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In early May, the FDA issued a draft guidance entitled “Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators Guidance for Industry.”

This is a 23-page document with much information on Investigator Initiated Trials / Studies (IITs/IISs) and which is aimed not so much at the industry but at the individual investigators doing studies on marketed drugs or drugs with an existing IND for a different indication. FDA calls these investigators “sponsor-investigators (SIs)”.

It does not apply to non-IND trials, devices or expanded access INDs.  FDA notes that this is not an exhaustive, step-by-step document but rather a summary of the important actions that the investigator needs to do. (I will use the acronym IITs to cover both IITs and IISs in this posting).

The main sections include:

There is not anything really new or ground-breaking here but it is an excellent summary in one place of most of the things the SI (and any associated sponsors or companies) need to do.

The FDA makes the key point that in these IITs, the SI must handle the responsibilities of both the sponsor and the investigator.

We’ll focus here only on the safety related matters.  For the remainder, see the document.  Note that this is a draft and comments are requested.

The sponsor-investigator is defined as “an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term, as defined in FDA regulations, does not include any entity other than an individual. As the name suggests, a sponsor-investigator assumes the responsibilities of, and must comply with, FDA regulations applicable to both a sponsor and an investigator. These responsibilities include the submission and maintenance of an IND.” (emphasis mine).

The most common situation occurs when a sponsor (usually a pharmaceutical company but also a government agency, academic institution or a private organization) asks or is requested by an SI to do a trial.  The SI is the individual who actually does the trial.  In most instances the SI “cross references” the sponsor’s already open IND.  There are other situations and they are noted in the draft guidance.

The guidance gives a fine summary of the required government forms (1571, 1572, 3674) required to be submitted by the SI.  In regard to safety, the Form FDA 1572 requires the SI to conduct the trial in accordance with the protocol, meet all informed consent and IRB requirements and comply with record keeping and adverse experience reporting.

Interestingly, the FDA notes that an Investigator Brochure (IB) is not required for an SI investigation; however, the SI should obtain the IB if it does exist in order to “ensure subject safety and to facilitate identification of serious and unexpected adverse reactions that may require expedited reporting to the FDA.”

Comment: I was not fully aware of the note FDA makes about an IB not being obligatory.  This makes sense if the drug is approved and the IB no longer used or up to date if, in fact, it even exists. In my many years of experience doing IITs (working for the pharma industry), we invariably supplied the IB to the SI.

Amongst the other things required in the SI’s submission to FDA, is a “description of the clinical procedures, laboratory tests, or other measures to be taken to monitor the effects of the investigational drug in human subjects and to minimize risk.”  Also required are all published material relevant to the safety of the proposed trial.

SI Responsibilities

This is the section of the document which discusses the responsibilities, including those regarding safety.

This section states the SI should conduct the trial under good clinical practices (GCP) including protection of human subjects and IRB review and approval of the studies.

This covers the usual responsibilities including monitoring of the investigation, protection of human subjects’ rights and well-being, data reporting and that the “safety reporting to the sponsor-investigator and the IRB, is accurate and complete”.

The SI must maintain adequate case histories and records including case report forms, supporting data, signed and dated consent forms, source documents etc.

The SI should expect that FDA may “periodically inspect trial sites” to ensure that all requirements are being met.

 No surprises here.  The SI must promptly review all information regarding safety and notify FDA of any unexpected fatal or life-threatening suspected ADRs within 7 calendar days. The SI must notify the FDA (and sponsors must notify all participating investigators) in an IND safety report of potential serious risks within 15 calendar days. The reports may be submitted in narrative format or using the MedWatch (3500A) form.  If other IND safety reports of a similar AR have been submitted, the SI must identify these reports and analyze their significance.  The SI also must notify the IRB of all unanticipated problems involving risk to human subjects.

The FDA refers to the guidance on “Safety Reporting Requirements for INDs and BA/BE Studies” for further information.

Again no surprises.  Within 60 days of the IND anniversary date, the SI must submit the IND annual report. In regard to safety, this includes:


There are no surprises here.  However, this is an excellent high-level review of most of what one needs to set up an IIT.  It is, as FDA says, not exhaustive, but it is very useful and should be read by anyone who works with INDs in the pharma world.

Obviously, the SI should read this!  In my experience, both setting up IITs and in doing audits of companies, there is often a woeful lack of understanding of the SI’s requirements and responsibilities.  Many SIs, as well as some CROs, academic centers and others in the US and abroad, do not fully realize what they are getting into nor do they quite understand their legal responsibilities and potential liabilities.  Many are not aware that their malpractice insurance may not cover clinical research. Many do not work directly with the clinical research office at their institution (if such an office exists).  Many who do work with the office have not, unfortunately, followed the rules fully. Often the clinical research office is understaffed and is not able to monitor all the ongoing trials in their institution.  Some medical centers and universities are so large and spread out geographically (especially as major medical centers are buying up area clinical practice groups) that some studies slip through the cracks.

This guidance also emphasizes the need for pharma companies to be sure that their medical liaisons and groups that set up and maintain IITs are fully empowered and well aware of the rules and requirements for IITs.  There must be written contracts between the sponsor (e.g. the one holding the original IND) and the potential SI.  All required documents (IB, annual reports, DSURs etc.) must be supplied and revisions and updates sent out.  The requirements noted in this guidance should be addressed in the contract and it should be clear who is responsible for each requirement.

The sponsor company holding the IND must decide how tightly they are going to track or monitor the ongoing IIT.  Certainly if they have a contract and are supplying some or all of the following: drug supplies, IB, informed consent, CRFs, safety reports from other participating investigators etc. the company is deeply involved and should track at an appropriate level the activities of the SI.  In particular regarding safety, all SAEs should be sent to the sponsor asap (perhaps raw information within a day or two, or a MedWatch form by calendar day 5 for 7 day reports or 12 for 15 day reports or some similar set-up).

In my experience, there is still a large amount of looseness in place regarding IITs.  Many companies and many academic centers do not have adequate SOPs, rules, restrictions and oversight in place.  This can place patients, SIs and companies at risk.  If a non-approved indication is being studied, this trial should have oversight sufficient to protect the patients and all others involved.  The section in this guidance on clinical holds indicates that FDA will certainly be monitoring these IITs.  The company, the institution, the IRB and all the other players involved must treat these trials as seriously as they treat any other IND clinical trial.


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