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  1. Clinical Trials and Human Subject Protection

FDA's HSP/BIMO Initiative Accomplishments: Update June 2014

New Regulations
New Guidance
Draft Guidance
Improvements to FDA’s Procedures
Public Hearing on FDASIA Section 907
Clinical Trial Transformation Initiative (CTTI)
International Harmonization, Capacity-Building, and Outreach Activities
Regulations in Development
Guidance in Development
BIMO Inspection Metrics

The Food and Drug Administration (FDA) has continued the Human Subject Protection (HSP)/Bioresearch Monitoring (BIMO) Initiative,1,2 intended to modernize and strengthen the agency’s oversight and protection of subjects in clinical trials and the integrity of resulting data. The HSP/BIMO Initiative encompasses clinical trials of FDA-regulated products, including those for human drugs and biological drug products, devices, and foods. The overarching goals of the agency’s BIMO program are to protect the rights, safety, and welfare of subjects involved in FDA-regulated clinical trials; to determine the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and to assess compliance with FDA’s regulations governing the conduct of clinical trials, including regulations for informed consent and ethical review.

Below are significant accomplishments and initiatives since the last report.

New Regulations

  • Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products – Final Rule.3 This rule finalizes the interim rule published in 2001 to bring FDA regulations into compliance with provisions of the Children’s Health Act of 2000 (the Children’s Health Act). The Children’s Health Act requires that all research involving children that is conducted, supported, or regulated by the Department of Health and Human Services (HHS) be in compliance with HHS regulations providing additional protections for children involved as subjects in research. FDA issued this regulation both to comply with the congressional mandate and because of increased enrollment of children in clinical investigations as a result of ongoing pediatric initiatives. (February 2013)
  • Human Subject Protection; Acceptance of Data from Clinical Studies for Medical Devices – Proposed Rule.4 FDA is proposing to amend its regulations on acceptance of data from clinical studies conducted outside the United States (US) in support of an investigational device exemption application, a premarket notification (510(k)) submission, a premarket approval application, a product development protocol, or a humanitarian device exemption application for a medical device. The proposed rule would require that these studies be conducted in accordance with good clinical practice (GCP), defined as a standard for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials that assures credible and accurate data and reported results, and protection of the rights, safety, and well-being of trial subjects. GCP includes review and approval by an independent ethics committee (IEC) before initiating a study, continuing IEC review of ongoing studies, and obtaining and documenting freely given informed consent of study subjects. With the above described changes, the proposed rule is intended to update the standards for the acceptance of clinical studies and to help ensure the protection of human subjects and the quality and integrity of data obtained from these studies. (February 2013)

