5-ASA therapy for active Crohn?s disease: Old friends, old data, and a new conclusion
Authors: B FEAGAN
Journal: Clinical Gastroenterology and Hepatology (2004)

"Well, all I know is what I read in the papers."—Will Rogers (1879–1935), New York Times, September 30, 1923In this issue of Clinical Gastroenterology and Hepatology, Hanauer and Stromberg provide us with some interesting old data regarding the efficacy of 5-ASA (mesalamine) for the treatment of Crohn's disease (CD). To appreciate the importance of this report, it is first necessary to understand the historical development of mesalamine compounds.The prototypic 5-ASA drug, sulfasalazine (SPS), has been used to treat CD for more than 40 years. During the late 1970s, two large multicenter randomized, controlled trials (RCTs) demonstrated that SPS was marginally superior to placebo for induction of remission in active disease. Specifically, the National Cooperative Crohn's Disease Study1Summers R.W Switz D.M Sessions Jr, J.T Becktel J.M Best W.R Kern Jr, F Singleton J.W National Cooperative Crohn's Disease Study results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar and the European Cooperative Crohn's Disease Study2Malchow H Ewe K Brandes J.W Goebell H Ehms H Sommer H Jesdinsky H European Cooperative Crohn's Disease Study (ECCDS) results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar showed remission rates, defined as a Crohn's Disease Activity Index (CDAI) score of less than or equal to 150 points, of approximately 40% in comparison to a 30% rate with placebo. Subsequently, a landmark experiment by Azad Kahn et al.3Azad Khan A.K Piris J Truelove S.C An experiment to determine the active therapeutic moeity of sulphasalazine.Lancet. 1977; ii: 892-895Abstract Scopus (610) Google Scholar performed exclusively in patients with UC demonstrated that 5-ASA is the active component of SPS. Accordingly, newer formulations of 5-ASA were developed that lacked a sulfa moiety. This innovation facilitated administration of higher doses of 5-ASA with improved tolerability. Clinicians quickly appreciated the favorable side effect profile of the new preparations after approval of these compounds for the treatment of UC. Results from RCTs in CD were eagerly awaited.Although initial studies of various 5-ASA formulations demonstrated equivocal results, in 1993, Singleton et al.4Singleton J.W Hanauer S.B Gitnick G.L Peppercorn M.A Robinson M.G Wruble L.D Krawitt E.L Mesalamine capsules for the treatment of active Crohn's disease results of a 16-week trial.Gastroenterology. 1993; 104: 1293-1301PubMed Google Scholar reported findings from a study of Pentasa that had a profound effect on clinical practice. In this dose-finding trial that evaluated 310 patients for 16 weeks, the remission rates for the placebo, 1 g/day, 2 g/day, and 4 g/day 5-ASA groups were 18%, 23%, 24%, and 43%, respectively (P < 0.0017 for the placebo vs. 4 g/day contrast). The authors concluded that high-dose 5-ASA "is a safe and effective single agent for treating and inducing remission in active Crohn's disease." On the basis of these data and an extensive and satisfactory experience with the newer 5-ASA formulations in UC, gastroenterologists abandoned their old friend SPS. By the mid-1990s, Pentasa and other new 5-ASA formulations had become treatments of choice for mild to moderately active CD, notwithstanding that none of the new agents was ever approved for this indication by the U.S. Food and Drug Administration.We now know that this evolution in clinical practice occurred in the absence of vital information. Most important were the unpublished results of 2 additional large-scale RCTs. (The existence of one of these trials was referred to in 1994 in a letter by Dr. Singleton.5Singleton J Second trial of mesalamine therapy in the treatment of active Crohn's disease.Gastroenterology. 1994; 107: 632-633PubMed Google Scholar) Thanks to Drs. Hanauer and Stromberg, we now have an opportunity to examine the data from these long lost studies.These investigators have used both meta-analysis and pooled analysis of individual patient data to combine results from all 3 trials. Given that no benefit over placebo for the 1-and 2-g/day doses was shown in the Singleton trial, only data from the 4-g/day (n = 304) vs. placebo (n = 311) arms were evaluated. The primary analysis, based on a comparison of the average change in CDAI scores, identified a significantly greater improvement with active treatment. However, important heterogeneity of treatment effect was identified in that the published study was primarily responsible for the observed difference in favor of Pentasa. Drs. Hanauer and Stromberg concluded that the clinical relevance of the statistically significant 18-point improvement "is not clear as, in individual trials, a 70–100 point decrease is generally required to establish clinical efficacy."In my opinion, an alternative conclusion is more plausible, namely that these data provide clear evidence that Pentasa is ineffective for the treatment of symptomatic CD.To justify this conclusion, it is necessary to provide some background regarding the CDAI. This instrument was developed in the mid-1970s as a quantitative measure of a physician's assessment of disease activity. The average change in CDAI detectable by a clinician ("slightly better" or "slightly worse") is 50 points.6Best W.R Becktel J.M Singleton J Kern Jr, F Development of a Crohn's disease activity index.