RESOURCES

   

Below are links to a variety of resources that may be helpful to investigators planning their clinical trials. These links are sorted by topic and each link is preceded by a brief description of the information available through this resource.

General Information

Clinical Trials.gov
This NIH Website provides information on clinical studies for a wide range of diseases and conditions, and a searchable database of Federal and private studies taking place nationwide.

General Clinical Trials Information
This links to information about the purpose and conduct of clinical trials. The information is largely geared to the participant population rather than the researcher. It provides a good overview of clinical trials and links to resources that may help identify clinical trials in areas of interest.

Clinical Research Guide for NHLBI Investigators
This site is designed to guide potential investigators in organizing a clinical research application and to provide information on conducting a study and maintaining an award. It is very helpful. In particular, the toolkit contains a number of resources of interest, many of which are named specifically in other areas on this page. Here you will find:

  • An Overview of Human Subjects Research
  • Pre-application Information
  • Peer Review Details
  • Funding Information
  • Grants Oversight and Management Tips
  • Closing a Study Specifics
  • Toolkit Resources

International Conference on Harmonization (ICH) Guidance
Links to all ICH Guidance from the FDA web site.  This documentation includes guidance on Good Clinical Practice (GCP).

Clinical Trials for Rare Diseases
2010 FDA Public Hearing on Treatments for Rare Diseases
A committee of expert FDA employees was convened to consider the ways that the agency reviews to treatments for people with rare diseases, and consider policy improvements that might help people with rare diseases get better treatments faster.

Institute of Medicine (IOM) report on Rare Diseases and Orphan Products: Accelerating Research and Development, 2010
The IOM report proposes an integrated national policy to promote rare diseases research and product development, and increase the options for diagnosing, treating, and preventing these diseases.

Critical Path Initiative Report to Congress
Improving the Prevention, Diagnosis and Treatment of Rare and Neglected Diseases

Institute of Medicine report on Small Clinical Trials: Issues and Challenges
The Committee on Strategies for Small-Number-Participant Clinical Research Trials,Board on Health Sciences Policy (Institute of Medicine) produced a report entitled Small Clinical Trials: Issues and Challenges that assesses the current methodologies and the appropriate situations for the conduct of clinical trials with small sample sizes. This report assesses the published literature on various strategies such as (1) meta-analysis to combine disparate information from several studies including Bayesian techniques as in the confidence profile method and (2) other alternatives such as assessing therapeutic results in a single treated population (e.g., astronauts) by sequentially measuring whether the intervention is falling above or below a preestablished probability outcome range and meeting predesigned specifications as opposed to incremental improvement. A free PDF of the report is available at:

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ACCTHD Resource Training

Expertise in clinical trial design and methodology is needed to navigate the specific challenges inherent in studying rare patient populations. As part of the support that the ACCTHD Resource provides to investigators, we host in-person trainings and webinars covering relevant clinical trial design and methodology topics. The presentations from these training events can be accessed below.
Enabling Research in Rare Hematologic Disorders (December 5, 2014 ASH Ancillary Meeting)

Training Session For Investigators Supported By the NHLBI to Develop Clinical Trials to Test New Therapies for Hematologic Disorders (June 22, 2015 ISTH Ancillary Meeting)

Training Session for Investigators supported by an NHLBI planning grant, Clinical Trials Planning Studies for Rare Thrombotic and Hemostatic Disorders (December 4, 2015 ASH Ancillary Meeting)

Training Session provided to Thrombosis & Hemostasis Disorders Consortium Investigators (Thrombosis & Hemostasis Disorders Scientific Symposium; May 17-18, 2016; Washington University School of Medicine, St. Louis, MO)

Research Design Strategies in Planning Studies for Thrombotic and Hemostatic Disorders (December 2, 2016 ASH Ancillary Meeting)

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NHLBI Multi-Site Clinical Trials (Collaborative R01) Funding

Guidance for Investigators: NHLBI Grant Funding Application Process for the Multi-Site Clinical Trials (Collaborative R01) FOA
This document was prepared by the Resource to summarize information from the NHLBI guidelines on submission of multicenter clinical trial applications that request $500,000 or more in direct costs in any year.

