By Maxine Bookbinder

May 9, 2016 | “Everybody is fighting for the same patient pool,” says Tim McGarty, Global Director, Clinical Innovative Services at Novartis Pharmaceuticals. “Today, there are more drugs, more studies, but fewer patients.”

To develop an advantage, AstraZeneca and Anolinx are collaborating on a competitive strategy by creating a trial design library, pseudo populations, increasing clinical efficiency, and generating a new clinical buzz word with an old idea.

Researchers have been applying the concept of protocol competitiveness without a formal label but as part of efficient planning, sound technical design, and operational feasibility for years. For example, risk avoidance and meeting the needs of patients and customers is an integral part of quality control that impacts trial outcome, says David Nickerson, Senior Director in Quality and Risk Management at Pfizer. “Protocol competitiveness is the extent to which a clinical protocol can be effectively conducted in order to provide data that are sufficient to reliably address the primary objective of the trial within the desired time frame and budget.”

Nickerson says that quality control includes diligent design and planning prior to the trial’s launch. “Protocol competitiveness is an especially important consideration when multiple clinical trials are ‘competing’ with each other for the same patients in the same geographic region. It can be enhanced through proactive quality by design efforts that seek to eliminate unnecessary protocol complexity, reduce risk and maximize technical and operational feasibility.”

AstraZeneca and Anolinx are working together to analyze and assess competitiveness between clinical trial protocols. Anolinx has developed a method for conducting this assessment which AstraZeneca is incorporating into a trial design library to help design and conduct future trials.

Don’t Ask, Tell

McGarty says The Health Information Technology for Economic and Clinical Health Act (HITECH Act) of 2009 was the catalyst to change what was already not working. HITECH states that, as of 2011, health care providers would be offered financial incentives to display “meaningful use” of electronic health records and, as of 2015, could levy penalties against companies that do not.

The “old school” method of waiting for appropriate patients to show up did not work and often resulted in insufficient participants, says McGarty. Sponsors relied on doctors to provide patient referrals, to air cheesy Better Call Saul- like TV ads, or to hope prospective patients would search on their own for trials.

The new design, which McGarty nicknamed “Don’t ask, tell,” allows companies such as Anolinx to develop query definitions, through sponsor-provided trial inclusions and exclusions that search electronic medical records and determine which doctors have large numbers of potential, appropriate patients. This is done only in hospital systems with whom Anolinx has business associate agreements in place, all patient information remains confidential, and all HIPPA regulations are strictly followed. 

If hospital administrators prefer, they can hold the patient lists and contact patients themselves without releasing any information to sponsors.

Either way, principal investigators can now quickly find patients who qualify for specific trials. Doctors can contact eligible patients directly, answer questions about and explain the benefits of trials. “We have direct access to data and to find patients,” says McGarty.

Analysis & Algorithms

“The competitiveness is the comparison of how each protocol defines a patient population,” says Aaron Kamauu, M.D., CEO of Anolinx. “The trajectory may be to take different drugs to market.” Competitiveness has always been an understood and accepted concept. “But until now, we didn't have a way to quantify it and understand the impact factors,” says Kamauu.

Kamauu credits Andy Wilson Ph.D. MSTAT, lead epidemiologist at Anolinx, for coming up with the method of how to do protocol competitiveness analysis. When considering inclusion and exclusion criteria, any two protocols may be competitive when vying for patients with the same medical condition. “So, the novel analysis we do is to quantify how competitive the two protocols are to each other, and determine which specific criteria have the largest impact on that level of competitiveness,” says Kamauu.

It is also a way to design new, or redesign, existing clinical studies. Protocol competitiveness designs can help ensure an appropriate patient demographic and choose sites that can support the trial and operate efficiently.

Access to algorithms like these did not exist just five years ago. “Previously [weak trial design] was typically discovered either ad hoc by one of the clinical trial team members or, more often, after the trials started,” says Kamauu. Sponsors ran into conflicts finding sites or patients due to competing protocols.

In an attempt to help design new trials, Anolinx and AstraZeneca extracted key information from PDF clinical trial protocols and deposited it into a newly-created trial design library, allowing researchers to view key information quickly and proficiently. Researchers can now search for a specific protocol or indication, such as bladder cancer, then for a primary objective, such as efficacy.

The company can also look at patients from previous research with specific indications and treatment patterns and form a pseudo population. “Imagine if we had one million patients at a fictitious clinical site, how many would be eligible for protocol number one? Number two? The more they overlap, the more they are competitive,” says Kamauu.

Another example is testing two protocols for an asthma therapy. One study involves participants who are severely asthmatic; the other enrolls patients who have mild symptoms. Both studies may run simultaneously at the same site by the same sponsor. These studies are not competitive, so patients who enroll in study number one do not qualify for study number two. “It’s like a Venn diagram,” says Kamauu, who notes that companies are analyzing the same populations for different responses. “The hallmarks are the inclusion and exclusion criteria, how closely they match, how closely they identify as 100% compatible to the protocol.”

Competition Within

Companies compete against themselves for a few reasons. For example, the FDA might require a company to look at specific multiple side effects of a drug it is testing or with a commonly-used drug. And sometimes, says Kamauu, a large pharma may have separate, independent departments testing without knowing about each other. Complimentary trials can involve testing the same drug, with one trial restrictive and another less restrictive. In such cases, says Kamauu, sites attempt to enroll patients in the more restrictive study first and, if they don’t qualify, “cascade” them to the other, more broadly-defined study.

TriNetx created a desktop tool that queries warehoused de-identified patient data at partner hospitals to determine if the patient population exists for a clinical and if the hospital wants to participate in the study. If it does, then the hospital contracts with pharma, and the qualified patients are invited to participate.

Protocol competitiveness does not directly shorten trial times; however, more efficient start up planning, including enrollment and site choice as a result of competitiveness can indirectly hasten completion.

It also does not directly impact amendments. “Just because two protocols have a high degree of competitiveness doesn't automatically cause the need for an amendment,” says Kamauu. “However, it can lead to an amendment if the sponsor finds that the level of competitiveness is causing significant challenges to enrollment. That is one reason why we are assessing protocol competitiveness before the study starts: to help avoid the need for an amendment.”

The benefits are quantifiable, says Novartis’ McGarty. By enrolling patients more quickly and efficiently, protocol competitiveness improves protocol feasibility analysis, reduces trial costs and time, and delivers drugs to market faster.

How the term originated is unclear. Kamauu who, along with his team, is credited with originating the idea and creating the method of assessing protocol competitiveness, says that it “is possible that we began the term ‘protocol competitiveness’ in the context of this project but the concept that two protocols could be competitive is not new.”

He adds that “the truly novel thing is assessing or analyzing the level of competitiveness between protocols and determining which aspects of each contributes most to the competitiveness between them. So, maybe the focus is the Analysis of Protocol Competitiveness.”