Rethinking the Sponsor-Investigator Relationship

To anyone involved in the long, risky, and painstaking process of bringing a breakthrough pharmaceutical to market, the scenario is all-too familiar: After spending a decade or more and an average of $609 million to shepherd a new chemical entity through discovery and pre-clinical testing, a sponsor takes the exciting step of launching a clinical trial. Across twenty test sites, qualified principal investigators are selected, regulatory documents are filed, approvals are obtained, contracts and budgets are negotiated, Clinical Research Associates (CRAs) are assigned, and investigator meetings are held.

A few weeks after the initial flurry of activity, there is discouraging news: a number of key milestones are not being met. Some sites are having problems with enrollment, complaining that patients they had in mind for the trial failed to qualify for requirements they now see as too stringent. The sponsor can’t get the electronic diary system to run properly at other sites, and the advertising campaign is still waiting for IRB approval.

Several months later, the 20 sites that were slated to test 240 patients have enrolled only 30.  Without a dramatic turnaround, the sponsor’s investment of $600,000 to initiate the sites on this trial will be lost, along with the estimated $40,000 per day of internal costs and the incalculable value of three-month’s time in the race to bring a potentially life-saving drug to market.

A Relationship in Trouble
As the trend in pharmaceutical research and development evolves from the highly profitable, blockbuster drugs of past decades to more personalized pharmaceuticals targeting smaller populations, the need for properly designed clinical trials is greater than ever. Yet there is little evidence that pharma companies have a handle on improving clinical trial performance. In 2007, the FDA published the results of a Pfizer internal survey indicating that eighty percent of the participants in its clinical trials between 2000 and 2006 came from just 26 percent of its research sites. Pfizer further reported that 11 percent of its sites managed to recruit just one subject, and 37 percent of its oncology trials failed to register any patients at all.

Pfizer is not alone in experiencing substantial difficulties in site productivity. Most sponsors acknowledge that clinical trials are risky investments, but efforts to come up with more effective business strategies-which generally involve outsourcing trial management-continue to prove disappointing. According to a recent study conducted by RapidTrials and Harvard Business School, 30 percent of all US sites identified and initiated between 2002 and 2005 failed to make a significant contribution to subject recruitment, and 70 percent of selected investigators performed only one trial per sponsor.

With soaring development costs and shrinking profit margins, the days of exclusive top-line focus for pharmaceutical and biotech companies are over. In this intensely competitive environment, sponsors are pressing to meet enrollment goals, minimize spending, and reduce the number of sites required to fulfill study objectives. As they look for new approaches that will translate into measurable bottom-line savings, companies need to do innovative thinking. They should start by reconsidering the sponsor-investigator relationship.

More than 60 percent of all research trials in the United States today are conducted at physicians’ offices and clinics. These sites have much to offer, including relationships with and access to fresh patient populations. They have the ability to make and implement decisions more rapidly than teaching institutions or Veterans Administration sites, which are governed by large, cumbersome bureaucracies. They also tend to have higher enrollment performance. If pharma companies are serious about improving clinical trial performance and reigning in costs, understanding and addressing the challenges faced by private/office-based test sites should be a high priority.

Developing a Strategy
Study-specific portals, document management, clinical trial management systems, and mass media advertising for patient recruitment have failed to produce the “magic bullets” pharma hoped for. Similarly, there is no one-size-fits-all strategy for refitting drug trials to meet the operational challenges of sites that vary widely in size and organizational structure. Yet almost all office-based sites share a few common characteristics: they are leanly staffed, their profit structures rely on maximizing the number of patient visits per day, and trial participation is not likely to be their top priority.

Given this profile, sponsors who are ready to think creatively about their approach should consider a trial management strategy that includes four essential elements:

• A shift from rescue to up-front investment

• Reorganization of clinical operations around the needs of sites

• Introduction of professional management skills into the development process

• Recognition and management of sites as critical sourcing partners

Investing up front
The adage about an ounce of prevention being worth a pound of cure may be counterintuitive in an industry devoted to producing cures, but when it comes to financing drug trials, sponsors would do well to take the advice to heart. Right now, most sponsors pay little attention to the end-to-end cost of trials, focusing instead on external vendor unit costs.  The failure to allocate sufficient funds to ensure adequate planning, market research, operational and clinical due diligence, training, and communication at the outset often leads to higher spending later in a trial.

In the new model, sponsors would assume greater initial responsibility for ensuring a practice protocol design that is consistent with clinical standards of care. The protocol would be pressure tested in the geographic area where the research will be conducted, among a random sample of practitioners who are compensated for their time. The practitioners would not necessarily be aligned with the sponsor company as opinion leaders. Furthermore, the up-front due diligence on a $5 million–$10 million drug study should be administered through an entity at arm’s length from the protocol authors in order to avoid any conflicts in identifying failed design.