New Guidance

  • Considerations When Transferring Clinical Investigation Oversight to Another IRB.5 This guidance describes the regulatory responsibilities of clinical investigators, sponsors, and IRBs when oversight of a previously approved clinical investigation is transferred from one IRB to another IRB. The guidance also addresses questions that have been previously raised concerning procedures and processes that are required and/or recommended by FDA when such oversight is transferred. (May 2014)
  • Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies Including Certain First in Human (FIH) Studies.6 This document is intended to provide guidance on the development and review of IDE applications for early feasibility studies of significant risk devices. Early feasibility studies allow for early clinical evaluation of devices to provide proof of principle and initial clinical safety data. These studies may be appropriate early in device development when clinical experience is necessary because nonclinical testing methods are not available or adequate to provide the information needed to advance the developmental process. However, as with all clinical studies, initiation of an early feasibility study must be justified by an appropriate risk-benefit analysis and adequate human subject protection measures. (October 2013)
  • Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND.7 This guidance is intended to assist clinical investigators, sponsors, and sponsor-investigators in determining whether human research studies must be conducted under an IND. With certain exceptions, clinical investigations in which a drug is administered to human subjects must be conducted under an IND as required in 21 CFR part 312. This guidance describes when an IND is required, specific situations in which an IND is not required, and a range of issues that, in FDA’s experience, have been sources of confusion or misperceptions about the application of the IND regulations. (September 2013) In February 2014, FDA reopened the comment period for 60 days and is considering the comments received.
  • Electronic Source Documentation in Clinical Investigations.8 This document revises and updates the revised draft guidance issued in November 2012. The guidance promotes capturing source data in electronic form, and is intended to assist sponsors, contract research organizations (CROs), data management centers, and clinical investigators in ensuring the reliability, quality, integrity, and traceability of electronic source data captured, used, and archived in FDA-regulated clinical investigations. (September 2013)
  • Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring.9 This guidance is intended to assist sponsors of clinical investigations in developing risk-based monitoring strategies and plans for investigational studies of human drug and biological products, medical devices, and combination products. This guidance describes monitoring strategies that focus on critical study parameters and suggests using a combination of methods to oversee a study effectively, such as greater use of centralized monitoring, where appropriate. (August 2013)
  • IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed.10 Although sponsors are primarily responsible for selecting clinical investigators and determining whether an IND/IDE is needed, this guidance addresses the role of institutional review boards (IRBs) in reviewing investigator qualifications and the adequacy of the research site, and in questioning the investigator about any determination of whether an IND/IDE is needed. (August 2013)
  • Fecal Microbiota Transplantation to Treat Clostridium Difficile.11 This guidance for immediate implementation informs the medical and scientific community that FDA intends to exercise enforcement discretion regarding IND requirements for the use of fecal microbiota for transplantation (FMT) to treat Clostridium difficile (C. difficile) infection not responding to standard therapies. The guidance recommends 1) that the treating physician obtain informed consent from the patient or the patient’s legally authorized representative for the use of FMT products, and 2) that the informed consent include, at a minimum, a statement that the use of FMT products to treat C. difficile is investigational and a discussion of its potential risks. FDA intends to exercise this discretion on an interim basis while the agency develops appropriate policies for the study and use of FMT products under IND. (July 2013) Note: In March 2014, FDA issued a draft guidance updating when it intends to use enforcement discretion.
  • Financial Disclosure by Clinical Investigators.12 This updated guidance responds to recommendations13 aimed at strengthening FDA’s oversight and review of clinical investigators’ financial disclosures and responds to questions FDA has received from industry and the public. Among other things, the guidance describes: (1) the sponsor’s responsibility to collect financial disclosure information prior to an investigator participating in a study under an IND or IDE, and to ensure that all required forms and attachments are submitted in marketing applications; (2) what is meant by “due diligence” in obtaining financial disclosures from investigators; and (3) how FDA will review financial disclosure information. FDA also reiterates its policy on public release of individual clinical investigator financial disclosure information and states its intention to provide summary information about the number of clinical investigators with disclosable financial interests/arrangements in the new product reviews FDA posts for an approval decision. (February 2013)
  • Humanitarian Use Device (HUD) Designations.14 This guidance document is intended to assist applicants in the preparation and submission of HUD designation requests to FDA’s Office of Orphan Products Development (OOPD). It is also designed to assist FDA reviewers in their evaluation and analysis of HUD designation requests. (January 2013)
  • Safety Reporting Requirements for INDs and BA/BE Studies.15 This document provides guidance to sponsors and investigators on safety reporting requirements for human drug and biological products that are being investigated under an IND and for drugs that are the subjects of bioavailability (BA) and bioequivalence (BE) studies that are exempt from the IND requirements. The guidance contains definitions used for safety reporting, makes recommendations on when and how to submit a safety report, and provides advice on other safety reporting issues that have generated questions from sponsors and investigators. (December 2012)
  • Safety Reporting Requirements for INDs and BA/BE Studies–Small Entity Compliance Guide.16 This guidance was published in accordance with the Small Business Regulatory Enforcement Fairness Act and is intended to help small businesses understand and comply with FDA’s safety reporting regulations for human drug and biological products that are being investigated under an IND and for drugs that are the subjects of bioavailability (BA) and bioequivalence (BE) studies that are exempt from the IND requirements. This guidance provides answers to several frequently asked questions FDA has received from investigators and sponsors about the safety reporting requirements that are applicable to small entities. (December 2012)

