As biopharmaceutical companies in­crease R&D investment in precision medicine, a trend that is expected to rise by one-third in the next five years, clini­cal research professionals will need to imple­ment operating practices and processes that can meet the complex demands of an indi­vidualized approach to drug development.

Precision medicine studies require the involvement of investigative sites that have experienced and highly trained staff able to handle complex, sophisticated protocols. Key challenges include the capability to collect and store frequent samples from pa­tients while also managing large amounts of data, including genomic information. Since companion diagnostics that identify bio­markers play a big role in precision medi­cine, clinical research professionals need to be adept at testing complicated protocols that involve a diagnostic. In order to iden­tify the small number of patients needed to meet very narrow protocol requirements in a precision-medicine paradigm, sites must also be part of broader networks that offer access to large electronic medical record systems.

The clinical research enterprise needs to recognize how precision medicine is chang­ing the drug development environment and respond to operational challenges, because the momentum for precision medicine is growing at a rapid rate.

According to research from the Tufts Center for the Study of Drug Development (CSDD) at Tufts University, biopharmaceu­tical companies have nearly doubled their R&D investment in personalized medi­cine during the past five years, and 42% of all drugs in the pipeline have the potential to become personalized medicines. Tufts CSDD predicts a 69% increase in the num­ber of precision medicines in development during the next five years. Today, personal­ized medicines represent 13% of all approved medicines and 137 drugs have genomic information in their label.

President Barack Obama gave precision medicine a boost last year when he an­nounced a $215 million na­tional Precision Medicine Initiative, which aims to speed the development of treatments through a pa­tient-centered approach, and establish a national database of genetic and other data from one million people in the U.S.

“Everyone in the clinical trials industry understands this is the direction research is going,” said Christopher-Paul Milne, director of re­search at Tufts CSDD.

Major changes required

While traditional clinical research relies on patient population averages, precision medicine seeks to identify the best treat­ment for each individual based on the pa­tient’s unique characteristics. The approach calls for identifying specific biomarkers for diseases and requires researchers to inves­tigate many different factors—including genetics, lifestyle and diets—to evaluate the effectiveness of an intervention on in­dividual patients. This new paradigm will require significant changes in clinical trial conduct in the coming years.

For example, researchers will need to ex­amine individual patients’ tissue samples before, during and after treatment, which can help them understand the uniqueness of individual responses to certain kinds of treatments. Those samples must be large enough to understand the disease, so inves­tigative sites must have the capabilities to obtain sufficient high-quality patient speci­mens; data needs to be collected frequently from each patient, perhaps for months or years.

Jeffrey Spaeder, M.D., chief medical and scientific officer at Quintiles, said that in order to meet the research demands of a preci­sion medicine approach, inves­tigative sites will require larger staffs that might include bio­statisticians, more clinical and site monitoring, and CRAs who comprehend biomarkers and stratification.

“Sites [have] needed to be more robust in working with subjects on informed consent and other qualifying issues. But now, with precision medicine, biomarkers will have a big role in making enrollment decisions along with laboratory results. Also, principal investigators (PIs) will have to be tenacious and consistent, and stay engaged and excited, to be part of the new paradigm of precision medicine,” Spaeder said. “Staffs may grow, but the tradeoff is that there are fewer patients. Clinical tri­als will have shorter durations, which could lead to a cost reduction of the clinical study, even with additional assays, tissue process­ing and analytics.”

Institutional review boards (IRBs) need to acquire the skill sets that will enable them to review the complex science and specific challenges of precision medicine studies while protecting patient rights. Lindsay Mc­Nair, M.D., chief medical officer at WIRB-Copernicus Group (WCG) and president of its consulting services, said WCG uses the same criteria applied to traditional clini­cal trials to assess new precision medicine study designs for elements related to partici­pant protection.

“For many years, clinical trials have in­volved the identification of molecular and genomic markers, either as an integral part of the research study or as a sub-study, or in the collection of samples for future use,” said McNair. “While precision medicine initiatives formalize and coordinate those efforts to maximize the information and medical advances that can come from it, the concerns about maintaining privacy re­main the same.”

Precision medicine aims to tailor treat­ments to the unique characteristics of in­dividual patients, and clinical trials require a small number of patients that meet very specific protocol requirements. Finding and enrolling these patients will be a significant challenge for investigative sites, sponsors and CROs. Precision medicine has already driven sponsors and CROs toward recruit­ing study volunteers from large healthcare systems and hospitals, which have sizable patient populations and electronic medical record infrastructure that can be culled to identify eligible patients.

Yet as precision medicine, which histori­cally has been dominated by oncology stud­ies, expands into other areas, such as immu­nology and anti-infectives, researchers will need to draw upon investigative sites of all sizes—including small, physician-run sites that have access to electronic health records, in order to identify patients. In addition, sponsors and CROs will need to cooperate in order to locate the highly specialized pa­tients required for precision medicine trials.

“While small sites won’t be the primary sites, there is no choice but to figure out a way to coordinate smaller sites,” said Amy Miller, Ph.D., executive vice president of the Personalized Medicine Coalition. “If you take the ROS marker in non-small cell lung cancer, for example, that’s only 1% of the lung cancer patient population, which is about 1,000 people a year. There is no way that one CRO working for one company is going to be able to find enough patients for a clinical trial. There has to be coordination. There has to be a little more flexibility from pharma companies to allow CROs to work with multiple drug companies on one par­ticular disease.”