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2972) Google Scholar The most robust end point for use in RCTs in active CD is remission, defined by a CDAI score of less than 150 points. Because patients who enter these studies have average CDAI scores in the range of 280–300 points, treatments that are highly effective for inducing remission (corticosteroids, infliximab) will typically show improvement in the average score of at least 100 points over placebo. Nevertheless, even if we conservatively accept that a 50-point improvement is clinically important, the change observed in the study of Hanauer and Stromberg was only 18 points, less than half that considered relevant by an experienced clinician! It is also noteworthy that for noninferiority studies ("equivalence" trials), a score of one-half that considered to be clinically important (in this case 25 points) is often used to define clinical insignificance. Thus, the 18-point "benefit" observed with high-dose Pentasa therapy is not clinically meaningful. This results in the conclusion that reasonable evidence now exists that Pentasa is ineffective for the treatment of active CD.Because high-dose 5-ASA is widely used as a first-line induction therapy, this conclusion will be unsettling to many clinicians. However, several other even more disturbing issues are raised by this report. Results from the 2 negative studies included in this analysis were available as internal corporate reports in 19917Marion Merrel Dow IncStatistical report. 1991Google Scholar and 1997.8Hoechst Marion Roussel IncClinical study report. 1997Google Scholar Why did it take so long for these important data to enter the public domain?An extensive literature exists describing the phenomenon of publication bias, in which the results of trials with positive findings are more likely to be published than those with negative results. Publication bias is a serious problem because clinicians require unbiased estimates of efficacy and safety to make informed treatment decisions. What are the origins of this bias? One hypothesis, popular among disgruntled academics, is that journal editors selectively accept studies with positive findings because they are of greater interest to readers. Recently Olsen9Olsen J.H Interpretation in drug epidemiology.Lancet. 1998; 352: 162Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar examined 745 manuscripts submitted for publication to the Journal of the American Medical Association between 1996 and 1999 and found that studies with statistically significant positive findings were no more likely to be published than those with negative results (odds ratio, 1.30; 95% confidence interval, 0.87–1.96). This finding is inconsistent with the belief that editorial fiat is an important source of the problem.Alternatively, strong evidence exists that publication bias originates from investigator behavior. For example, Dickersin et al.10Dickersin K Chan S Chalmers T.C Sacks H.S Smith Jr, H Publication bias and clinical trials.Control Clin Trials. 1987; 8: 343-353Abstract Full Text PDF PubMed Scopus (528) Google Scholar tracked the publication record of all 737 studies submitted to the Institutional Review Boards at Johns Hopkins Health Institutions in 1980. Studies that reported positive findings were more likely to be published (odds ratio, 2.54; 95% confidence interval, 1.63–3.94). Again, editors were not responsible for the difference; only 6 of the 124 unpublished studies were reported to have been rejected by a journal. The inescapable conclusion is that investigators are less enthusiastic about negative findings and often choose not to make the effort to publish. This is a serious problem not only because of the issue of bias. We need to consider that one reason that patients participate in clinical studies is that they believe that their involvement will provide new information that will ultimately improve the health of others. Accordingly, failure of investigators to publish negative findings can be construed as a breach of public trust.Another even more unsettling possibility is that investigators and sponsors might fail to submit negative data for publication to protect their own interests. The extensive involvement of industry in all aspects of clinical investigation is a fact of modern life. Academic investigators who conduct RCTs routinely interact with multiple corporate sponsors. As a consequence, conflicts of interest might exist that lead to selective reporting of results. If this were the case, studies with negative results sponsored by industry would be less likely to be published than those with positive findings. Lexchin et al.11Lexchin J Bero L.A Djulbegovic B Clark O Pharmaceutical industry sponsorship and research outcome and quality systematic review.BMJ. 2003; 326: 1167-1170Crossref PubMed Scopus (1597) Google Scholar have recently performed a systematic review of all studies that have examined the relationship between industry sponsorship of research and publication. They also evaluated