Draft Guidance

  • Humanitarian Device Exemption (HDE): Questions and Answers.17 This guidance answers commonly asked questions about Humanitarian Use Devices (HUDs) and the Humanitarian Device Exemption. This guidance also addresses changes in the HDE program resulting from recent statutory changes. (March 2014)
  • Antibacterial Therapies for Patients With Unmet Medical Need for the Treatment of Serious Bacterial Diseases.18 This guidance is intended to assist sponsors in the clinical development of new antibacterial drug therapies. Specifically, the guidance explains FDA’s current thinking about possible streamlined development programs and clinical trial designs for (1) drugs to treat serious bacterial diseases in patients with unmet medical need, and (2) drugs that are pathogen-focused antibacterial drugs (e.g., drugs with a narrow spectrum of activity or are only active against a single genus and species of bacteria) and are used for the treatment of serious bacterial diseases. (July 2013)
  • Charging for Investigational Drugs under an IND – Qs and As.19 This guidance provides information for industry, researchers, and physicians about the implementation of FDA’s regulation on charging for investigational drugs under an IND (21 CFR 312.8), which went into effect on October 13, 2009.(May 2013)
  • Expanded Access to Investigational Drugs for Treatment Use – Qs and As.20 This guidance provides information for industry, researchers, physicians, and patients about the implementation of FDA’s regulations on expanded access to investigational drugs for treatment use under an IND (21 CFR part 312, subpart I), which went into effect on October 13, 2009. (May 2013)
  • Providing Submissions in Electronic Format – Summary Level Clinical Site Data for the Center for Drug Evaluation and Research’s (CDER’s) Inspection Planning.21 This guidance applies to submissions to CDER. It requests voluntary submission of a summary level clinical site dataset within New Drug Applications (NDAs), biologics licensing applications (BLAs), and supplemental applications containing new clinical study reports. The dataset describes and summarizes the characteristics and outcomes of clinical investigations at the level of the individual study sites. The guidance recommends a standardized electronic format for these datasets and should permit timely identification of clinical investigator sites for on-site inspection during the review of marketing applications. (December 2012)

Improvements to FDA’s Procedures

  • Website Improvements
    • FDA added a new webpage listing IRBs that have received a letter from FDA imposing restrictions.22 (September 2013)
    • FDA updated its website to consolidate listings of clinical investigators for whom FDA has initiated disqualification proceedings and those who have been disqualified.23 Previous website listings did not provide the disposition of disqualification proceedings for investigators who received a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) letter from FDA, but for whom proceedings were not pursued. (December 2012)
  • Clinical Investigator Restricted Agreement Compliance and Change in Status from “Restricted” to “Restrictions Removed – Staff Manual Guide (SMG) 7713.24 This SMG provides FDA staff with a process to evaluate whether a clinical investigator who has entered into a restricted agreement with FDA is complying with the agreed upon restrictions and conditions. This SMG also provides procedures for removal of a clinical investigator’s restricted status if FDA finds that the investigator has complied with all restrictions and has met all required conditions. (December 2012)
  • Warning Letter Initiative.25 In 2009, FDA implemented a pilot program that establishes a 15 business day timeframe for the submission of post-inspection responses to FDA 483 observations. The pilot mandated that FDA would conduct a detailed review of any timely responses received before issuing a warning letter. If, after reviewing a firm’s timely response, FDA determined a warning letter was necessary, the warning letter would acknowledge receipt of the response and reply as to the apparent adequacy of the firm’s described corrective actions. The purpose of this program was to facilitate the timely issuance of warning letters, promote prompt correction of violations, and promote efficient use of agency resources. FDA assessed the Warning Letter Initiative and found that generally, firms were able to respond to FDA-483 observations within the 15-day timeframe. As a result, the agency has determined to make the program permanent. The Office of Regulatory Affairs plans to update the Regulatory Procedures Manual to reflect this policy.