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Biostatistics

FDA Drug Study Designs – Information Sheet
FDA regulations [21 CFR 314.126] cite five different kinds of controls that can be useful in particular circumstances: 1) placebo concurrent control, 2) dose-comparison concurrent control, 3) no-treatment concurrent control, 4) active-treatment concurrent control, and 5) historical control. No general preference is expressed for any one type, but the study design chosen must be adequate to the task.

Adaptive Randomization
Adaptive randomization is a form of treatment allocation in which the probability of patient assignment to any particular treatment group of the study is adjusted based on repeated comparative analyses of the accumulated outcome responses of patients previously enrolled. Previously, this randomization method had been used in placebo controlled studies chiefly to place more patients into the group with better outcomes. More recently the approach has been revised to suit the objective of dose-response evaluation. The method allocates fewer subjects to doses that appear to have a low probability of a treatment-related efficacy response, to have a high probability of an adverse event, or to be unlikely to contribute additional information on the shape of the dose response profile.

FDA Guidance on Non-Inferiority Trials
This guidance provides a general discussion of regulatory, study design, scientific, and statistical issues associated with the use of non-inferiority studies to establish the effectiveness of a drug, and includes examples of successful and unsuccessful efforts to define non-inferiority margins and conduct NI studies

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Management of Clinical Trials Materials

Under Development

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Ethics and Protection of Human Subjects

Office of Human Research Protection (OHRP) Policy and Guidance
OHRP has published a variety of policy and regulatory guidance materials to assist the research community in conducting ethical research that is in compliance with the HHS regulations. These include guidance documents and frequently asked questions (FAQs) addressing various topics, findings in the form of OHRP letters addressing regulatory issues, and other media including decision tree graphics and educational videos. This link provides easy access to those documents.

Federal policy regarding the Genetic Information Nondiscrimination Act (GINA)
Participants in clinical trials are prohibited by Federal law from being discriminated against based upon the sequencing of their DNA. This is becoming an increasingly important issue with NIH-sponsored clinical trials, particularly in trials that involve sequencing of participant tissue samples. Investigators should consider including language in the Informed Consent document for clinical trials involving DNA sequencing, that indicates that participants will be protected from discrimination based on their genetic code.

Educational and Training Materials Offered through the OHRP
OHRP offers a wide variety of educational and training materials to investigators involved in conducting clinical studies involving human subjects. Formats of these materials include training videos and webinars, a video series, the OHRP PRIM&R “Investigator 101” CD-ROM, online training modules, and an Institutional Review Board Guidebook.

Investigator Training Offered by the NIH Office of Extramural Research
All investigators participating in research involving human subjects are required to take training on the protection of human research participants. Most institutions now require specific training meeting this requirement through resources approved by OHRP. However, at this site, the NIH offers an on-line course in English and Spanish for investigators whose institutions do not require the completion of specific courses meeting the OHRP training requirements. These materials are especially important for community physicians and in international settings.

NHLBI Guidelines for Avoiding Conflicts of Interest in Multicenter Clinical Trials
The integrity of the study must not be compromised by financial interests. To assure that, investigators cannot have financial arrangements that reward a particular study outcome, proprietary interest in the intervention being tested, significant equity in the manufacturer of the intervention, or significant payments of other sorts. Specified financial arrangements must be disclosed. The sponsor of the IND or IDE is responsible for collecting information about financial interests. The NHLBI, even if it is not the sponsor of the IND or IDE, will take an active role in ensuring that these requirements are followed.

NHLBI Guidance for Addressing Tissue Sharing in Informed Consent
The purpose of this guidance is to bring to the attention of investigators, NHLBI staff, and any other relevant parties the need to include in all informed consent documents appropriate language regarding the potential use of tissue by investigators outside the collecting study.