A candid, site-specific assessment of study feasibility and attention to the patient perspective are equally essential in preventing waste.  Sponsors should give careful consideration to the implications of the study’s clinical and operational requirements, and milestones from the site’s perspective. How many hours per day, week, and month will be required for site personnel to accomplish the goals? Does the site have the specific resources available to meet the peak periods of demand? What are the initial cash requirements to fund the study’s equipment, patient recruitment, and staff costs? Can sites afford the loss of revenue when staff members take time away from seeing patients to participate in training and investigator meetings, pre-study, and initiation visits?

Once the sponsor completes a comprehensive assessment of the costs and benefits for the site,  they are ready to determine where additional investments are needed. Sponsor teams should be willing to collaborate with the sites to develop and document detailed plans for meeting recruitment goals. They should provide resources to help sites streamline start-up and overcome recruitment obstacles.

The cost of this type of planning and start-up support can be substantial, but in relation to the investment sponsors typically make in less effective rescue spending, the payoff is impressive. In a recent Phase IV clinical trial conducted by a top-five pharmaceutical company,  up-front investment of this kind, and careful monitoring of progress, led to patient enrollment rates that were 50 percent higher than average and cut the study enrollment period in half. The same study showed a 24 percent decrease in total costs, due to a reduction in the number of person hours. Studies such as these suggest that a well designed protocol, adequate compensation, and mutual sponsor-site agreement on benchmarks and metrics would better guarantee accountability and enable problems to be addressed before they become entrenched.

Reorganizing to Win
In “Win-Win Sourcing,” a recent article in the journal Strategy and Business, authors Bill Jackson and Michael Pfitzmann highlight the success of a strategy called “knowledge-based sourcing,” which Japanese automakers Honda and Toyota have employed to guide their interactions with suppliers. “With this approach,” they write, “Manufacturers and suppliers share a long term commitment to improving each other’s capabilities, starting by working together to eliminate wasted effort and inefficiencies. Instead of being at odds, they collaborate openly on lowering costs and raising overall performance, with the expectation that this mutuality will continue over many years, benefiting many companies.”

Pharma companies need to take a page from the automakers’ playbook. Applying knowledge-based sourcing to clinical testing-in effect working with community-based investigators instead of around them-would require a significant strategic realignment. Instead of focusing on incremental improvement and refinement of internal processes, pharma companies would begin to examine variables outside their own organizations. CROs and clinical operations groups would shift their emphasis to understanding the clinical trial experience from the investigator’s point of view and make addressing and overcoming problems with site productivity a top priority.

Knowledge-based sourcing could change this scenario by opening lines of communication and encouraging teamwork between the sponsor and investigator. Sponsors often assume the CRA will perform this function, but ironically, the qualities that make a good CRA-attention to details, strict adherence to guidelines and regulations, preference for working independently-are almost the opposite of what is needed.

The compliance-related support offered by traditional monitors or CRAs is essential, but it doesn’t address enough of the factors that affect trial performance. In addition to compliance-only experts, sites need help with issues related to process, logistics, recruitment, and communication. To target these needs, companies need to offer sites a new type of resource, a go-to person or site manager who has a fair amount of business training, an understanding of health care system basics such as billing, referrals, staffing, and reimbursement, and the mindset and motivation to engage in creative problem solving.

As the sponsor’s primary point of contact with the site, the site manager would supplement the CRA’s activities and offer support in areas such as: fielding training inquires from the site, identifying local resources that can help sites fulfill protocol-specific requirements, tracking performance, identifying best practices, and helping sites prioritize the demands of various stakeholders. Other recommendations for building more productive relationships with investigators include:

• Avoid taking the path-of-least-resistance when selecting sites. Sites that accept protocols, budgets, and contracts unchallenged may not understand the requirements or may not have adequately reviewed or assessed the work at hand. The best sites will be well informed about their patient population, staff capabilities, and costs and clearly communicate what they need to be successful.

• Train clinical operations group members to engage in productive dialogue with sites over complex issues.

• Be sure that study physicians practice medicine in a manner consistent with the protocol and that staff members have the necessary time and training to carry out their responsibilities.

• If special equipment is needed, be sure sites have it-and know how to use it-before trial launch.

• Always consider process changes in light of the impact they might have on trial sites.

• Keep in mind the 300:1 rule-that’s the ratio of patients to study subjects in traditional medical practices. Clinics’ systems and resources are arranged to meet the needs of the 300, so the sponsor must advocate for the one. 

Connecting the Dots: Trial Management 101
Along with gaining a better understanding of the daily realities of office-based trials, pharma and biotech companies must be prepared to manage issues that stand in the way of productivity. Electronic data capture (EDC) systems (used by most sponsors to collect study data at research sites), e-diaries, and document management systems for regulatory document submission, are several examples. To be effective, these systems require a high-speed Internet connection, properly installed software, and employees trained and certified in electronic data entry.