The industry is seeing some pre-compet­itive cooperation between drug companies in this area. Illumina is partnering with AstraZeneca, Janssen Biotech and Sanofi to develop a universal next-generation se­quencing (NGS)-based oncology test sys­tem and helps the three drug companies find participants for their research studies.

“We are going to see more of that coor­dination for funneling patients into clinical trials,” said Miller.

New data collection requirements

Large biologic databases, along with pow­erful methods of characterizing patients, have accelerated the move toward precision medicine and provide the tools and depth of understanding needed to deal with the complexities of molecular and genomic sig­natures characteristic of many diseases.

In clinical trials, such capabilities can provide the ability to monitor drug effects more effectively, while supporting adaptive study designs that help to improve over­all probability of technical success, reduce costs and identify targeted therapies for the right patients. However, precision medicine requires a different type of clinical trial because it focuses on individual reactions rather than average therapy responses, and the data requirements can impose signifi­cant administrative burdens on investiga­tive sites.

Matthew Wiener, founder and chief sci­entific officer of Pharmatech, a specialized oncology-focused CRO and site manage­ment organization, said he recently re­viewed two protocols that had 14 objec­tives—including the primary, secondary and exploratory objectives. Many data points needed to be captured, including a quality-of-life questionnaire, pharmacoge­netic data points and other bioassay infor­mation that must be sponged, shipped and stored.

“It becomes very complex with 160-page protocols. The administrative burden is sometimes overwhelming for our sites and they can’t take on more trials. Not only is there more complexity to precision medi­cine trials, but the increased data require­ments, along with regulatory data, can be a no-win situation for some sites as things will not move quickly,” said Wiener. “Fi­nancial compensation often doesn’t line up with the work we are asking them to do.”

Other concerns

Oncology products continue to rank highest in terms of the average share of per­sonalized medicines in development across all phases; Tufts CSDD also found that 73% of oncology drugs in development are per­sonalized medicines. The complexity of these preci­sion medicine oncology tri­als raises concerns for spon­sors, CROs and sites since the studies often require ad­ditional education and train­ing for staff and improved site logistics.

“As many as 10 people can be involved in making sure that oncology patients in a precision medicine trial properly get the tested medi­cation,” said Linda Strause, Ph.D., principal and founder of Strategic Clinical Con­sultants, who oversees clini­cal operation programs for sponsors and CROs, often on oncology trials. “That means coordinators communicating with patients, and educating the physician PI to explain how an autologous immuno-therapy or tar­get therapy works in precision medicine and what that means in terms of potential re­sponse from patients.”

Keren Moss, executive medical director for the Oncology Business Unit at INC Research said new insights into the molecular pathol­ogy of cancers create opportunity for the de­velopment of targeted therapies and a clearer approach to finding clinical benefit for pa­tients, yet they also challenge existing models for trial design and therapeutic development. The industry has seen many “basket” trials where cancer patients are assigned to treat­ments based on biomarker information in­stead of a specific type of cancer.

“Precision medicine has revolutionized the way we conduct clinical trials over the past few years. The availability of truly targeted therapies, combined with reliable target as­says/tests, has significantly changed how we design and plan to enroll patients into ap­propriate clinical trials—right drug, right patient, right trial,” said Moss. “Each trial is a niche population; no longer are we simply investigating lung or colorectal cancer. Many trials now identify appropriate patients based on a unique bio­marker/molecular abnormality.”

Moss also sees the existing de­velopment models evolve into a more collaborative approach un­der precision medicine. Rather than give all patients the same therapy, precision medicine tri­als can be designed to involve several sponsor companies in evaluating tumor markers and tailoring treatments based on multiple tumor characteristics.

“Many trials now may involve multiple drugs and require several companies to collaborate. This enables us to evaluate multiple pa­tients with more targets. The one study, one target, one drug para­digm—while still very much in use—is something we are rapidly moving away from,” said Moss.

For patients, precision medicine trials combine prevention and treatment strate­gies that take individual variability into account. Clinical trial opportunities in biomarker-targeted trials are integrated with cancer patient care and treatment selection practices where the criteria are far more stringent than traditional trials that offer narrow and inefficient methods to access rare and highly dispersed cancer patients. Moreover, the current research paradigm for molecular targeted drugs, noted Pharmatech’s Wiener, is that bio­marker testing requires the patient to con­sent to trial participation and then delay drug treatment for several weeks to await the laboratory results.

Looking ahead

Biopharmaceutical companies have shown they want to invest in precision medicines, which represent innovative ap­proaches to treating disease, despite the many challenges. Delivering on the prom­ise of precision medicine, however, will take a massive effort not only from biopharma­ceutical companies and researchers, but from investigative sites and others involved in the clinical research enterprise.

“In 2014, 20% of the FDA’s new drug ap­provals were for personalized medicine. For 2015, it’s about 22% or 23%. This shows that it’s a sustainable phenomenon. Fur­thermore, we expect one in five new drugs that hit the market to be personalized med­icines. If that is a sizeable minority of the new drugs, then absolutely, the enterprise will have to change,” said Miller.

Karyn Korieth can be reached via email atkaryn.korieth@centerwatch.com.

This article was reprinted from Volume 23, Issue 02, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. Subscribe >>