Changing the Culture of Clinical Trials: Reviving a Failing Effort

Surprised? Take issue with this statement? Yes, we know vastly more about what makes a cancer cell tick than we did a decade ago. A technical tour de force such as fully sequencing the cancer genome has been successfully performed, not just once but a dozen times. Not a day goes by without a report on personalized cancer care coming soon to a clinic near you. So what’s the problem?

Lagging enrollment in US oncology trials

The fundamental issue is that not enough patients are enrolling in clinical studies for us to translate the scientific advances into clinical gains. Several hundred drug candidates are in the pipeline, yet only a few trickle through to successful phase III trials leading to FDA approval. Recent reports have been very troubling. A well-publicized report issued by the federal government1 noted that more pivotal studies are being conducted outside the United States than within the country, and concerns exist about oversight and conduct of clinical trials performed beyond the confines of North American and Western Europe. The US pharmaceutical and biotech industries remain robust in performing preclinical discovery and development of anticancer drugs; yet when it comes to pursuing clinical trials as a country, we are failing.

Perhaps most remarkably, the Institute of Medicine just released a report lambasting the clinical trial infrastructure that has dominated clinical cancer research for the past three decades.2 This report acknowledged the severe underfunding of cooperative group trials sponsored by the National Cancer Institute (NCI), and it also lamented the vast bureaucratic hurdles which need to be navigated to even get a trial launched. For instance, it takes more than 2 years for a phase III trial to go from inception to the first patient visit, never mind completion of the study. Both the outgoing and incoming heads of the NCI have taken this report to heart and promise a wholesale change in the organization of the national effort in the future.

While we are waiting for that initiative, there are plenty of open trials to complete now. Both NCI-sponsored and pharmaceutical company−sponsored oncology studies almost always lag in accrual behind their projections. Why does that phenomenon exist, and what can we do to change it?

Competing forces in clinical trial accruals

Given that 80% of cancer patients are treated in community, nonacademic settings, this is the place to start in order to understand the competing influences that ultimately determine clinical trial accruals. Unfortunately, based on community trends, the accrual crisis will likely get worse before it gets better. Driving this concern is the full impact of the Medical Modernization Act of 2003, just now reaching its full expression by markedly altering the reimbursement formula from the Centers for Medicare and Medicaid Services (CMS), the nation’s largest payer. In addition, insurers and health plans are taking a close look at chemotherapy reimbursement and are also dramatically changing their benefit structure based on rising drug costs and the specter of health care reform. Caught between these trends, practices are experiencing profound financial consequences. Any oncology practice service line that is not clearly carrying its own weight has come under scrutiny.

Research is often the highest-profile and most resource-heavy program to be evaluated in this new era of cost-consciousness. Practices that were comfortable in the past supporting a research department that did not cover its costs are absolutely no longer able or willing to justify a financially unsuccessful operation by citing the goodwill to the practice, the patient, and the community of having access to high-quality clinical trials testing novel molecules. Even those facilities whose research programs do support themselves financially are threatened by the sheer volume of patients, the increasing chronicity of many common cancers, and the seemingly perpetual lack of qualified research coordinators.

Physician’s role is crucial

Numerous surveys have shown that it is the attitude of physicians toward clinical trial involvement—informing patients of the opportunity and encouraging them to enroll—that makes the greatest difference in accrual rates. Patients cannot agree to a trial if they are not aware that they might quality for one. While, in certain communities, there exists a large contingent of educated consumers who arrive at their physician’s office with an Internet-generated list of available trials, these patients represent a minority overall.

A physician who is well versed in a trial and knows the clinical characteristics of his or her patients stands the best chance of successfully matching the trial with an appropriate subject. This is not a trivial exercise in the community setting, where most oncologists are generalists and may not have all of the trial criteria at their fingertips. A well-established relationship between the physician and the research coordinator is vital to assure that adequate numbers of appropriate potential candidates are screened for protocols. Such a relationship requires a commitment on the part of the practice to support adequate numbers of research staff to provide rapid access to patients and doctors, an achievement often difficult to attain.

A bell curve of research interest

Spending the time to acquaint oneself with protocol inclusion and exclusion criteria is a function of the desire to conduct trials. The level of enthusiasm for research demonstrated by the community oncology physician can be sorted into three groups, roughly approximating a bell curve. A small group, perhaps 10% to 15%, has little to no interest in clinical trials and will rarely enroll any patients; a similarly sized group of physicians on the opposite end of the spectrum is heavily committed to the clinical trial enterprise and considers research studies before any other treatment for their patients. The large remaining segment represents the majority of practitioners. This middle group genuinely wants to support research and occasionally gets excited about a particular protocol, based on a highly successful pilot project or promotion by key opinion leaders. This middle group of physicians tends to refer patients for two specific types of research studies: adjuvant trials and phase I studies. It is this prevailing culture that accounts for much of the current concern with regard to clinical trial accrual.