Public Hearing on FDASIA Section 907

On April 1, 2014, FDA held a public hearing to obtain input on the issues and challenges associated with the collection, analysis, and availability of demographic subgroup data (i.e. sex, race/ethnicity, and age) in applications for approval of FDA-regulated medical products. The Agency will utilize input from this public hearing to develop a plan that is pragmatic and public-health focused. The open public docket for this meeting is now closed. Comments that were submitted to the docket may be reviewed at Docket No. FDA-2013-N-0745.26

Based on the findings of a report issued in August 201327 and stakeholder input, FDA will issue an action plan of recommendations to support improvements in demographic subgroup inclusion, analyses of data, and transparency by August 2014.

Clinical Trial Transformation Initiative (CTTI)28

CTTI is a public-private partnership founded by FDA and Duke University in 2007. CTTI’s goal is to identify and promote practices to improve the quality and efficiency of clinical trials. CTTI conducts projects to generate empirical information about how clinical research is currently conducted and to identify and test ways to improve quality and efficiency. CTTI is composed of representatives from government, industry, patient advocacy groups, professional societies, academia, and international regulators. Recent activities29 include:

  • Improving Public Access to Aggregate Data in ClinicalTrials.gov: Aggregate Analysis of ClinicalTrials.gov (AACT) Database.30 Although the ClinicalTrials.gov dataset is publicly available, it was difficult for users to access aggregate information to gain a better understanding of the current state of clinical trials in the US over time. For example, it was difficult to compare trials within or between different medical specialties, identify unmet needs, or see what research has already been done in a specialty before designing another trial. To remedy this problem, CTTI created and annually updates the AACT database, a searchable, publicly downloadable database of clinical trials registered on ClinicalTrials.gov. AACT includes a data dictionary and allows researchers to perform analyses on a study dataset (a group of several studies). Several research studies using AACT have been published to date.31
  • Use of Central IRBs for Multicenter Clinical Trials.32 Because research institutions differ in their willingness to defer to a single central IRB for multicenter clinical trials, CTTI performed a collaborative research project to identify barriers to such use. The project team reviewed and analyzed peer-reviewed journal articles on the use of central IRBs for multicenter clinical trials in the US and published their findings.33 CTTI held discussions with IRB experts and representatives of research institutions, and then convened an expert meeting with diverse stakeholders and thought leaders. The project team drafted a guide that separates institutional and ethical responsibilities, and makes recommendations on how these responsibilities might be assigned.34 The Team also drafted a guide35 to support communications and contractual arrangements between institutions and a central IRB. CTTI issued a final report and project recommendations.36 (January 2013)
  • Workshops on Quality by Design in Clinical Trials. The CTTI monitoring project identified quality risk management (QRM) and specifically quality by design (QbD) from the pharmaceutical manufacturing sector as a potential model that could contribute to high data quality and integrity in clinical trials. To help stakeholders gain a common understanding of QRM principles and their application in a clinical trial setting, CTTI has convened annual workshops on QRM/QbD, to explore best practices in prospectively designing quality into the clinical development lifecycle.37 From 2011 through December 2013, workshop participants representing regulators, sponsors, academia, patient advocate groups, clinical investigators, and other interested parties, identified principles of QbD and QRM and developed a guide to assist others in translating these principles to practice.38 FDA staff also presented information on Quality Risk Management and FDA’s Risk-Based Monitoring Guidance at the EMA-CTTI workshop held in London. (December 2013)
  • Antibacterial Drug Development. CTTI convened 2 workshops to identify potential pathways for, and accelerate the development of, new antibacterial drugs for unmet medical needs. The workshops included discussions on clinical trial design and endpoints for treatment of patients with hospital–acquired or ventilator-associated bacterial pneumonia (HABP/VABP). (October 2012,39 August 2013,40 and November 201341)

    As a follow-up, CTTI is completing a project aimed at creating and testing a new and efficient protocol for conducting clinical trials for antibiotics designed to treat HABP/VABP. The trial protocol will incorporate principles developed as a result of CTTI’s QbD workshops.