For site personnel or patients accustomed to paper-based medical records, the process of working with an EDC or e-diary system can be intimidating. If a site has trouble initializing the system, or if the process of entering information in one system is too difficult or time-consuming, sites may give up or focus their efforts on another study with an easier EDC system.  Keep in mind that sites working simultaneously on multiple studies are often working with a series of tools and systems that are unique to each sponsor or study. One site recently reported using seven unique technologies-interactive voice recognition, document management, EDC system, e-diary, ECG system, central lab, and patient recruitment-over the course of one study.

If a site is participating in five studies, each requiring seven systems, then it is possible that a single study coordinator may be expected to access 49 different technologies, each with a different user name, password, navigation, hotline, and training program. Once the study is complete, they may never use the systems again. Forced to prioritize their time, it is reasonable to expect that study coordinators will favor user-friendly studies with low operational and technology hurdles, even if that means turning down trials of drugs with greater lifesaving potential.

These nuts-and-bolts issues drive down retention and enrollment rates and drive up trial costs. The good news is that these kinds of procedural problems are not impossible to solve. A skilled manager with appropriate authority at the sponsor organization would realize that at some sites it makes sense to employ alternative data-entry options-including hiring someone to enter data into a system from a paper e-diary. Instead of frustrating the site staff with requirements that don’t work, the manager would have the option of modifying processes and procedures. 

The bottom line is that in order to improve relationships and productivity at clinical sites, sponsors must begin to show as much innovation and professionalism in the way they manage investigational product testing as they do in other aspects of the drug development process.  In many cases, this will mean adding professionals who not only have regulatory or scientific experience, but also the knowledge, skills, and authority to build a constructive interface with research sites.
Sponsors should also be prepared to:

• Expand their scope of accountability and ownership of protocol implementation at a site. Go beyond training the site on the protocol and regulatory requirements and include help with planning, staffing, training, workflow, and recruitment.

• Add or replace current CRAs/monitors (clinical research professionals) with professionals who have skills better suited to partnering with sites to achieve higher productivity.

• Recognize they must do more than simply coach current CRAs and monitors on the “soft skills.”  In order to have a measurable impact, site managers need to add value in the form of expertise and resources that the sites would not be likely to access on their own. 

• Add a business component to considerations of clinical trial feasibility. An investment of $10 million–$20 million merits rigorous internal due diligence.

• Design metrics and reports to help sites and sponsors identify problems and solve them together, rather than to assign blame.

• Include subjective and objective evaluation measures for both parties.

• Share metrics in a real-time, transparent manner that makes it obvious when something is wrong.

• Establish accountability measures that target performance in areas that matter most, such as enrollment and patient evaluation, rather than tangential issues such as attendance at investigator meetings or time to first subject visit. Measuring the wrong activities may entice staff to rush feasibility and startup, which ultimately can sabotage chances for timely enrollment.

In addition, it is vital for sponsors to take responsibility for connecting the dots between expectations and results. If, for instance, recruitment is delayed for some reason and an expired study drug must be recalled, reasonable parameters and plans for the recall should be developed in concert with each site.

Building a Partnership
Treating the investigator and his or her coworkers as important sourcing partners is a novel idea, but its time has come. According to one recent projection, in the next five years, sponsors will spend $1.8 billion to activate new investigators in the United States. A staggering $550 million of that will be spent on low- or non-performing sites

To break out of dysfunctional patterns of interaction and increase the potential for trial success, R&D managers must roll up their sleeves and get involved in the logistical and organizational complexities inherent in overlaying research in a typical clinic environment.

Most companies recognize the need to think more creatively about their relationships with large sourcing partners, such as staffing companies and data management organizations. Unfortunately, when it comes to managing their interactions with office-based research sites, the current approach to cost-cutting focuses on quick-fix solutions, such as slashing headcount and hiring contract service providers. These measures do little to address the underlying problems that plague clinical trials.

A more thoughtful, long-term strategy is needed. Rather than relying on entities outside the company to address problems, sponsors should take ownership of helping sites manage recruitment and logistics. Clinical testing is an important cost center that merits careful attention from senior management. Every year, pharma and biotech executives authorize spending in the millions on trials that take place in doctors’ offices and clinics. Yet how many of those executives have spent even an hour or two observing workflow, customer service, and levels of activity at a typical community-based site?

A new approach is long overdue. A thoughtful strategy that emphasizes knowledge-based sourcing, up-front investment, a realignment of clinical operations to focus on trial management, and the introduction of sound business principles in the development process will go a long way toward improving performance and reducing unproductive spending. When compared to developing a compound that can reverse the growth of cancer tumors or attack the latest strain of drug-resistant bacteria, managing the clinical trial process is not that difficult. Sponsors can-and in today’s difficult  economic climate, must-meet this challenge.