Use” – Evidentiary standard necessary to support use • Three categories of expanded access: – Individual patients, including emergency use (21 CFR 312. 310) – Intermediate-size patient populations (21 CFR 312. 315) – Treatment IND or treatment protocol (21 CFR 312. 320) 21

Expanded Access – Investigational Drugs Resources – Expanded Access (Compassionate Use) Website – Guidance on Expanded Access to Investigational Drugs for Treatment Use – June 2016 • Provides information on expanded access regulations for investigational drugs for treatment use under an IND • Addresses most frequently asked questions – Guidance on Individual Patient Expanded Access Applications – Form FDA 3926 – June 2016 • Describes form used for submission process for individual patient expanded access INDs 22

Charging for Investigational Drugs 21 CFR 312. 8 • For a clinical trial, only the direct costs of making the investigational drug available (manufacturing and/or acquiring and shipping and handling, not research and development or labor) can be recovered – Evidence drug has potential clinical benefit and a clinical trial is essential to demonstrating safety and effectiveness – Cost extraordinary due to manufacturing complexity, scarcity of a natural resource, large quantity needed, or some combination of the above 23

Charging for Investigational Drugs 21 CFR 312. 8 • In general, reasonable assurance charging will not interfere with development of the drug for marketing approval • For treatment INDs and protocols – Assurance to include evidence of sufficient trial enrollment and adequate progress towards marketing – Required to submit development milestones for the following year – Authorization limited to a specified number of patients and for a maximum of 1 year, though a request for reauthorization is possible 24

Charging for Investigational Drugs • Guidance on Charging for Investigational Drugs Under an IND – June 2016 – Provides information on implementation of FDA’s regulation for charging for investigational drugs under an IND • Clinical trials • Expanded Access for treatment use – Addresses most frequently asked questions 25

Expanded Access – Medical Devices • Mechanisms for expanded access to investigational devices: – Emergency Use – Compassionate Use • Individual Patient/Small Group Access – Treatment Use – 21 CFR 812. 36 • Must meet specified criteria 26

Expanded Access – Medical Devices Resources • Expanded Access for Medical Devices Website • Guidance on IDE Policies and Procedures – Chapter III – Expanded Access to Unapproved Devices 27

Charging for Investigational Devices • 21 CFR 812. 7(b) – Prohibits a price larger than necessary to recover costs of manufacture, research, development, and handling • 21 CFR 812. 20(b)(8) – IDE application to include amount to be charged an explanation of why sale does not constitute commercialization of the device • 21 CFR 812. (c)(1)(x) – Treatment IDE – if device to be sold, application must include price, which is to be based on manufacturing and handling costs only 28

Charging for Investigational Products 21 CFR 50. 25(b)(3) - Any intended charges for an investigational product during a clinical trial must be disclosed to the subject and a description of those costs must be included in the informed consent document 29

Resources • Guidance for Industry, Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects – final October 2009 – http: //www. fda. gov/downloads/Drugs/Guidance. Comp liance. Regulatory. Information/Guidances/UCM 187772. pdf • Financial Disclosure by Clinical Investigators, Guidance for Industry – final February 2013 http: //www. fda. gov/downloads/Regulatory. Informatio n/Guidances/UCM 341008. pdf 30

Resources • Expanded access to and charging for investigational drugs – http: //edocket. access. gpo. gov/2009/pdf/E 9 -19005. pdf – http: //edocket. access. gpo. gov/2009/pdf/E 9 -19004. pdf Include preambles explaining rationale and comments received to proposed rules • Charging for Investigational Products – Information Sheet http: //www. fda. gov/regulatoryinformation/guidance s/ucm 126427. htm 31

Resources • Expanded Access to Investigational Drugs for Treatment Use – Qs & As – June 2016 http: //www. fda. gov/downloads/Drugs/Guidance. Complia nce. Regulatory. Information/Guidances/UCM 351261. pdf • Individual Patient Expanded Access Applications Form FDA 3926 – June 2016 http: //www. fda. gov/downloads/Drugs/Guidance. Complia nce. Regulatory. Information/Guidances/UCM 432717. pdf • Charging for Investigational Drugs Under an IND – Qs & As – June 2016 http: //www. fda. gov/downloads/Drugs/Guidance. Complia nce. Regulatory. Information/Guidances/UCM 351264. pdf 32

Resources • Expanded Access (Compassionate Use) - General Info and Expanded Access for Investigational Drugs/Biologics http: //www. fda. gov/newsevents/publichealthfocus/ expandedaccesscompassionateuse/default. htm • Expanded Access for Medical Devices http: //www. fda. gov/Medical. Devices/Device. Regulati onand. Guidance/Howto. Market. Your. Device/Investigat ional. Device. Exemption. IDE/ucm 051345. htm • Guidance on IDE Policies and Procedures http: //www. fda. gov/Medical. Devices/Device. Regulati onand. Guidance/Guidance. Documents/ucm 080202. ht m 33

HSP/GCP Resources GCP website – http: //www. fda. gov/Science. Research/Special. Topics/Run ning. Clinical. Trials/default. htm alias – www. fda. gov/gcp Source for Regulations, Guidance Documents and Proposed Guidance/Rules relating to HSP and GCP Questions on general GCP/HSP issues or policies: gcp. questions@fda. hhs. gov 34

Office of Good Clinical Practice Staff • • • Joanne Less, Ph. D. , Director Sheila Brown, R. N. , M. S. Janet Donnelly, CIP, RAC Bridget Foltz, M. S. , MT(ASCP) Doreen Kezer, M. S. N. Pat Mc. Neilly, Ph. D. , R. Ph. , CIP Janet Norden, M. S. N. , R. N. Kevin Prohaska, D. O. , M. P. H. Nicole Wolanski 35