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The Multi-Institutional Phase I Study: Disadvantages Without Advantages?

Department of Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands

The famous Dutch soccer player Johan Cruijf, who now is a commentator for Dutch television, introduced the saying that "Every advantage has its disadvantage" (or vice versa). Does this also apply to the multi-institutional phase I study?

Phase I studies are the core of drug development. Among many other aims, they are essential for the identification of safety risks and for the selection of a drug dose that can be used for further development. Drug development is a highly competitive field, and therefore, time is of the essence. This means that every phase I study should provide information as quickly as possible; with the highest possible certainty; and, preferably, with the fewest possible patients, given the limited chance for actual patient benefit. With the assumption that adding more centers would be the optimal strategy to speed patient accrual, pharmaceutical industries in particular are currently pursuing the model of large, multicenter, phase I studies in a continuous drive to further expand these numbers. In addition to this, end points also are changing—from the usual and well-defined maximum-tolerated dose (MTD) to the more obscure and undefined optimal biologic dose (OBD)—because of the shifting focus of mechanism of action of anticancer drugs.

In the current issue of the Journal of Clinical Oncology, Dowlati et al¹ present an interesting literature review that involves 463 phase I studies that were published during 8 years in two major oncology journals: JCO and Clinical Cancer Research. This selection presents a possible limitation of the analysis, because both journals, although international, are based in the United States. The analysis, therefore, seems to present some publication imbalance, as 70% of the reviewed studies were performed in North America. Although this may cause the performance of phase I studies performed in the rest of the world to be overlooked, it is likely a minor issue when assessing the results of the study. Nearly 60% of the reported studies were pharmaceutical industry–sponsored, which reflects new drug development that largely is—and will likely remain—a pharmaceutical industry–related initiative. Interestingly, only 30% of the studies reported the accrual time.

If we first look at the number of sites involved, 55% of phase I studies were performed at a single institution, whereas other studies were performed in two to 16 sites. The large numbers at the upper boundary are surprising, because it is a real challenge to keep all sites informed on a real-time basis about safety issues observed in patients. Although the authors indicated that there was no significant change over time in the proportion of studies that involved multiple institutions, it is notable that 17.3% of the 249 trials reported until 2003 involved three or more sites, whereas 27% of the 214 trials reported in 2003 and beyond involved three or more sites. This is consistent with the collective experience and the concerns of numerous investigators in phase I trials, and it probably indicates that we indeed are involving more and more centers in phase I trials. There was no correlation between the number of participating sites and the mechanism of drug action. One would have expected that, in studies with potentially difficult accrual because of limitations (such as the presence of a specific and infrequently expressed molecular target), more centers would have been required. Apparently, the trend is not to limit the involvement of larger numbers of centers to only such studies but rather to pursue the expansion of the number of participating centers in all phase I studies.

In the analysis of Dowlati et al,¹ chemoradiotherapy and gene therapy phase I studies often involved three or more sites. Disease-specific phase I studies also were more likely to be multi-institutional compared with general solid tumor studies. In contrast, there did not seem to be an association between the involved sponsor and the number of participating institutions. The possibility of bias in this observation may be related to the fact that the analysis basically involved only industry-initiated and NCI-related studies. Other independent organizations, such as the European Organisation for Research and Treatment of Cancer, have always minimized the numbers of sites in phase I studies but were not part of the analysis.

Accrual time was not different when comparing trials that involved either one or more than one institution. In the attempt to shorten accrual time, the multicenter phase I studies did not achieve this aim. Although Dowlati et al¹ suggest that this may be cause by competing studies at the sites, which would hamper accrual, there may be other explanations. The cohorts in phase I studies are small by definition. This means that, with more centers involved, the interval between the accrual of subsequent patients in each center increases accordingly. If this interval exceeds a certain threshold, it is conceivable that the momentum and enthusiasm of the investigator site is lost and that accrual will slow. It is also possible that competition among centers to enroll patients leads to the selection of patients that are more likely to be relatively unfit, which leads to increased inevaluability rates. Alternatively, the waiting time for patients to enter the study could become too long when there is limited slot availability, which would cause patients to search for alternatives or eventually to drop out during the waiting period. One of the incentives to participate in conducting trials is the scientific contribution and the possibility to publish; with more centers involved, the likelihood of being represented among the list of coauthors diminishes. For this reason, most multicenter, single-patient, early cohort, phase I studies experience great difficulty in achieving even this limited accrual in a short period of time, particularly if the number of dose levels that involve only one patient becomes large. This could result in paralysis of the whole study.

Studies with specific biologic targets may fit into the research scope of a site, which could enable translational research institutional studies. The involvement of multiple centers may limit these possibilities or may result in the improper handling and management of samples, which would jeopardize the interpretation of essential pharmacologic results.

The observation that accrual time was longer in phase I trials of hematologic malignancy compared with trials involving disease-specific or general solid tumors might suggest that accrual time will be dependent on the availability of eligible patients with specific or rare characteristics. This is a trial design issue, and it suggests that drug-target frequency and site number in specific circumstances can be interrelated.