  • Mini-Sentinel – Use of Electronic Health Data to Support Clinical Trials.42 CTTI is collaborating with Mini-Sentinel to assess the feasibility of using the Mini-Sentinel Distributed Database to (1) quickly identify and assess health and safety problems related to FDA-regulated medical products, and (2) facilitate recruitment and follow-up of participants in individual- and cluster-randomized trials. (May 2013 Poster, Society of Clinical Trials)43
  • Large Simple Trials (LSTs).44 Many clinical trial sponsors, investigators, and government agencies believe that more LSTs could improve the clinical trial system in the US. LSTs are usually randomized controlled trials enrolling large numbers of subjects with broad inclusion criteria and simple protocol designs that are practical in the clinical setting. LSTs collect the minimum amount of data necessary to answer the question being posed, and generally have objective measurements (e.g., mortality, length of hospital stay) rather than a subjective measure of improvement as the study endpoint(s). Such objective endpoints make it more likely that the study will have a clear result. That, in turn, makes it more likely that study results will be more useful to doctors’ and patients’ treatment decisions.

    The project’s goal is to identify barriers to doing LSTs and find ways to remove or reduce those barriers. CTTI surveyed sponsors and others in the field to identify current views of LSTs and barriers to conducting LSTs and then convened an expert meeting to review survey results, discuss the challenges of LSTs, and talk about ways to facilitate use of LSTs. (May 2013)45,46

    The project team plans to publish a summary of the current practices and issues and provide recommendations from the expert meeting.

  • Defining Key Elements of GCP Training.47 CTTI's Workshops on Quality by Design identified investigator training and qualifications, and sponsors' selection of qualified investigators as factors critical to ensuring quality in the conduct of clinical trials. This project seeks to facilitate a more efficient GCP training process by 1) issuing recommendations regarding key elements that should be included, 2) gathering information about current practices; and 3) discussing strategies to reduce the burden of redundant GCP training.

International Harmonization, Capacity-Building, and Outreach Activities

Increasing globalization of clinical trials presents challenges to both U.S. and foreign regulators. To address these challenges, FDA has sought to leverage its resources more efficiently by engaging in collaboration and outreach with international regulatory authorities. FDA conducted numerous programs to train other countries’ governments and international health regulatory bodies on GCP or to assist them in establishing or improving their GCP inspectional capacity. These activities include:

