Early-Phase Clinical Research Unit Provides Proof-of-Concept Expertise

August 22, 2011

The recent integration of the Duke Clinical Research Unit (DCRU) into the Duke Clinical Research Institute (DCRI) has added a unique model for conducting early phase clinical studies into DCRI’s toolkit of clinical research services.

Placing the DCRU within the DCRI combines early phase clinical research expertise with a powerhouse infrastructure comprising more than 200 practicing clinicians across all therapeutic areas; a massive collection of patient registries and outcomes data; and highly skilled professional staff in the areas of statistics, clinical operations, data management, communications, and information technology.

DCRU feature (Duke unit)

As the world’s largest academic research organization, the DCRI is known for conducting multinational clinical trials, managing major national patient registries, and performing landmark outcomes research. The DCRI has conducted more than 730 studies, enrolled more than one million patients, and collaborated with more than 5,000 investigators in 64 countries. The DCRI’s phase III and IV megatrials, in particular, directly affect treatment guidelines regarding patient care.

The DCRU is a study site—a 30,000 square-foot, state-of-the-art research facility located within the Duke University Medical Center (DUMC)—as well as a collection of resources necessary to the conduct of small but highly complex phase I and II trials. It supports study sponsors and investigators who are 1) testing new drug candidates and other cutting-edge therapies or 2) seeking to identify and validate novel biomarkers of disease and treatment response.

Placing the DCRU within the DCRI combines early phase clinical research expertise with a powerhouse infrastructure comprising more than 200 practicing clinicians across all therapeutic areas; a massive collection of patient registries and outcomes data; and highly skilled professional staff in the areas of statistics, clinical operations, data management, communications, and information technology. Because of this integration, the DCRI can now offer study sponsors and investigators exhaustive scientific and operational support for activities in all stages of clinical research, from first-in-human testing to applying for FDA-approval.

“Our clients can avoid reinventing the wheel when transitioning from one phase of a clinical study to the next,” said DCRI clinical trials project leader Kathy Moore. “They can do their early clinical work with us, then take their compound right into phases III and IV while using the same database structures, the same statisticians, and the same operational staff who already know more or less what [the sponsors] want.”

This integration is also expected to enhance the career development of DCRI faculty by creating opportunities for them to be involved in the entire drug development process.

“Ideally, we would assign one or more faculty members to a compound that is being studied in the laboratory so that he or she can guide the design of a first-in-human or proof-of-concept study,” said John Sundy, MD, PhD, director of the DCRU and director of immunology and inflammation medicine research at the DCRI. “If the compound is safe and shows promise, then we’ll move that project and researcher along to later phases of the development pathway, all the way to regulatory approval. Integrating the DCRU into the DCRI definitely allows us to offer a more comprehensive packet of clinical research services, but it also broadens our own investigators’ perspective and knowledge base.”

 

Exhaustive study of new drugs

DCRU studies encompass more than 20 therapeutic areas. Many incorporate patient populations that are not typically studied and thus have very little data available regarding drug behavior. These populations include children, pregnant women, the elderly, and patients with chronic kidney disease, impaired liver function, or other co-morbidities that interfere with how the body absorbs and metabolizes medications. The DCRU’s hospital-based unit makes it easier for researchers to work with these types of patients and conduct research within the context of their care.

“We are doing more and more early phase drug development work in patients who actually have the disease being treated because we have access to those patients,” said Sundy. “Being part of Duke also puts our research subjects in an environment where there’s adequate physician support at all levels to help in the case of an adverse event or some other problem that arises. Freestanding or independent early phase units do not have these advantages.”

To accommodate the unique needs of the DCRU, the DCRI is adjusting its operational models. This includes reducing the time it takes to build clinical trial databases from an average of 8–12 weeks, which is standard for phase III and IV trials, to 4–6 weeks, which is standard for phase I and II trials. The DCRI is also incorporating pharmacokinetics (PK) and pharmacodynamics (PDs) analyses into its statistical models. PKs (what the body does to a drug) and PDs (what a drug does to the body) analyses are used extensively in early phase clinical research.

“Some early phase studies look at dosage, safety, and toxicity. Others test for proof-of-concept,” said Sundy. “Proof-of-concept, meaning—does the drug cause a biochemical change that we’re expecting to see? Does it have off-target effects that may lead to safety concerns? Does it go where it’s supposed to go in the body? They examine whether the scientific mechanism for which the drug is designed is accomplishing its goals.”

Rigorous proof-of-concept studies typically require genomics, proteomics, metabolomics, advanced imaging, and other sophisticated research tools that rarely exist in a clinical setting but can be accessed through the DCRU. By augmenting these resources with the scientific and operational capabilities of the DCRI, Sundy hopes to create a new paradigm that incorporates the exhaustive study of new compounds into standard practice in early phase research.

“The average cost of developing a new drug is now approaching $1.8 billion, and a huge portion of that money is spent on late phase studies. If a drug fails at that point, you’ve already sunk a lot of money into it, and that’s money that can’t be reinvested in another compound,” he said. “We want to get rid of drugs that don’t work and advance drugs that show merit as early as possible, but also with the most information possible. This creates a situation where, if it turns out that a drug doesn’t work, money can be reinvested in other compounds. At the same time, we can say with confidence that we didn’t inappropriately terminate promising drugs.”

 

Best-in-class partners

In line with this vision, the DCRU is now part of a global network of early phase clinical research units with the ability to conduct exhaustive proof-of-concept studies across ethnically diverse populations. Other members of the network include the SingHealth Investigational Medicine Unit (IMU) in Singapore and the Medanta Duke Research Institute (MDRI) in India.

The SingHealth IMU is a 32-bed early-phase clinical research unit that opened in July 2010 at Singapore General Hospital at Outram Campus and is affiliated with the Duke- National University of Singapore Graduate Medical School (Duke-NUS) in Singapore. It is funded by SingHealth, Duke-NUS, the Singapore Institute for Clinical Sciences, and Singapore’s National Medical Research Council.

Duke has also partnered with Medanta-The Medicity, a conglomeration of multi-super specialty institutes in Gurgaon, India, to establish the MDRI, a 60-bed early phase clinical research facility that is expected to open later this year. Under the terms of the agreement, Medanta will fund the creation and operation of the 27,000-square-foot facility, whereas Duke will provide the scientific, clinical research, and operational expertise. Medanta and Duke will share joint oversight over implementation and management of the unit and ensure adherence to the highest ethical standards and transparency.

“The idea is to look for best-in-class partners that would allow everyone involved to leverage scientific and operational expertise, access to [diverse] patient populations, and funding sources,” said Krishna Udayakumar, MD, MBA, director of Duke Medicine Global. “If we want to work with the best and the brightest doctors and students and trainees in India, for instance, we have to engage them in their local environment. There are also certain disease entities and patient populations not accessible in the U.S. that would be accessible in other places, whether in Singapore or India or somewhere else in the world. Lastly, obtaining research funding from, say, the government of Singapore would not be possible if Duke didn’t have a local presence there.”

As more pharmaceutical and biotechnology companies in Asia move toward developing their own compounds and intellectual property, Duke hopes to be part of a local solution that produces high-quality research that meets international standards. Udayakumar notes that bringing clinical research expertise to as many places as possible supports Duke’s role as a global educator and makes its work more relevant.

“Our plan right now is to consolidate the operations of these three units and develop a real model for scientific and operational partnership, and then from there, we would very much be in favor of looking at additional partners,” he said. “Developing strong collaborations with medical centers and research units around the world is something that the DCRI has done quite successfully over the years. This expansion is a continuation of that strategy.”