Investigator Initiated Trials

Investigator-initiated trial: Definition

Investigator-initiated trials (IIT) are clinical trials initiated and managed by an investigator, institution, or a group of institutions that are not pharmaceutical companies.[1] These trials are also commonly known by the following terms:

• Investigator-sponsored trials (IST): IITs are sometimes called investigator-sponsored trials (IST) because the entity taking responsibility for and initiating a clinical trial is officially called a sponsor.
• Investigator-initiated studies (IIS): The term 'trial' is often replaced with 'study,’ as a clinical trial is a type of study designed to evaluate new medical interventions.
• Investigator-initiated research (IIR): Any clinical research trial/study initiated by an investigator.

Some other names for investigator-initiated trials include noncommercial trials, academic clinical trials, and physician-led studies.

In an investigator-initiated trial, the same person or entity acts as - and assumes the roles and responsibilities of - both the investigator and the sponsor.

What is the difference between a sponsor and an investigator in clinical trials?

Sponsor and investigator are two major roles in a clinical trial. The sponsor is the entity that initiates a clinical trial, takes full responsibility for it, and coordinates trial activities across all trial sites. The sponsor may be an individual, a pharmaceutical company, an academic institution, or a private firm.[²]

On the other hand, an investigator is a person or a group of people who actually conduct the operations involved in the clinical investigation. The investigator is responsible for distributing/administering the investigational product, conducting study visits, communicating with patients, and gathering data. Typically, a clinical trial involves a principal investigator (PI), either centrally or at each individual study site, who leads a diverse team of other members to execute the trial.

Sponsors don't partake in the actual conduct of the trial, unless the investigators themselves sponsor the trial, as is the case for investigator-initiated trials.

Investigator-initiated trials vs. sponsor-initiated trials

In sponsor-initiated trials, an individual or a firm (usually pharmaceutical or biotech companies) initiates a research study, taking on the legal liabilities and responsibilities associated with it. They select a team of qualified investigators to conduct the trial while they monitor its progress and ensure the protection of human subjects.

In investigator-initiated trials, the sponsor's role and duties are merged with the investigator's role and duties. This means that the same individual or firm, usually non-pharmaceutical researchers like clinicians and researchers working in health or academic institutions, is both the sponsor and the investigator - appropriately referred to as the “sponsor-investigator.”

A key difference between IITs and sponsor-initiated trials is that IITs are often smaller in scale. The reason for this is that IITs typically involve more-limited resources and funding.

IITs may feature more flexible study designs, as sponsor-investigators can explore their unique hypotheses and research questions. Comparatively, sponsor-initiated trials tend to be conducted on a larger scale, with a more rigid study design established by the sponsor institution.

The regulatory requirements for sponsor- and investigator-initiated trials also differ, but both types of studies must comply with ethical standards, obtain approval from institutional review boards (IRBs), and fulfil strict safety and efficacy standards before the investigational product can receive marketing approval.

The unique utility of investigator-initiated trials

Most trials initiated by pharmaceutical companies are conducted to gain regulatory approval for new drugs and other interventions, or to support marketing claims for an existing drug.

On the other hand, investigator-initiated trials can serve more diverse purposes. They are positioned to address real-world problems and experiences with a particular product in the market. Further, they can help tackle questions that were left unanswered in other clinical trials, filling knowledge gaps that haven't been addressed.

Some specific scenarios where IITs may be the preferred choice include:

• To test an existing drug for a different treatment process or new therapeutic indication
• To compare two or more treatment choices, particularly when they belong to different pharmaceutical companies
• To develop new clinical practice guidelines

Clinical studies of this nature are usually not of interest or commercially viable for the pharmaceutical industry. Hence, research institutions, clinicians, physicians, hospitals, and other investigators may decide to take the initiative to sponsor such clinical studies themselves.

IITs have numerous benefits for researchers, patients, and the healthcare sector. They increase the amount of information available regarding product safety and efficacy, and can be designed to solve actual problems faced by clinicians in real-world settings during routine practice. The data gathered and interpreted by non-industry sources is also often considered to be more credible.

Additionally, IITs require cross-functional collaboration between departments of the sponsor-investigator institution, which also enables the development of new and innovative ideas and processes.[³]

Investigator-initiated trials: Sponsor-investigator's responsibilities

In an investigator-initiated trial, the roles of a sponsor and an investigator are assumed by the same individual or firm, commonly called a sponsor-investigator.

