Last October we reviewed some KMR data, combined it with our own findings (see here) and concluded that while the industry's overall productivity at developing new drugs has not substantially changed during the past decade, the period between starting a compound's clinical trials and its registration filing has increased by more than a year during this time. The single biggest reason why clinical development takes longer is that it simply requires more time to enroll enough patients in drug trials. Over a decade or more that contributes to the growing costs of running trials, even as it increases the time required for each compound to start generating sales.
While several factors can plausibly contribute to longer patient recruitment times, a largely overlooked reason stems from the fact that pharma has never given it the sort of attention and resources commonly devoted to other aspects of drug development. This presents an interesting bit of irony, if only because 85 percent of the entire cost for developing a compound occurs during the middle and late clinical stages.
Our assessments of the reasons for delayed patient recruitment have shown that clinical trial sites are organized into social networks with defined statuses, roles and norms. Program teams charged with successfully managing a compound's clinical development within their pharma companies are only vaguely aware of these social networks, if at all. Yet social network behavior is the efficient factor controlling the pace at which their sites screen and recruit patients.
The clinical sites engaged on any given trial divide into several segments. One type consists of large centers with many people dedicated to clinical studies. Such centers are analogous to factories or mills because each one will have more than twenty open studies running at all times. While scientific interest or academic publications may provide some of the incentive at centers affiliated with medical schools, most clinical mills conduct trials mainly as a profit-making venture. Even for many of the academic centers, however, the functions of principal investigators remain closer to those of a plant manager than a medical scientist.
At the other extreme stand small medical practices where a physician may sign on as an investigator because of a special interest in some aspect of a particular study. More typically, small practice physicians trying their hand as investigators see clinical trials as a convenient way to earn extra income. In most cases, their initial experience disabuses them about the practicality of conducting clinical trials as a part-time avocation.
Spanning the range from high-powered academic centers to solo practitioners in the boondocks, investigators typically enact one of several roles. Distinguished academicians in the mix occupy positions as key opinion leaders (KOLs), meaning other investigators will rely on their judgment concerning where the test drug potentially stands on the spectrum from breakthrough to me-too. Investigators of all sorts want to attach their names to major breakthroughs
In reality breakthrough compounds represent no more than five percent of what's in clinical development. That means most investigators on any given study look to another sort of opinion leader in deciding how much time and effort a particular test drug is worth. The thought leaders here are "Operations KOLs." Their experience and business acumen will guide them and the other investigators in their reference group on factors such as the study's per patient fee and the feasibility of identifying patients that meet inclusion/exclusion criteria.
Word about these business elements of a study circulates among its contracted investigators more quickly than news of a sex scandal. When we review a sponsor's operations records on a study where patient recruitment has stalled, we sometimes find that sites from the most to the least productive ones haven't even screened a patient candidate within the previous ninety days. When we then get out to the field, we invariably find that word has come down from the study's Operations KOLs. The project has been designated as a dog that will not adequately repay the time and effort needed to successfully enroll patients. At that point the sponsor needs to seriously revise the way it thinks about its study by framing it as a negotiated transaction more than a scientific endeavor.
Once sponsors can frame their studies as negotiated transactions, we have found that some relatively straightforward tactics can kickstart patient recruitment and keep it moving at an acceptable pace. These include often overlooked matters such as better communication to clarify inclusion/exclusion criteria, restructured payment terms for study sites, and assistance at targeting likely candidates. Sponsors unwilling to adopt such measures must either make major protocol revisions to the study, entailing huge expenditures of time and money, or forget about developing their compound.
Although clinical and clinical operations teams will agonize over their study designs, overload their inclusion/exclusion criteria and maintain the groupthink illusion that their compound is the most outstanding therapy in a generation, few will bother to identify the Operations KOLs on a study and what it takes to make them enthusiastic about enrolling patients in it.
Investigators are not the only personnel type at study sites involved in a social network. Study coordinators who actually do the work of identifying, screening and recruiting patients also operate within social networks. On a particular study, these people will typically get acquainted at an investigators kickoff meeting. If their sites are geographically remote, meaning they don't compete for the same patients, they will exchange cards and keep in touch to collect and disseminate their recruiting experiences on the study at hand. In time the more astute coordinators will become thoroughly familiar with the patterns of their counterparts as well as office workers in adjoining cubicles.
That became apparent when my colleague, Ross Weaver, interviewed a perceptive study coordinator in connection with a gastroenterology study. He was discussing potential enrollment obstacles with her when she said, "Let me take a look at your list of coordinators and I'll tell you who can do what." The list included several dozen sites across North America, yet the coordinator was able to offer succinct predictions for each one. "Susie will screen a lot of people for you," she said, "Beth will randomize at least five, and Ellen will do more or less the same. Most of the others won't do jack."
Once again, the awareness of such a network among sponsor teams and what it takes to cultivate influentials remains negligible. The contract research organizations (CROs) that receive tens of millions of dollars from sponsors for each study they manage, claim an intimate knowledge of the sites they engage. To whatever extent that may be true, they typically fail to use their familiarity with network dynamics to accelerate patient recruitment. That is because a substantial chunk of CRO revenue comes from enrollment failure. Every time a sponsor issues a change order to extend the enrollment period or add more study sites, the CRO tacks on an additional fee.
New product development in pharmaceuticals was able to function well for decades without understanding the social elements that affect trial site activity. Costs were manageable, fixed overhead had not yet gotten out of control, promotion to individual physicians rested securely on a huge asymmetry of information, and the passive willingness of third-party payers to reimburse meant that any approved product was apt to generate healthy revenue. All those features are now extinct or headed into the sunset.
In the inherently high risk activity of clinical development, where only one out of every ten compounds makes it to approval, drug companies ignore these social network aspects of trial sites at their own peril.
Daniel R. Hoffman, Ph.D. is the president of Pharmaceutical Business Research Associates (PBRA) in Glenmoore, and a partner of the Clinical Trial Recovery Specialists in Exton. You can contact him here: DRHoffman@ClinicalTrialRecovery.com