  • Active participation in the Office of Science and Technology Policy’s Human Subjects Research Subcommittee (HSRS) and the HSRS International Working Group. (Ongoing)
  • Train the Trainers GCP Workshops
    • Advanced (Phase 3) - China Food and Drug Administration (CFDA; formerly the State Food and Drug Administration, SFDA). (China, October 2012)
    • Intermediate (Phase 2) - Southern African Development Community (SADC); regulatory authorities from 13 countries participated: Angola, Botswana, Lesotho, Malawi, Mauritius, Mozambique, Namibia, Seychelles, South Africa, Swaziland, Tanzania, Zambia, and Zimbabwe (Zambia, August 2012)
    • Advanced (Phase 3) - Russia and its regulatory agency, Roszdravnadzor (Russia, June 2012)
    • Basic (Phase 1) - Middle East/North Africa regulatory authorities from Bahrain, Egypt, Ethiopia, Jordan, Lebanon, Oman, Saudi Arabia, and Turkey. (Saudi Arabia, March 2012)
  • Meetings, Presentations, or Training for International Regulatory Officials and Major International Conferences
    • Bioequivalence inspection training for Jordan FDA, CROs, clinical investigators, and pharmaceutical companies (Jordan, November 2013)
    • Movement Towards Responsible and Ethical Research Conference sponsored by the Association for Accreditation of Human Research Protection Program (India, June 2013)
    • Republic of Turkey Ministry of Health (FDA,White Oak Campus, June 2013)
    • National Institute for Research in Tuberculosis, Indian Health Ministry, sponsored by the World Health Organization - Strategic Initiative for Developing Capacity in Ethical Review, Forum for Ethical Review Committees in the Asian and Western Pacific Region (FERCAP) Ethics Committee (India, June 2013)
    • CFDA Bioresearch and Monitoring technical experts and regulators (China, May 2013)
    • Video-conference, CFDA (April 2013)
    • BioAsia 2013 Conference (Biosimilars) attended by regulators from 11 countries and delegates from 47 (India, January 2013)
    • FERCAP (Sri Lanka, November 2012)
    • SADC and representatives of Zambia’s Pharmaceutical Regulatory Authority (Zambia, August 2012)
    • GLP Training Workshop for India’s Ministry of Science and Technology, Department of Science and Technology (DST), National GLP Compliance Monitoring Authority (NGCMA) (India, July 2012)
    • Saudi Food and Drug Authority (Riyadh, Saudi Arabia, February 2012)
    • Central Drugs Standard Control Organization (CDSCO) and the Office of the Drug Controller General of India (India, October 2011)
  • FDA-EMA Good Clinical Practices (GCP) Initiative. Begun in 2009, this initiative allows FDA’s Center for Drug Evaluation and Research and the European Medicines Agency (EMA) to share inspectional information on dozens of applications, collaborate on numerous joint and observational inspections, participate in bilateral training programs, and keep each other informed of GCP-related legislation, regulatory guidance, and related documents. The inspection reports have been useful for FDA in inspection planning for applications that have been conducted at foreign clinical sites. FDA and EMA are continuing the initiative, which has expanded to include products reviewed by the Center for Biologics Evaluation and Research (CBER), and regularly sharing information at bi-monthly meetings.
  • FDA-EMA Bioequivalence Initiative.48 Following the model of the FDA-EMA GCP Initiative, this program 1) allows FDA to share information on inspections of bioequivalence studies submitted in support of generic drug approvals with the EMA, and 2) provides a mechanism to conduct joint facility inspections for generic drug applications submitted to both agencies. (December 2013)

Regulations in Development

  • Reporting Information Regarding Falsification of Data – Final Rule.49 FDA proposed to amend its regulations to require sponsors to report information indicating that any person has, or may have, engaged in the falsification of data in the course of reporting study results, or in the course of proposing, designing, performing, recording, supervising, or reviewing studies that involve human subjects or animal subjects conducted by or on behalf of a sponsor or relied on by a sponsor. FDA proposed this change because ambiguity in the current reporting scheme has caused confusion among sponsors. The final rule is intended to help ensure the validity of data that the FDA receives in support of applications and petitions for FDA product approvals and authorization of certain labeling claims and to protect research subjects.
  • Human Subject Protection; Acceptance of Data from Clinical Studies for Medical Devices – Final Rule. FDA proposed to amend its regulations on acceptance of data from clinical studies conducted outside the US in support of an investigational device exemption application, a premarket notification (510(k)) submission, a premarket approval application, a product development protocol, or a humanitarian device exemption application for a medical device. To update the standards for the acceptance of clinical studies and to help ensure the protection of human subjects and the quality and integrity of data obtained from these studies, FDA proposed to require that these clinical studies be conducted in accordance with good clinical practice. FDA is currently working on the final version of this proposal.
  • Good Laboratory Practice (GLP; 21 CFR part 58) - Notice of Proposed Rulemaking (NPRM). FDA’s GLP Working Group is developing an NPRM to respond to comments submitted to the Advance Notice of Proposed Rulemaking (ANPRM), published in December 2010.50

