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10 Steps to Clinical Study Startup: Step 8 - Regulatory Documents and Critical Submissions

by Jae Chung

The collection of regulatory documents (also known as, "essential" documents) is the most important part of the study startup process, which ensure that sites are eligible to conduct a study.

10 Steps to Clinical Study Startup: Step 8 - Regulatory Documents and Critical Submissions

The "Essential" Documents

They provide the audit trail necessary to ensure compliance and are the first chapter needed for the re-creation of the study in the eyes of the regulators and auditors. Unfortunately, it is also the part that has been fraught with timeline, quality and compliance issues. There are many efficiencies to be gained in proper collection, management and tracking of all the essential documents. The documents can be outline in three basic categories:

  1. Federal/National Regulatory (i.e. FDA-USA, BfArM-Germany)
  2. Institutional Review Board (IRB)/Ethics Committee (EC) submissions
  3. Standard Operating Procedure (SOP) requirements

Federal/National Regulatory (i.e. FDA-USA, BfArM-Germany)

A minimum list of essential documents can be referenced in the ICH (International Conference on Harmonisation) E6 Guidelines. These essential documents indicate the approval and compliance of the sponsor, CRO, investigator, and IRB/EC as it relates to current government regulations and Good Clinical Practice (GCP). They are typically the first things that are reviewed during an audit by the sponsor, CRO, IRB and regulatory agencies.

Federal/National Regulatory Submission

When it comes to documents related to submission to federal/national regulatory agencies:

  • Protocol
  • Informed consent/patient cards
  • Investigators Brochure (IB)/Package insert
  • FDA Form 1572
  • Principal Investigator (PI) signed CV (within last 2 years) and current Medical License
  • PI signed Financial Disclosure Form (FDF); depending on regulatory agency
  • Protocol signature page

The protocol and IB are provided by the sponsor and are final, approved versions. The FDA Form 1572 is the US specific federal form and is the statement by the investigator that they will abide by the federal guidelines set forth in the Code of Federal Regulations as it relates to the use of drugs in an investigational setting.

The most significant issue found with regulatory documents is their completeness and accuracy, which significantly contribute to study startup delays. Many times, mistakes are found in the names of Sub-Investigators, addresses, and even the name of the protocol, which can impact study startup timelines, as the PI may not be available to sign off on a revised 1572. A thorough review will prevent delays.

Institutional Review Board (IRB)/Ethics Committee (EC) submissions

IRB/EC submissions contain many of the same documents for regulatory agency submissions with the addition of:

  • Site specific Informed Consent Form (ICF)
  • Health Insurance Portability and Accountability Act (HIPAA) or Electronic Medical Records (EMR) Consent Form
  • Executed Clinical Trial Agreement (CTA) and Budget
  • CVs, Medical Licenses and FDFs of Sub-Investigators as listed on the FDA Form 1572

The documentation requirements differ depending on the type of IRB/EC (local versus central) but are essential to ensuring a complete regulatory package is provided. In many countries in the European Union (EU), not only must sponsors contend with the requirements of their national regulatory agency but also local or provincial governing bodies. Being able to track and manage the different requirements for each helps to ensure timely startup of the clinical trial.

Carol Aliyar
Executive Vice President
Global Head Study Start Up
Syneos Health
"All organizations involved in conducting clinical trials whether pharmaceutical companies or CROs recognize the importance of having a dedicated Site Startup Department to navigate the complexities of differing regulations and processes in different countries as we undertake global drug development. It has become a complicated relay race with documents and processes being handled off between multiple parties. The race is on, to maximize the site recruitment months for both sites and patients. Site Startup teams are working to improve processes and leverage technology with the Study Startup remit to reduce cycle times and offer a more controlled and predictable experience for all."

Standard Operating Procedure (SOP) requirements

Each sponsor develops Standard Operating Procedures (SOPs) in addition to and in alignment with global regulatory requirements. These SOPs may require additional requirements – but not less than the needs of the regulators – and are developed to ensure compliance to the company standards and policies.

Regulatory agency approval of protocol and protocol specific needs

Some examples are noted here:

  • Site drug destruction policies and procedures
  • Training records
  • Instrument calibration procedures
  • IRB/Central Ethics Committee (CEC)/Local Ethics Committee (LEC) approval of Protocol and ICF with accompanying roster or assurance number
  • Central and/or Local Laboratory reference ranges and Certifications (i.e. CAP, CLIA)
  • Clinical Trial Insurance

The collection of the required forms is one step in the pathway to site activation and is combined with other activities to ensure a site is ready for patient enrollment, such as, conducting official training of the site staff in the protocol and protocol-required procedures, which will be conducted in one or more avenues such as the Investigator's Meeting (IM) and/or Site Initiation Visit (SIV).

Helpful tips for regulatory document tracking

The preparation and collection of regulatory documents can seem overwhelming especially with the vast amount of documents needed for regulatory, IRB/EC submissions, as well as, those required for internal SOPs. Accuracy, completeness, and consistency between all the documents is critical to keeping the timeline short. For example, names and addresses of PI and Sub-I's on their CVs, medical licenses and FDFs must match those listed on the FDA Form 1572. All committee approvals should reference the actual protocol, as well as, the ICF along with any other materials submitted for review.

A systematic approach and use of technologies which facilitate the document management process of tracking, submission, and review of not only each of the essential documents but the overall process will help to streamline operations and minimize startup timelines. All systems should enable study managers to determine whether study startup is moving along as expected. This will further allow sponsors to: 1) determine if there will be any delays and 2) proactively address bottlenecks before they become critical risks. The ability to communicate within and outside of your organization in a transparent and proactive manner will ensure all team members are aligned and management is informed.

Average Cycle Time to Complete Reg

Christine Pierre
The Society for Clinical Research Sites (SCRS)
"A critical element of successful study execution is a meaningful site initiation visit (SIV). Neither the SIV nor the study should initiate before all elements of study execution, including third-party processes, are in place. Given the many investigators and site staff that cannot attend investigator meetings due to time and financial constraints, the SIV is a spring broad for sites and partners to ensure the site is adequately knowledgeable about the fine points of study execution. A well-executed SIV provides the opportunity to lay out a roadmap for success."

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