NHLBI Guidelines for Human Tissue Repository
The guidance in this document covers operating principles and NHLBI staff responsibilities that are consistent with OPRR regulations and other ethical issues related to tissue repositories.

Informed Consent Checklist
This page describes required and additional elements in consent forms from the Office of Human Research Protections (OHRP), requirements for documentation of informed consent, waivers, and additional protections for children.

Program for Readability In Science and Medicine (PRISM) Toolkit
Group Health Research Institute created this document to help research teams develop study materials that participants can easily read and understand in "plain language," that describes exactly what the reader needs to know without using unnecessary or overly complex words.

NHLBI Toolkit for Multicenter Clinical Research Studies
Resources helpful in initiating, managing, and conducting a multi-center clinical research study.  Includes templates for:

  • Conflict of Interest Disclosure for Investigators
  • Consent Form Template
  • Data Monitoring Plan Checklist
  • Evaluation Tool to assess Clinical Sites and Data Coordinating Center
  • Manual of Operations and Protocol Templates

FDA Guidance on Running Clinical Trials

Comparison of DHHS and FDA Regulations Regarding Human Subject Protection

Understanding the Health Insurance Portability and Accountability Act (HIPAA)

HIPAA and Clinical Research

Certificates of Confidentiality
Certificates of Confidentiality are issued by NHLBI to help researchers protect the privacy of research subjects. The Certificate protects investigators and institutions from being compelled to release information that could be used to identify subjects participating in a research project. This page contains information about how to apply for a Certificate of Confidentiality through NHLBI.



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Regulatory Compliance

FDA Clinical Trials Guidance Documents
Guidance documents accessible from this page represent the Agency's current thinking on good clinical practice (GCP) and the conduct of clinical trials. As with all guidance documents, they do not create or confer any rights for or on any person and do not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute and regulations. However, in many places throughout these documents, specific regulations are cited and the requirements of the regulations are reiterated. The regulations are enforceable.

Investigational New Drug (IND) and New Drug Application (NDA) Process Overview
This guidance document provides an overview of the information regarding the design, development, and regulatory US Food and Drug Administration approval of new drugs and/or studies involving the use of investigational new drugs. It is designed to provide the investigator with a general understanding of the role and responsibility as a Sponsor and/or investigator, where to find direction and regulatory requirements, and how to complete the IND exemption or NDA submission process.

Investigational New Drug (IND) Application
The FDA website provides this comprehensive information on investigational new drug applications.

Device Advice: Investigational Device Exemption (IDE)
The FDA provides this information on applying for an investigational device exemption (IDE), which allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated.

Science Moving towArds Research Translation and Therapy (SMARTT) Webinar Presentation
Preparing for a pre-IND Meeting/Requirements for IND Submission. Topics include:

  • When and how to request a pre-IND meeting
  • Key elements of the FDA briefing package
  • Best practices and guidance for IND submissions

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Site Selection

Available on the NHLBI Toolkit Resource web page
  • Evaluation Tool to Assess Clinical Sites


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Participant Recruitment and Retention

Guidance for Investigators: Clinical Research Subject Recruitment and Retention
This document was prepared by the Resource to summarize information from the NHLBI guidelines on clinical study recruitment and monitoring (see below), outline basic principles for subject retention, and present additional considerations for studies supported by FDA.

Guidance and Implementation for Monitoring Adequacy of Accrual of Participants to NHLBI Supported Human Subjects Research
This guidance pertains to all clinical trials of 150 or more subjects, observational studies with 1,000 or more subjects, Clinical research networks; and ancillary studies of 1,000 or more subjects if they are separately funded and have separate consent.

AccrualNet
This site supports successful clinical trial accrual at each stage by providing links to existing tools and materials; a searchable, annotated list of published journal articles on clinical trial recruitment; a space to ask questions, post tips, share experiences, insight, materials and strategies; and training opportunities to orient and educate new staff to successful recruitment strategies.

ResearchMatch
ResearchMatch aims to serve as an effective, useful, and complementary recruitment tool that will help connect willing volunteers with researchers who are searching for appropriate volunteers to be placed in their research studies (not just clinical trials).


