Gerald L. Klein M.D. Principal MedSurgPI
Peter C. Johnson M.D. Principal MedSurgPI
IITs Can Be an Effective Way to Obtain Proof-of-Concept Data More Quickly Than the Bureaucracy of a Large Firm Would Allow
The investigator-initiated trial (IIT) is a unique type of clinical trial in which the clinician is both the sponsor and the investigator.
A clinical investigation is defined as an experiment in which a drug or device is administered or dispensed to, or used, involving one or more human subjects. Such an experiment is any use of a drug or device [whether approved or unapproved] except for the use of a marketed drug or device in the course of medical practice.
A sponsor of an investigational new drug (IND) application is the party who submits the application to FDA. In the absence of any other sponsor (e.g., pharmaceutical company), the investigator conducting the proposed clinical investigation is the sponsor of the IND application (when needed), as outlined here:
21 CFR 312.3 and ICH E-6 (GCPs) 1.54
— Plans, designs, conducts, monitors, manages the data, prepares reports, and oversees all regulatory and ethical matters
— 21 CFR §312 Subpart D
This person takes on the regulatory responsibility of initiating and conducting a clinical trial. These trials may either be post-marketing studies or for unapproved products or indications.
IITs can be an effective tool for both large and small biopharmaceutical companies. If this program is conducted properly it may be a way to obtain expedited proof-of-concept data more quickly than the internal bureaucracy of a large company would allow. The IIT program should be conducted in a transparent, compliant, best practice manner to ensure proper execution of a quality program, which will subsequently allow the optimum use of the generated data.
From the company perspective, the IIT should be separated from marketing and kept under the auspices of medical affairs, in order to help comply with 68 Fed. Reg. 23736 (anti-kickback regulation). A formal set of standard procedures should be in place for these studies. A company may decide to use a committee consisting of representatives from medical affairs, clinical research, regulatory, and commercial, to determine which IITs should be approved and funded. It is desirable to provide instructions about the application process for IITs on a company’s website with the company’s required information needed to review and make a decision.
Medical Science Liaisons (MSLs). These are highly trained medical educators (typically but not always M.D.s or Ph.D.s) who convey the science rationale behind medical products to clinicians—and respond to their scientific queries. MSLs may not be involved in selling products and should not report to a commercial superior.
MSLs should play an important role in communicating the areas of research that your company is interested in pursuing to the appropriate key opinion leaders (KOLs). They should artfully explain the types of studies that the company would be willing to support financially, the types of trials for which they would provide only product support, and those trial types that they will not support at all. The MSLs should also discuss with KOLs what additional scientific support they could provide if needed. Examples of this include support for data management and statistical analysis.
Some important regional KOLs may not be very experienced in the design, conduct, and requirements of clinical trials and may need additional assistance from an MSL. The MSL should explain the necessary steps for applying to the company for an IIT grant. Rather than trying to teach an inexperienced clinician directly how to undertake an IIT, it may be more effective to unite him/her with a more experienced physician who has the same interest as the original KOL. Collaboratively, they can work on the IIT and more easily overcome potential obstacles.
When the IIT has been completed, the medical affairs team should discuss its interest in sponsoring the results that will be presented at an appropriate scientific conference, either in the form of a poster or an oral podium presentation. The investigator may need some assistance in editing and formatting the data for such a presentation as well as similar help in the preparation and submission of a manuscript. Some companies may want to pay for the article to be an open access publication, so that a larger audience may read the manuscript without having to pay a journal fee.
Types of Clinical Trials
There are diverse types of clinical trials that could provide significant scientific data and impact both product development and commercial operations. These include pharmacoeconomic, quality of life, observational studies, and both retrospective and prospective double- and single-blinded randomized, controlled trials.
Open-label studies such as case-control trials are not blinded, but can provide valuable scientific information at a lower cost than double-blind studies. Epidemiological studies can determine the specific risk factors in a population and then, using a prophylactic study design, determine with reasonable assurance the effectiveness of a therapeutic or device to prevent or decrease the problem. Patient reported outcomes (PROs) are becoming increasing important and widespread. In this type of trial the results come directly from the patient.
“Pragmatic” studies evaluate the real-life effectiveness of a product by the way the product is actually being used by healthcare providers, hospitals, and patients. They can be quite effective in comparing diverse treatments. A well-known example of this was a pragmatic study published in the New England Journal of Medicine comparing the use of a once per day tablet (leukotriene antagonist) versus an inhaled corticosteroid in the first study and a long acting bronchial dilator in the second study for treatment of bronchial asthma.
Most experts thought that because the inhalers had been shown to be so efficacious in randomized clinical trials that it would easily win in a comparative study. Yet the authors concluded that the results found no significant difference in the efficacy results. However, adherence was better in the use of a tablet than in the use of an inhaled steroid or long-acting bronchodilator.
In summary, a carefully planned and executed IIT strategy can provide quicker proof-of-concept data and accelerate drug and device development as well as provide increased marketing penetration of approved products.