Preference for adjuvant trials

It is not hard to understand why adjuvant trials have been so fully embraced to the detriment of studies evaluating new agents in metastatic disease. There are many more potential subjects to choose from in the adjuvant setting. These patients tend to be healthier and are enthusiastic about participation when the outcome is clearly an additional opportunity for cure rather than palliation or life extension. That enthusiasm for adjuvant trials comes with a cost, however. First, the unassailable fact is that many, if not most, of these patients have absolutely no chance to benefit, given that many have been cured by the primary surgical treatment. Moreover, a significant fraction will be helped by the standard adjuvant regimen, such that the remaining population to potentially benefit from a new intervention becomes quite small. Finally, follow-up needs to be lengthy in order for the intervention to be confirmed as beneficial, a costly endeavor indeed.

This is not to denigrate well-conducted adjuvant trials―there remains definite clinical need in these patient populations, and the opportunity to increase cure rates is compelling. It must be acknowledged, however, that the resources of physicians and research coordinators are finite and are becoming even scarcer in the current environment. It is all too likely that accrual to adjuvant trials competes with accrual to studies testing new compounds.

Patient pool may be small

The clinical trial culture further assumes that patients who have the least to gain―those for whom standard treatments have failed to work―are also favored protocol subjects. Indeed, a panel of experts convened at the recent conference of the National Comprehensive Cancer Network to talk about research suggested increasing the accrual of patients to phase I trials if no standard therapy options for them exist. Our current research paradigm mandates that phase I studies be conducted to assess safety and dosing, but these trials are conducted at a relatively small number of sites. Most patients faced with advanced disease do not have the desire or the means to leave their community. The philosophy of expanding accruals by referral to phase I trials ignores the rich resource of patients with newly diagnosed metastatic disease who were never made aware of the large menu of trials often existing in their own communities. Why?

No time to rest on our laurels

It seems that medical oncologists have developed a degree of complacency about clinical trials, based upon the modest but steady successes of the past three decades. In the past decade alone, we have tripled median survival in stage IV non−small cell lung cancer and in metastatic colorectal cancer, and we have doubled overall survival in advanced metastatic breast cancer―all justifiably excellent achievements. But that’s hardly enough. Patients are looking for cures or years of life extension. We all await the blockbuster drug or novel pathway discovery that will achieve these goals. Realistically, however, our progress will likely continue to be incremental in the foreseeable future. Therefore, we need to complete the backlog of cancer trials without delay so that drugs that are truly valuable can be validated more rapidly, and those that are failures can be rejected, allowing us to move on to the next promising agent. We have to admit that our current standard of care is just not good enough, and we need to support studies testing new agents even in well-established settings.

Getting the research enterprise moving again

If we focus on overcoming the biases that favor best first- and second-line treatments, even in the absence of strong evidence, it is likely that the research enterprise will move much faster. To accomplish this, clinicians must abandon the current philosophy of “I will only consider a research trial when I have nothing left that works to offer” or “I will offer clinical trial enrollment only to my healthiest adjuvant patients.” Accrual numbers could certainly double immediately if a cultural shift could take place among physicians who now only occasionally suggest the research option.

Embracing this shift requires seriously acknowledging existing biases and trying to adjust them in favor of accepting a little more uncertainty with regard to patient outcome. Admittedly, an uncomfortable discussion with patients might ensue. Instead of framing the conversation as, “This treatment results in the best outcome for your stage IV cancer,” the physician might have to express the facts as, “Even our best combination therapy doesn’t prolong life, so it’s urgent that we try new approaches.” It’s not an easy task to accept our therapeutic limitations, but we need to do so without removing the core of hope and optimism that form the heart of the oncologist-patient relationship.

Oncologists strive to do better by their patients, and, in that context, presenting the prospect of a broad spectrum of clinical trials more frequently, as well as earlier in the course of metastatic disease, becomes a gratifying venture on multiple levels. Recognition of our failures to adequately support clinical cancer research can easily lead to success, by making these simple but critical changes to the prevailing culture.

References

1. Challenges to FDA’s Ability to Monitor and Inspect Foreign Clinical Trials. DHHS Office of the Inspector General; June 2010; OEI-01-08-00510.

2. A National Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program. Nass S, Moses H, Mendelsohn J, et al. Institute of Medicine, National Academies Press. Washington, DC; 2010.