Guidance in Development

  • Exculpatory Language – Final Guidance. This guidance discusses the regulatory prohibition of exculpatory language in informed consent documents and includes examples of language that OHRP and FDA consider acceptable as well as examples of language that the agencies would consider exculpatory.
  • Additional Protections for Children Enrolled in Research (21 CFR part 50 subpart D) – Draft Guidance. This guidance is intended to assist sponsors, clinical investigators, and IRBs in the development, conduct, and oversight of pediatric research involving FDA-regulated products. The draft guidance will discuss different pathways for pediatric product development that are consistent with 21 CFR part 50 subpart D, and the ethical and regulatory issues that need to be considered.
  • A Guide to Informed Consent – Draft Guidance. This guidance describes in detail basic and additional elements of informed consent and includes topics such as review of patient records, children as subjects, and subject participation in more than one study.
  • Use of an Electronic Informed Consent in Clinical Investigations: Questions and Answers – Draft Guidance. This guidance is intended to assist clinical investigators, study sponsors, and IRBs on the use of electronic media and processes to obtain informed consent for FDA-regulated clinical investigations.
  • IRB Written Procedures – Draft Guidance. This guidance is intended to assist IRBs and institutions in developing written procedures that comply with the requirements in FDA regulations at 21 CFR parts 50 and 56 and HHS regulations at 45 CFR part 46.
  • Core Responsibilities, Functions, and Operations of IRBs – FAQs. This draft guidance is intended to assist the research community in understanding the core responsibilities of IRBs for review and approval of research, as required by HHS regulations at 45 CFR part 46 and FDA regulations at 21 CFR parts 50 and 56.
  • Disqualification of Institutional Review Boards (IRBs) –– Staff Manual Guide (SMG). This SMG describes internal procedures for FDA staff related to disqualifying IRBs that refuse or repeatedly fail, to comply with regulatory requirements for ethical review of clinical studies and human subject protection and how noncompliance adversely affects the rights or welfare of the human subjects in a clinical investigation.

BIMO Inspection Metrics
Each year, FDA’s field investigators conduct on-site inspections of BIMO establishments, including sponsors, monitors, clinical investigators, IRBs, and GLP laboratories that conduct nonclinical safety studies (including animal toxicity studies) to support FDA-regulated research. The agency performs these inspections to determine whether the inspected party’s practices and procedures comply with applicable regulations. Here is a link to summary information provided by FDA’s Centers about these inspectional activities: BIMO Inspection Metrics.

# # # # #


1 The HSP/BIMO Council, which is overseeing this initiative, includes representatives from each of FDA's Centers, the Office of Regulatory Affairs (ORA), and the Office of the Commissioner (OC).

2 Information on the HSP/BIMO Initiative and progress reports can be found at: HSP/BIMO Initiative. These progress reports include HSP/BIMO accomplishments and initiatives from all FDA Centers and Offices.

3 http://www.gpo.gov/fdsys/pkg/FR-2013-02-26/pdf/2013-04387.pdf

4 http://www.gpo.gov/fdsys/pkg/FR-2013-02-25/pdf/2013-04201.pdf

5 Considerations When Transferring Clinical Investigation Oversight to Another IRB

6 Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies

7 Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND

8 Electronic Source Data in Clinical Investigations

9 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf

10 IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed

11 Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies - Guidance for Immediate Implementation; For information about the May 2013 public workshop on FMT, see Fecal Microbiota for Transplantation; Public Workshop. For the March 2014 draft guidance on enforcement discretion, see Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies - Draft Guidance. (Note: The March 2014 guidance titled “Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation to Treat Clostridium difficile Infection Not Responsive to Standard Therapies” was revised in March 2016.  This footnote has been updated to provide the correct link.)

