- Email: [email protected]
Multicenter investigator-initiated trials
228
Letters to the Editor might resolve the controversy concerning one- versus two-tailed tests. I'm not as sanguine as he. The person examining the interval can't help but notice whether the interval includes the value associated with the null hypothesis, is entirely on one side of that value, or is entirely on the other side. The three possible outcomes would lead to three different decisions, the same three that result from two-tailed significance tests.
REFERENCES 1. Fleiss, JL: Some thoughts on two-tailed tests. Controlled Clin Trials 8:394, 1987 2. Lan KKG, Friedman L: Monitoring boundaries for adverse effects in long-term clinical trials. Controlled Clin Trials 7:1-7, 1986 Joseph L. Fleiss, Ph.D.
Professor & Head Division of Biostatistics School of Public Health Columbia University MULTICENTER INVESTIGATOR-INITIATED TRIALS The editorial on multicenter investigator-initiated trials raises several important issues. We cannot address issues related to other institutes; therefore, we will confine our remarks to the National Heart, Lung, and Blood Institute (NHLBI). First, in the NHLBI, investigator-initiated clinical trials, many of them multicenter, are not decreasing. As seen in Table 1, in 1975, there were six NHLBIinitiated trials and one investigator-initiated trial. In 1980, there were 11 NHLBIinitiated trials and 7 investigator-initiated trials. In 1985, the numbers were 10 and 24, respectively, a reversal in the proportion. In 1987, this pattern continued, with 17 NHLBI-initiated trials and 28 investigator-initiated trials. Even the percent of dollars allocated to the clinical trials originating with investigators has increased over time. For example, in 1975, 2.6% of the money allocated to NHLBI supported clinical trials went to the one investigatorinitiated study. In 1980, this increased to 16.5%. During the past few years, it has ranged from 32% to 40%. Although the average cost of Institute-initiated studies remains higher than that for investigator-initiated trials (but not as much as so as in the past), differences in sample size, nature of the intervention, and kinds of participants make precise cost comparisons difficult. The "competition" between Institute- and investigator-initiated trials is not destroying the latter. Rather, both are flourishing. Second, the existence of a "pilot" or "feasibility" study can in no way guarantee the funding of a full-scale trial. The decision to proceed with the full-scale program is made on its merits, as is the decision as to the best mechanism of support. Similarly, there can be no guarantee of funding for any of the individual components of the trial. As with all funding decisions, the peer review process is paramount, and scientific merit must be sufficient and adequately documented. Third, let us assure you that NHLBI-initiated clinical trials do not gain
229
Letters to the Editor Table 1
Comparison of Institute- and Investigator-Initiated Trials Investigator Initiated
NHLBI Initiated 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987
Number
$ (000)
Number
$ (000)
6 6 12 13 13 11 9 10 12 12 10 11 17
40,669 46,631 43,932 53,712 61,668 46,244 44,171 29,256 29,423 22,809 33,732 30,300 47,679
1 1 1 2 3 7 10 11 17 18 24 28 28
1,105 1,545 1,420 4,427 4,148 9,137 10,091 12,108 11,532 13,577 16,949 20,093 22,278
approval easily. Yes, we do have access to advisory committees and other consultants. To not make use of them would be irrational, as it would impair the science. Yet there are also hurdles to surmount. These hurdles are usually more numerous and more difficult than those faced by investigator-initiated trials. For example, Institute-initiated trials must receive strong backing of a Divisional Advisory Committee, the Division Director, the Institute Director, and the NHLBI Advisory Council.Further, until the protocol is reviewed in detail by an outside advisory group of peer scientists and recommended for approval, no study can begin enrolling patients. It has been our perception that this process is considerably more rigorous than that pursued by the usual investigator-initiated trial. Investigator-initiated trials that are assigned by the Division of Research Grants to NHLBI are typically considered by the Clinical Trials Review Committee. It is the rare application that is found to be unworthy of such review. We encourage prospective applicants to contact Institute staff before submission. This serves two purposes. It enables staff, who may have considerable expertise, to informally critique a draft as regards study design and grants administration. It also gives the applicant an opportunity to learn whether his or her idea has sufficient importance and relevance to be funded, should it receive a sufficiently high priority score. Because this preliminary contact is not a consistent, or required, step in preparing an application, we have recently decided that investigator-initiated clinical trials need to undergo formal concept review in addition to study section review and have implemented that process. The process consists of a review by a subcommittee of the Advisory Council, supplemented by other scientists with appropriate expertise. This review takes place after the initial peer review, but before Council consideration. The intention is not to duplicate the scientific review of the study section, but to consider aspects such as program balance, overlap with current programs, and cost as it relates to perceived importance. Reviewed applications would include not only those in the "fundable range," but others. The purpose of considering applications not likely to be funded is to provide the applicant with information to help him or her decide if a revised sub-
230
Letters to the Editor mission is warranted. For example, if certain technical flaws were to be corrected and a better priority score assigned would the trial be sufficiently important to merit funding? We realize that these are different points of view concerning the funding process. We hope, however, that we have shown that things are not onesided, and that at the NHLBI, at least, multicenter investigator-initiated trials are considered major components of our program. Claude Lenfant, M.D. Director, NHLBI William Harlan, M.D. Director, DECA Lawrence M. Friedman, M.D. Associate Director
Letters to the Editor might resolve the controversy concerning one- versus two-tailed tests. I'm not as sanguine as he. The person examining the interval can't help but notice whether the interval includes the value associated with the null hypothesis, is entirely on one side of that value, or is entirely on the other side. The three possible outcomes would lead to three different decisions, the same three that result from two-tailed significance tests.