Rapid accrual and the subsequent conduct of phase I trials not only requires appropriate numbers of eligible patients and committed investigator sites but also requires some common-sense flexibility about inclusion and exclusion criteria and dose-escalation schedules. Far too often, inclusion and exclusion criteria are unrealistically conservative and are without justification from animal toxicology. Often, predefined dose-escalation steps are prescribed in a phase I protocol, which necessitates the submission of amendments either to speed the conduct of the study in the low-dose range or to allow the study of intermediate dose-levels when serious toxicities have been observed. The mandatory submission of these amendments and the involved review processes—particularly within industry—lead to tremendous delays in trial performance.

Issues such as site selection (based on track record and incentives) and trial design therefore may be far more important than simply the expansion of the number of participating sites.

There is a common understanding that, because of the limited chance of patient benefit balanced against the risks,^2-4 selectivity is needed in the number of patients entered onto phase I trials. Pairwise comparisons in the analysis of Dowlati et al¹ showed that there was a significant difference between single-site studies and multisite studies. In this respect, phase I studies that involved two or more sites achieved the opposite of what was commonly intended or expected. What was intended or expected? This part of the analysis may be somewhat skewed by the observation that considerably fewer patients per trial were enrolled onto disease-specific phase I studies enrolled than onto either general solid tumor studies or studies in hematologic malignancies.

The use of either an MTD an OBD as a primary end point did not influence the number of institutions involved in the phase I trials reported. However, studies that used an OBD had a significantly shorter accrual time and accrued smaller numbers of patients. Because OBD will usually be achieved earlier than MTD, this is not surprising. However, highly specialized laboratory facilities often are needed for a proper assessment of these end points, which requires close cooperation and optimal communication between clinical and preclinical scientists. It is our view, again, that this can be achieved more easily by a small group of well-embedded and dedicated researchers.

It is difficult to find clear advantages of multicenter phase I studies. The goal of gaining early efficacy data is also difficult to justify. The expanded cohort, no matter how big it is, can never replace a proper phase II study, for which there are other issues.^5-7 The expanded cohort is valuable merely for a more detailed assessment of toxicity and for the assessment of interindividual variations in pharmacokinetics or pharmacodynamics. For this purpose, an expanded cohort of 10 to 12 patients is usually more than sufficient.

What remains are the many disadvantages of multi-institutional phase I studies. They increase the complexity of trial performance. Because of administrative and regulatory issues, costs increase. Moreover, the effective exchange of safety information is crucial in phase I studies. This is hampered by the involvement of larger numbers of sites, and even more so if different time zones are involved. This puts patients potentially at unnecessary, unacceptable risks. Fewer patients per site could also lead to a decreased recognition of adverse effects, which is an important safety concern.⁸ The analysis of Dowlati et al¹ also suggests that, when adding more sites, more patients will be needed to achieve the end point, which further adds costs and an ethical dilemma.

It is, thus, difficult to perceive the advantages of performing a phase I study in multiple centers, whereas the disadvantages are many. With the possible exception of disease-oriented phase I studies; studies with rare molecular targets; and studies of major technical complexity, such as gene therapy, we therefore suggest that there are many reasons to limit the number of centers involved in a phase I study to as few centers as possible. Investigators should resist pressure from the industry to perform a phase I study that involves many sites without an appropriate justification.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS

Conception and design: Jaap Verweij, Ferry Eskens, Maja de Jonge

Manuscript writing: Jaap Verweij, Ferry Eskens, Maja de Jonge

Final approval of manuscript: Jaap Verweij, Ferry Eskens, Maja de Jonge

REFERENCES

1. Dowlati A, Manda S, Gibbons J, et al: Multi-institutional phase I trials of anticancer agents. J Clin Oncol 26:1926-1931, 2008[Abstract/Free Full Text]

2. Roberts TG, Goulart BH, Squitieri L, et al: Trends in the risks and benefits to patients with cancer participating in phase I clinical trials. JAMA 292:2130-2140, 2004[Abstract/Free Full Text]

3. Horstmann E, McCabe MS, Grochow L, et al: Risks and benefits of phase I oncology trials, 1991 through 2002. N Engl J Med 352:895-904, 2005[Abstract/Free Full Text]

4. Cheng JD, Hitt J, Koczwara B, et al: Impact of quality of life on patients expectations regarding phase I clinical trials. J Clin Oncol 18:421-428, 2000[Abstract/Free Full Text]

5. Booth CM, Calvert H, Giaccone G, et al: Endpoints and other considerations in phase I studies of targeted anticancer therapy: Recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). Eur J Cancer 44:19-24, 2008[CrossRef][Medline]

6. Booth CM, Calvert AH, Giaccone G, et al: Design and conduct of phase II studies of targeted anticancer therapy: Recommendations from the task force on methodology for the development of innovative cancer therapies (MDICT). Eur J Cancer 44:25-29, 2008[CrossRef][Medline]

7. Ratain MJ, Humphrey RW, Gordon GB, et al: Recommended changes to oncology clinical trial design: revolution or evolution? Eur J Cancer (in press)

8. Tolcher AW, Takimoto CH, Rowinsky EK: The multifunctional, multi-institutional, and sometimes even global phase I study: A better life for phase I evaluations or just "living large"? J Clin Oncol 20:4276-4278, 2002[Free Full Text]

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