After a five- to eight-year decline, investigator-initiated trials (IITs) are gaining renewed interest as more biopharmaceutical companies are using them as a creative and cost-effective way to innovate and further improve patient safety.

Unlike industry-sponsored trials focused on regulatory approval of new medications, IITs are developed and executed under the direction of third-party clinical investigators who are physician researchers, often within an academic institution. The investigator or affiliated study sponsor, working in an academic medical center, is responsible for study conception, design, operational execution, data handling, and data analysis and interpretation, along with subsequent publication.

IITs also require institutional review board (IRB) approval of the protocol.

The value of such studies serves an important function in the development of drugs and devices beyond new product regulatory approval because there is no way to completely understand all the potential risks and uses of a product until it is in the general population. Traditional company-sponsored clinical trials cannot be developed to answer all those questions. That’s why companies are turning to IITs as a vital way to expand their knowledge about safety and additional uses that can improve the health of more patients and meet regulatory requirements.

The trials, which generally run from several months to two to three years, are unsolicited and rely on investigators to conduct them to advance medical and scientific knowledge under the same regulatory scrutiny as trials initiated by the industry. Typically, IITs—sometimes referred to as Investigator Initiated Sponsored Research (IISR) programs—are conducted to support researchers who are not affiliated with a specific biopharmaceutical company but are studying the company’s products or disease areas of interest. Ideally, the completed IISR study will be published in a journal.

Biopharmaceutical companies provide financial support and/or drug products for IITs as part of a written agreement that requires independent investigators to comply with applicable local laws, rules, guidelines and regulations.

“While IITs are a niche academic area, they are often used to augment sources of evidence, and are gaining interest among a growing number of companies as they fill the spaces around the company’s directed trials, such as new indications and for new patient populations,” said Scott Cunningham, the leader of the Association of Clinical Research Professionals (ACRP) Investigator Initiated Sponsored Research Interest Group. “What we’ve found from a survey within ACRP, which will be published soon, is large and small biopharmaceutical companies are utilizing IITs more effectively but we haven’t seen the same with medium-sized biopharmaceutical companies where the number of IITs is either flat or down—and we are not sure why. IITs are still a niche area that simply has not taken off, but is widely talked about.”

Although the investigator’s goals may be purely scientific, a biotechnology or pharmaceutical company might find one or more studies worthy of support. Among them, as cited by the Journal of Clinical Research Best Practices:

• Explore use of a marketed drug for new indications, in new populations, in new dosages regimes or in new combinations with other treatments.
  Evaluate biomarkers that could be useful in diagnostic tests or treatment management.
• Redefine safety and effectiveness information.
• Foster scientific exchange and collaboration.
• Demonstrate the company’s willingness to expose its marketing claims to third-party research.

Increasing IIT activity

In recent years there has been an increase in IIT activity in clinical trials sponsored and conducted by academic investigators, according to the National Institutes of Health (NIH), where the number of IITs tripled between 2011 and 2014.

“Among the reasons for the increase in investigator-initiated research trials is that nowadays, those investigators have better access to information, they understand what needs to be done to get a project submitted and approved by a company like ours, so I think people are more knowledgeable today about the entire IIT concept and process,” said Janssen Pharmaceuticals Vice President and Global Head of Medical Affairs Operations Carlos Castillejos. “Investigator-initiated trials or investigator-initiated studies are very interesting ways to experiment with compounds and show regulators that we are managing things properly. For us, this year has been the highest number of IITs ever.”

IISR studies also have increased at Millennium, the Takeda Oncology Company, which has more than 100 ongoing studies—most of them in the U.S. and Europe—according to Liviu Niculescu, Millennium’s vice president of medical affairs.

“At Takeda, our large IIT oncology program is for new drugs on the market or close to getting approved, but we also have proof-of-concept-stage studies,” said Niculescu. “We use these studies to explore numerous patient populations, sometimes different doses in small trials that give us mostly a signal for seeking information and for other cancers. For example, with a trial drug to treat multiple myeloma, the approval direction is focused on a certain patient population with this indication. However, it may also work in colorectal cancer, but we aren’t going to start a new development program. Yet we know some investigators who are specialists and have a career in research of colon cancer. So we may turn to them to try our cancer medication on a few patients to see if it might work.”

Niculescu said that the use of IISR programs has increased slightly and works fairly well in providing new knowledge and increased patient safety. The company uses a dedicated portal for independent investigators to submit their proposals, which also functions as a gateway for investigator communication and updates with medical science liaisons and company medical directors.

“You learn a lot from these discussions with investigators working in academic medical centers, but the negotiations with everyone involved and making sure we are all meeting many regulatory guidelines can take as long as a year,” said Niculescu.