Sponsor-investigators initiate and take responsibility for the trial as sponsors.[⁴] As investigators, they lead the actual conduct of the trial. They must comply with the regulatory requirements applicable to both the investigator and the sponsor. The following are some of the main responsibilities of a sponsor-investigator in IITs:

• Securing funding for the trial
• Applying for appropriate insurance
• Obtaining informed consent from the participants
• Establishing written procedures (SOPs associated with GCP)
• Ensuring and managing resources (investigational product, staff, medical supplies, etc.)
• Maintaining proper trial documentation and submissions (informed consent, trial protocols, IRB submissions, etc.)
• Ensuring regulatory compliance (approvals by and reporting to review boards and regulatory agencies).
• Monitoring the progress of the investigation
• Safeguarding the rights and safety of participants

Investigator initiated trials: Guidance for prospective investigators

Many investigators wanting to initiate a clinical research study are faced with high barriers relating to the knowledge/expertise and the resources that are required to handle the IND submission and to conduct a clinical trial in general (spanning a multitude of disciplines and considerations that extend far beyond the scope of typical clinical practice or research). However, many resources are available online to assist interested investigators in preparing and submitting the required applications to FDA's Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER).

For example, Novartis has published a detailed guide for sponsor-investigators that includes considerations for assessing the feasibility of conducting a clinical study, an overview of the submission and application process, an overview of the IIT process and safety reporting requirements, and details on study results and publications.

Another helpful resource is the information published by the FDA itself that explains everything about how sponsors-investigators can submit Investigational New Drug Applications (INDs).

Regulatory submissions and requirements for investigator-initiated research studies

A sponsor-investigator must follow FDA regulations that apply to both investigators and sponsors. One of the primary regulations a sponsor-investigator wanting to test a new drug or a new use for an existing drug must comply with is the submission of the IND (Investigational New Drug) application.

Filing an IND requires the completion of 3 forms:[⁵]

• FDA Form 1571 - The cover page of the IND application containing important study details. This form establishes a contractual agreement between the sponsor and the FDA. This form must be attached to the initial IND submission, along with any amendments, IND safety reports, annual reports, or general correspondence the sponsor submits to the FDA about the IND.[⁶]
• FDA Form 1572 - Statement of Investigator: This form requires details regarding the investigators and study sites. Sponsor-investigators can send copies of Form FDA 1572 with its attachments to the FDA to satisfy field 13, items 6 b-d of Form FDA 1571.
• Form 3674 - Certification of the requirement to post the trial on clinicaltrials.gov: This form certifies that the trial is registered in the national database of clinical trials. IDE (Investigational Device Exemption) applications do not require this form.

The IND application includes information relating to the following considerations:[⁷]

• Animal pharmacology and toxicology details to ensure that the drug is safe for initial testing in humans. This includes data on any previous experience with the drug in humans, and any anticipated risks, precautions, side effects, and special monitoring considerations. Sponsor-investigators can meet this requirement by submitting a Letter of Authorization cross-referencing a third party's application.
• Data related to drug composition, manufacturer, stability, and production controls. This information ensures the company can manufacture and supply consistent and pure batches of the drug.
• Clinical protocols. Details on the clinical protocol help the FDA evaluate if human subjects would be exposed to any unnecessary risks during the trials.
• Investigator information. Information on investigators' qualifications must be included to demonstrate that they have the required training and knowledge to effectively fulfill their clinical commitments and duties.

Conclusion

Investigator-initiated trials can be designed to address research questions that are of high value to clinical practice but which are not typically being pursued by the pharmaceutical industry or other commercial entities. Many important research questions may not be considered financially viable by these organizations, even if they can potentially lead to significant clinical benefits; IITs can help bridge the gap between clinical research and clinical practice.

In addition, IITs are often conducted in academic medical centers or other research institutions with a strong focus on collaboration and interdisciplinary research. This can lead to innovative study designs, the incorporation of cutting-edge technologies and methodologies, and even the identification of new targets and pathways for drug development.

Becoming a sponsor-investigator of an investigator-initiated trial can be a complex and challenging undertaking. It is essential to be familiar with the regulatory, financial, scientific, and ethical considerations involved in clinical research, but there are support and guidelines available, and the efforts can bring about significant benefits - both for the sponsor-investigator and the broader public benefitting from the resulting healthcare advances.