Clinical trial management

A clinical trial is the application of the scientific method to human health. Since such trials require the use of human test subjects and can severely impact the well being of the subjects, as well as treatments of other people and large amounts of capital for those performing the trial, the proper management of clinical trials is crucial.

Clinical trial recruitment
Over the last ten years, getting patients and doctors into clinical trials has become the most delay-ridden aspect of the drug discovery and development process. When implemented effectively, clinical trial recruitment (CTR) initiatives can be highly successful. Time lines can be dramatically reduced and recruitment targets can be met ahead of schedule; every day saved in the progression to marketing authorization can equate to millions of pounds made in patent-protected sales revenue. However, great care is needed in the development of a CTR program. Considerable ethical scrutiny is applied to all patient recruitment materials and initiatives. For example, in 2002 the European Commission issued guidelines for consultation which require patient advertising and details of recruitment initiatives to be submitted to appropriate ethics committees. Unfortunately, there is no simple code of established practice, no unified regulatory body and no recourse to appeal. If an ethics committee doesn't like what a CRO has planned, the CRO can't use it. In Europe, this aspect has yet to be effectively addressed.

Enhancing CTR is obviously an area in which great caution is required. Some investigating doctors, for example, question the need for extra activities as, they claim, there are sufficient numbers of suitable patients among those already attending their clinics. However, practical experience has shown that this is an over-estimation of the number of patients that physicians will be able to recruit and it is estimated that only about 10% of a physician’s patients will actually wish to enroll in a clinical trial.

Perhaps more importantly, there are also objections raised from within the industry. These usually centre on a highly cautious approach to the ethics and legitimacy of patient-facing initiatives. Some nervousness is understandable given the strict controls that govern DTC marketing but for clinical research there is a critical need for increased patient understanding and education. The signs are that the caution of the industry is slowly giving way to a new openness and confidence.

A review of recent press coverage also highlights a deep skepticism of industry involvement in clinical research. If not approached ethically, a firm’s CTR campaign can leave them wide open to aggressive media criticism and adverse advocacy relationships. The key point to remember is that the objective of all this work is ultimately to improve care for the patient. A strenuous effort to maintain this focus throughout clinical development will ultimately allow pharma companies to reap considerable rewards.

Over the past several years these problems have been addressed in the US, where clinical research receives more and more active support of government bodies, advocacy groups, charities and patient groups. This provides a collaborative environment and ensures that there is always an independent counterpoint when the integrity of industry-sponsored studies is attacked.

The American public sees a vast amount of government-sponsored education, designed to maximize understanding of clinical trials. A quick look at Cancer.gov and ClinicalTrials.gov, both run by the National Institutes for Health, illustrates just how much work is being done. This in turn is supported by private efforts such as Centerwatch.com, which is currently offers a 300-page book on informed consent for patients.

US public/private partnership
The nature of American healthcare provision no doubt motivates patients to seek free or subsidized medication, but the investment, approach and partnerships in the US are demystifying clinical trials and generating considerable goodwill toward industry-driven research.

A recently announced US public/private partnership designed to improve trial recruitment demonstrates how support for industry research can be broadened. The initiative created a $6m fund, which the contributing pharma companies and National Cancer Institute will use to accelerate patient recruitment for Phase I and II cancer studies. Naturally, the credibility of the public bodies involved enhances the effectiveness of the scheme.

Study designs and methods
A common pitfall is insufficiently rigorous evaluation of study designs and methods. A "straw poll" during a clinical project management training course revealed that virtually all clinical protocols have at least one amendment during the study. The reasons appear to cover the full range, from reliance on well-established designs without  allowing newer, more creative ideas to be considered and, at the other  extreme, not testing new methods for the current application. For example, in a recent angina study, treadmill exercise testing was used as the  primary efficacy criterion. This is, of course, extremely well-validated methodology, but, in this case, the patients were elderly, so the exercise  protocol was substantially modified to reduce the physical demand. The problem was that with such a mild exercise protocol, less than half the  patients recruited showed sufficient electrocardiogram (ECG) changes to  qualify for randomization. A quick pilot study would have alerted the sponsors before committing to major cost.

The role of senior management
A recurring theme in clinical research is the role of senior management. this refers not to the head of clinical research, not the head of R & D, but corporate management. The costs and risks of failure in the clinical phases are so large that they should be  occupying much of top management's attention. Yet, in many companies, requirements, objectives, budgets, and deadlines, are imposed without any  negotiation. On top of this, major changes are commonly dictated by management, usually by changing priorities. How can the clinical project manager fulfill top management's aspirations, with-in an increasingly  constrained environment?

Managing risk
All research and development must involve some risk. Some of the risks are typically encountered in the main stages of a typical clinical trial.

Risk distribution in clinical phases
Delivering the results on time, to the required standard, may have a lower risk in phase I than in later phases, mainly because subjects are  healthy and not potentially complicated patients, and thus, recruitment can  be predicted with some confidence. However, first administration to humans is something of a leap into the unknown, and safety problems are always to  be considered. What is possibly less obvious is the risk of any early-phase design errors to later phases and to the whole drug project. Once phase III is imminent, perhaps there is a degree of confidence emerging, as much more is known about the drug. The requirement for phase III, therefore, may be seen as accumulating data to enable a product license  application. In fact, the great expansion of activity dictated by phase III studies introduces even more complexity and a new set of risks. The application of the drug to a more realistic clinical setting means that we  will not necessarily by studying "clean" patients. Patients will often have other diseases on top of that under study and will only be under observation  for a small proportion of the time. Attention to clinical protocol design, thus, is at least as critical as in phases I-II.

Key tasks and external agencies
The most common reason for late tasks and projects is that they started late. Before patients can be screened for entry, a well-established set of start-up tasks must be completed, and of these, some are relatively easy to plan, and others are less predictable. Those relying on internal agreements (e.g., drug supplies, protocol sign-off), can be expedited by instilling the right culture of negotiation between departments and individuals. But what of the external elements, particularly regulatory and ethics approvals? The former is, fortunately, reasonably easy to plan, because, in most countries, there are clear limits to the time and effort required to meet regulatory requirements. Much more difficult is the matter of approval of ethical standards. Across the EU, as well as in Australia, Canada, and USA, ethics committees' practices may vary enormously so that, when planning a multinational study, good local knowledge is crucial. Even inside the borders of the same country or state there is often inconsistency, especially since the demise of single central approval for multicenter studies. Theoretically, local research ethics committees (IRBs) are expected to follow Department of Health guidelines, but, if they choose not to do so, there is apparently no redress, so one may be presented with unexpected delays in particular centers because of widely varying IRBs' practices. There is a move toward rationalization in the form of a two-level approval process. A central committee will review the study and, if approved, pass it on to local committees for ratification. Within the U.S., the Institutional Review Board (IRB) has clearly-defined responsibilities and reporting lines. In Australia, central approval is still possible, and the ethics committee sees itself more as a partner in research than as regulator; the very rapid start-up of studies is possible. The message here is that, if compelling reasons to conduct one's studies in any particular country are not available, be creative with your planning, and consider the big advantages you might gain in another part of the world. If you are forced to work around the conditions outlined above, obtain the best and most recent information you can from the ECs/IRBs and from their users, and build this realistically into your plans. The results may not be to your idealization, but you will have a better chance of keeping to them.

Referenced external sites

 * Cancer.gov
 * ClinicalTrials.gov
 * Centerwatch.com
 * MedTrials.co.uk