Risks and challenges

One of the greatest challenges for IIT teams is the contract negotiations toward a clinical trial agreement, which averages 70.5 days among the companies surveyed for a recent report by Cutting Edge Information, a Research Triangle Park, N.C.-based business management and consulting firm. The primary reasons for such elongated timelines: complicated contract review processes and complex negotiations and/or disagreements.

The study also found the average amount of time for investigator-sponsored research approvals from concept submission to concept decision is 48.1 days, as sponsors seek to bridge the gap between scientific discovery and its translation into new medicines.

The growing body of research has led sponsor companies to devote more resources to keeping track of it all. A recent Cutting Edge study found that the percentage of biopharmaceutical companies using a dedicated team to handle IIT management continues to grow. In 2006, half of surveyed teams reported having such a dedicated group; that number rose to 91% of respondents in 2014.

Trial protocol complexity has a major impact on the proposed budget, noted Cutting Edge. Its survey of IIT managers cited funding requests ranging from $10,240 for a urology chart-review study up to $6.5 million for a 50-site, 1,000-patient multiple sclerosis study. IIT teams provide on average a $115,000 grant per study.

According to Cutting Edge, biopharmaceutical companies may receive anywhere from two to 800 IIT submissions in a given year—often with the lengthier proposals that require longer reviews and the need for teams to properly vet each proposal. If they don’t, companies risk putting their products—and the resulting data—in poorly designed studies with inexperienced or unqualified investigators.

Disciplined approach

At Janssen, Castillejos said longer approval times also reflect greater discipline in making sure all the safety aspects are managed properly. In the past 10 years, he noted, there has been greater clarity and delineation between sponsors’ and independent investigators’ respective responsibilities.

Castillejos cited how Janssen typically converses with investigators on a range of issues, saying that the most requested proposals that Janssen receives for IITs are in oncology, cardiovascular, metabolism and immunology where the company typically works with investigators on compounds in late development.

Janssen has received requests, sent by investigators and academic organizations, for IITs that could provide a better understanding of particular compounds on a population subset or in a particular setting where the company has not done that work internally.

“After a thorough evaluation of the scientific and safety merits of a particular concept and what is the potential benefit to the organization, we then decide whether to support it or not,” said Castillejos. “We don’t promote what we are doing or looking for because we will wait for investigators to come to us with a proposal for what they want to do and why—and if there is a potential impact to benefit patients, only then will we decide to fund it. The proposal always starts on the investigator’s side.”

That approach is similar in the Asia-Pacific region, where IITs also are widely used to advance medical science, knowledge and patient safety, according to Stephanie Tan, M.D., associate director with the Quintiles Asia Site and Patient Network.

“These investigators at academic centers also provide real-world information from the clinical side in how a drug fares, and can launch a study if they see documented adverse events,” said Tan, who has co-authored a guide on developing and conducting IITs. “Lately there has been a lot of interest in the Asia-Pacific, where these trials are increasingly seen as worthwhile to address unmet needs. The average trial lasts 18 to 24 months. The only real limitation is that funding for this kind of research is limited.”

For physician researchers who develop IITs in North America, their investigative studies in some cases can be part of a biopharmaceutical company’s strategy to expand information around the product or therapeutic area. Whether the company will benefit from the study, whether it involves the product or therapeutic area or whether the investigator is important to the company should not be criteria for approval, noted Cunningham.

He said the development of IITs must be carefully considered, with appropriate planning, because budgets too often are not aligned with fair market value. Other major risks are team inexperience, which can lead to the study not being conducted, and inappropriate reporting of data. He said the renewed interest in IISR/IITs comes as pharma companies are increasing their programs globally with more industry dollars and a decrease in funding from government—notably the NIH—which impacts academic centers.

“Most companies are requiring investigators to log on to ClinicalTrials.gov to show who the sponsor is for each trial,” said Cunningham. “For physician researchers often working with tight budgets, conducting investigator-initiated trials is a pathway to publishing research. This type of research shouldn’t be a way to make a substantial amount of money, as the end goal is to create evidence that supports the therapeutic area, gain knowledge about the disease endpoint and benefit patients.”

Looking ahead, Cunningham noted that the outlook for IISR programs is strong, provided regulatory requirements don’t change drastically.

“There will be an uptick in these types of studies as biopharmaceutical companies continue to see the value of this type of independent study,” he said, “because good ideas are everywhere and external research supports the development of new applications and new products in new areas for growth.” 

Ronald Rosenberg is a former business and science reporter for The Boston Globe. He has written features for New Scientist and Inc. magazine. His lengthy journalism career includes editing an award-winning weekly newspaper in Cornwall, N.Y. Ron also was a media relations specialist for the science faculty at Boston University, and a Knight Science Journalism Fellow at the Massachusetts Institute of Technology.

This article was reprinted from Volume 22, Issue 10, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>