12 Financial Disclosure by Clinical Investigators

13 See the Office of the Inspector General (OIG), HHS report, The Food and Drug Administration’s Oversight of Clinical Investigators’ Financial Information (OEI-05-07-00730) at http://oig.hhs.gov/oei/reports/oei-05-07-00730.pdf

14 Humanitarian Use Device (HUD) Designations

15 Safety Reporting Requirements for INDs (Investigational New Drug Applications) and BA/BE (Bioavailability/Bioequivalence) Studies

16 Safety Reporting Requirements for INDs and BA/BE Studies - Small Entity Compliance Guide

17 http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM389275.pdf

18 Antibacterial Therapies for Patients With an Unmet Medical Need for the Treatment of Serious Bacterial Diseases 

19 Charging for Investigational Drugs Under an IND - Questions and Answers

20 Expanded Access to Investigational Drugs for Treatment Use - Questions and Answers

21 Bioresearch Monitoring Technical Conformance Guide

22 Institutional Review Boards – Restrictions Imposed Letters and Disqualification Proceedings

23 Clinical Investigators - Disqualification Proceedings

24 FDA Staff Manual Guide SMG7713 - Compliance Activities: Clinical Investigator Restricted Agreement Compliance and Change in Status from "Restricted" to "Restrictions Removed."

25 Federal Register, August 11, 2009, Review of Post-Inspection Responses.

26 Action Plan for the Collection, Analysis, and Availability of Demographic Subgroup Data in Applications for Approval of Food and Drug Administration-Regulated Medical Products; Notice of Public Hearing; Request for Comments, Docket FDA-2013-N-0745-0022

27 FDA Report: Collection, Analysis, and Availability of Demographic Subgroup Data for FDA-Approved Medical Products, August 2013

28 For more information about specific and additional projects, visit CTTI's website: http://ctti-clinicaltrials.org

29 CTTI’s annual reports are available at http://ctti-clinicaltrials.org/who-we-are/annual-reports

30 AACT is available for download on the CTTI website: http://ctti-clinicaltrials.org/what-we-do/analysis-dissemination/

31 For more information, see http://ctti-clinicaltrials.org/what-we-do/analysis-dissemination/state-clinical-trials/products

32 For more information, see http://ctti-clinicaltrials.org/what-we-do/study-start/central-irb

33 Check DK, Weinfurt KP, Dombeck CB, Kramer JM, Flynn KE. Use of central institutional review boards for multicenter clinical trials in the United States: A review of the literature. Clin Trials 2013;10:560-67; https://journals.sagepub.com/doi/full/10.1177/1740774513484393.

34 See also “Using Central IRB’s for Multicenter Clinical Trials in the United States,” published January 30, 2013, in the journal PLOS ONE: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0054999

35 https://www.ctti-clinicaltrials.org/files/recommendations/considerations_document_-_use_of_central_irbs_for_multicenter_clinical_trials_nb2web.pdf 

36 https://www.ctti-clinicaltrials.org/news/conducting-multi-center-trials-new-recommendations-and-tool-research

37 http://ctti-clinicaltrials.org/what-we-do/investigational-plan/qbd-qrm

38 CTTI Quality by Design Project - Critical to Quality (CTQ) Factors Principles Document 

39 Anti-Bacterial Drug Development: Issues in the Design of Trials in Patients with Unmet Need and in Patients with Hospital-Acquired and Ventilator Associated Bacterial Pneumonia, October 11-12, 2012

40 Antibacterial Drug Development Working Group Webinar, August 29, 2013

41 Optimizing Operational Efficiencies for Data Collection in HABP/VABP Trials, November 12, 2013

42 Advancing the Use of Mobile Technologies for Data Capture & Improved Clinical Trials

43 http://www.ctti-clinicaltrials.org/files/documents/MS_Randomization_POSTER_20130514_v1.pdf

44 Facilitating the Use of Large Simple Trials (LST)

45 Expert Meeting on Large Simple Trials (LSTs), May 13-14, 2013

46 See also, the draft Guidance for Industry: Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Postapproval Clinical Investigations, which contains points to consider for large outcome trials.

47 Improving the Qualification of Investigators and their Delegates

48 http://www.fda.gov/downloads/InternationalPrograms/FDABeyondOurBordersForeignOffices/

49 http://www.gpo.gov/fdsys/pkg/FR-2010-02-19/pdf/2010-3123.pdf

50 The ANPRM and comments may be viewed at www.regulations.gov, Docket #, FDA-2010-N-0548.

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