REFERENCES 1. Fleiss, JL: Some thoughts on two-tailed tests. Controlled Clin Trials 8:394, 1987 2. Lan KKG, Friedman L: Monitoring boundaries for adverse effects in long-term clinical trials. Controlled Clin Trials 7:1-7, 1986 Joseph L. Fleiss, Ph.D.
Professor & Head Division of Biostatistics School of Public Health Columbia University MULTICENTER INVESTIGATOR-INITIATED TRIALS The editorial on multicenter investigator-initiated trials raises several important issues. We cannot address issues related to other institutes; therefore, we will confine our remarks to the National Heart, Lung, and Blood Institute (NHLBI). First, in the NHLBI, investigator-initiated clinical trials, many of them multicenter, are not decreasing. As seen in Table 1, in 1975, there were six NHLBIinitiated trials and one investigator-initiated trial. In 1980, there were 11 NHLBIinitiated trials and 7 investigator-initiated trials. In 1985, the numbers were 10 and 24, respectively, a reversal in the proportion. In 1987, this pattern continued, with 17 NHLBI-initiated trials and 28 investigator-initiated trials. Even the percent of dollars allocated to the clinical trials originating with investigators has increased over time. For example, in 1975, 2.6% of the money allocated to NHLBI supported clinical trials went to the one investigatorinitiated study. In 1980, this increased to 16.5%. During the past few years, it has ranged from 32% to 40%. Although the average cost of Institute-initiated studies remains higher than that for investigator-initiated trials (but not as much as so as in the past), differences in sample size, nature of the intervention, and kinds of participants make precise cost comparisons difficult. The "competition" between Institute- and investigator-initiated trials is not destroying the latter. Rather, both are flourishing. Second, the existence of a "pilot" or "feasibility" study can in no way guarantee the funding of a full-scale trial. The decision to proceed with the full-scale program is made on its merits, as is the decision as to the best mechanism of support. Similarly, there can be no guarantee of funding for any of the individual components of the trial. As with all funding decisions, the peer review process is paramount, and scientific merit must be sufficient and adequately documented. Third, let us assure you that NHLBI-initiated clinical trials do not gain
229
Letters to the Editor Table 1
Comparison of Institute- and Investigator-Initiated Trials Investigator Initiated
NHLBI Initiated 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987
Number
$ (000)
Number
$ (000)
6 6 12 13 13 11 9 10 12 12 10 11 17
40,669 46,631 43,932 53,712 61,668 46,244 44,171 29,256 29,423 22,809 33,732 30,300 47,679
1 1 1 2 3 7 10 11 17 18 24 28 28
1,105 1,545 1,420 4,427 4,148 9,137 10,091 12,108 11,532 13,577 16,949 20,093 22,278
approval easily. Yes, we do have access to advisory committees and other consultants. To not make use of them would be irrational, as it would impair the science. Yet there are also hurdles to surmount. These hurdles are usually more numerous and more difficult than those faced by investigator-initiated trials. For example, Institute-initiated trials must receive strong backing of a Divisional Advisory Committee, the Division Director, the Institute Director, and the NHLBI Advisory Council.Further, until the protocol is reviewed in detail by an outside advisory group of peer scientists and recommended for approval, no study can begin enrolling patients. It has been our perception that this process is considerably more rigorous than that pursued by the usual investigator-initiated trial. Investigator-initiated trials that are assigned by the Division of Research Grants to NHLBI are typically considered by the Clinical Trials Review Committee. It is the rare application that is found to be unworthy of such review. We encourage prospective applicants to contact Institute staff before submission. This serves two purposes. It enables staff, who may have considerable expertise, to informally critique a draft as regards study design and grants administration. It also gives the applicant an opportunity to learn whether his or her idea has sufficient importance and relevance to be funded, should it receive a sufficiently high priority score. Because this preliminary contact is not a consistent, or required, step in preparing an application, we have recently decided that investigator-initiated clinical trials need to undergo formal concept review in addition to study section review and have implemented that process. The process consists of a review by a subcommittee of the Advisory Council, supplemented by other scientists with appropriate expertise. This review takes place after the initial peer review, but before Council consideration. The intention is not to duplicate the scientific review of the study section, but to consider aspects such as program balance, overlap with current programs, and cost as it relates to perceived importance. Reviewed applications would include not only those in the "fundable range," but others. The purpose of considering applications not likely to be funded is to provide the applicant with information to help him or her decide if a revised sub-
230
Letters to the Editor mission is warranted. For example, if certain technical flaws were to be corrected and a better priority score assigned would the trial be sufficiently important to merit funding? We realize that these are different points of view concerning the funding process. We hope, however, that we have shown that things are not onesided, and that at the NHLBI, at least, multicenter investigator-initiated trials are considered major components of our program. Claude Lenfant, M.D. Director, NHLBI William Harlan, M.D. Director, DECA Lawrence M. Friedman, M.D. Associate Director