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Development of Training Manuals and Operating Procedures

Available on the NHLBI Toolkit Resource web page:
  • Protocol Template
  • Outline for a Manual of Operations for Policies and Procedures in a Multi-center study or Network


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Safety Monitoring

NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies
This document outlines the National Heart, Lung, and Blood Institute (NHLBI) policy for data and safety monitoring of clinical studies for all human subjects research funded in whole or in part by the NHLBI. The NIH requires the monitoring activities of all NIH-sponsored or -conducted clinical studies to be commensurate with their risks, nature, size, and complexity. This policy complies with the NIH mandate by making the NHLBI responsible for oversight of data and safety monitoring to ensure that an appropriate monitoring system is in place for all NHLBI-supported trials and that the Institute is informed in a timely manner of all recommendations emanating from monitoring activities.

NHLBI Tool Kit Resource
This page includes a link to a Data Monitoring Plan Checklist.

FDA Guidance Document - The Establishment and Operation of Clinical Trial Data Monitoring Committees for Clinical Trial Sponsors: Guidance for Clinical Trial Sponsors - Establishment and Operation of Clinical Trial Data Monitoring Committees
This guidance discusses the roles, responsibilities and operating procedures of Data Monitoring Committees (DMCs) (also known as Data and Safety Monitoring Boards (DSMBs) or Data and Safety Monitoring Committees (DSMCs)) that may carry out important aspects of clinical trial monitoring. This guidance is intended to assist clinical trial sponsors in determining when a DMC may be useful for study monitoring, and how such committees should operate.

Adverse Event and Unanticipated Problem Reporting Policy
This policy describes the requirement for reporting adverse events (AE) and unanticipated problems (UP) for the clinical research studies funded in whole or in part by National Heart, Lung, and Blood Institution(NHLBI) extramural programs.

NIH Guidance on Reporting Adverse Events to Institutional Review Boards for NIH-Supported Multicenter Clinical Trials
This National Institutes of Health (NIH) document provides guidance to investigators engaged in NIH-supported multi-center clinical trials to promote effective reporting of adverse events to the appropriate IRBs. The mechanism for reporting should be optimized to protect study participants from research risks, while at the same time reducing the regulatory burden on these committees. It is recognized that multiple parties, e.g., NIH, Food and Drug Administration (FDA), or industrial sponsors, must be notified of adverse events. However, this document provides guidance specifically for IRB notification.

21 CFR 312.23: IND Safety Reporting
Legal requirements for reporting safety information to the FDA for studies run under Investigational New Drug (IND) applications.

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Resource Sharing

NHLBI Policy for Data Sharing from Clinical Trials and Epidemiological Studies
The purpose of this policy is to describe the requirements for data sharing in applicable NHLBI-funded studies.

Data Sharing Workbook
The goal of this workbook is to show how investigators working in a variety of areas have shared their data.

Biological Specimen and Data Repository Information Coordinating Center (BioLINCC)
BioLINCC manages the NHLBI specimen and data repository and facilitates sharing of data and specimens from NHLBI-supported studies. The site contains information about resources available through the site and instructions for submitting new collections.

Guidelines for NHLBI Data Set Preparation
The purpose of this document is to provide information and guidance in the preparation of NHLBI data repository datasets and associated documentation for submission to the Biological Specimen and Data Repository Information Coordinating Center (BioLINCC) in accordance with the NHLBI Policy for Data Sharing from Clinical Trials and Epidemiological Studies.

Frequently Asked Questions about Sharing Data from NHLBI Funded Studies
This webpage provides answers to frequently asked questions about the data sharing policy for NHLBI-funded studies.

Genome-Wide Association Studies (GWAS)
In January 2008, the NIH implemented a policy for the sharing of data obtained in NIH-supported or conducted GWAS. The purpose of the policy is to foster science for the benefit of the public through the creation of a centralized NIH GWAS data repository. This Website supports the GWAS policy's implementation.


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Site Monitoring

Under Development

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