whether quality of research could explain the failure to publish negative results. Thirty studies were identified. Studies funded by pharmaceutical companies were significantly less likely to be published than those funded by other sources. Sixteen studies evaluated the relationship between source of funding and outcomes. Thirteen of these studies found that RCTs and meta-analyses sponsored by pharmaceutical companies favored the product of the sponsor. There was no relationship between source of funding and methodologic quality. The authors concluded that differences in the quality of research methodology could not account for the lower rate of publication. Publication bias is one potential explanation for these findings. In support of this hypothesis, the authors cited several high-profile examples in which unfavorable or inconclusive results regarding pharmaceuticals were suppressed by the sponsor.What can be done about this problem?There is plenty of work for everyone if publication bias is to be minimized. Academic investigators and institutions must understand the negative consequences of selectively reporting positive results. Steps should be taken to ensure that research approved by Institutional Review Boards is submitted for publication. For example, should monitoring of publication come under the auspices of these boards? Institutions should ensure that contracts with industry sponsors are not encumbered by restrictive publication clauses, and investigators should vigorously defend their right to publish data. Industry needs to be aware of the negative consequences associated with suppression of data and to develop policies that mandate publication of all clinically relevant information. Editors need to continue to publish important negative findings. Governments and regulatory authorities should work with researchers to develop prospective registries of all RCTs so that unpublished studies can be identified. The latter proposal is almost 20 years old12Simes R.J Publication bias the case for an international registry of clinical trials.J Clin Oncol. 1986; 4: 1529-1541Crossref PubMed Scopus (605) Google Scholar; it is time to take action so that the "Pentasa problem" does not recur!Returning to the clinic, the take away message from the study by Drs. Hanauer and Stromberg is a simple one. If you are currently using the newer 5-ASA formulations to induce remission in patients with mild to moderately active CD, you should reconsider this practice. Strong and consistent evidence exists that SPS is modestly effective for the treatment of active disease; it is now clear that this is not equally true for the newer 5-ASA compounds. We have treated our old friend SPS poorly. Perhaps it is time to get reacquainted. "Well, all I know is what I read in the papers."—Will Rogers (1879–1935), New York Times, September 30, 1923 In this issue of Clinical Gastroenterology and Hepatology, Hanauer and Stromberg provide us with some interesting old data regarding the efficacy of 5-ASA (mesalamine) for the treatment of Crohn's disease (CD). To appreciate the importance of this report, it is first necessary to understand the historical development of mesalamine compounds. The prototypic 5-ASA drug, sulfasalazine (SPS), has been used to treat CD for more than 40 years. During the late 1970s, two large multicenter randomized, controlled trials (RCTs) demonstrated that SPS was marginally superior to placebo for induction of remission in active disease. Specifically, the National Cooperative Crohn's Disease Study1Summers R.W Switz D.M Sessions Jr, J.T Becktel J.M Best W.R Kern Jr, F Singleton J.W National Cooperative Crohn's Disease Study results of drug treatment.Gastroenterology. 1979; 77: 847-869PubMed Scopus (1068) Google Scholar and the European Cooperative Crohn's Disease Study2Malchow H Ewe K Brandes J.W Goebell H Ehms H Sommer H Jesdinsky H European Cooperative Crohn's Disease Study (ECCDS) results of drug treatment.Gastroenterology. 1984; 86: 249-266Abstract Full Text PDF PubMed Scopus (862) Google Scholar showed remission rates, defined as a Crohn's Disease Activity Index (CDAI) score of less than or equal to 150 points, of approximately 40% in comparison to a 30% rate with placebo. Subsequently, a landmark experiment by Azad Kahn et al.3Azad Khan A.K Piris J Truelove S.C An experiment to determine the active therapeutic moeity of sulphasalazine.Lancet. 1977; ii: 892-895Abstract Scopus (610) Google Scholar performed exclusively in patients with UC demonstrated that 5-ASA is the active component of SPS. Accordingly, newer formulations of 5-ASA were developed that lacked a sulfa moiety. This innovation facilitated administration of higher doses of 5-ASA with improved tolerability. Clinicians quickly appreciated the favorable side effect profile of the new preparations after approval of these compounds for the treatment of UC. Results from RCTs in CD were eagerly awaited. Although initial studies of various 5-ASA formulations demonstrated equivocal results, in 1993, Singleton et al.4Singleton J.W Hanauer S.B Gitnick G.L Peppercorn M.A Robinson M.G Wruble L.D Krawitt E.L Mesalamine capsules for the treatment of active Crohn's disease results of a 16-week trial.Gastroenterology. 1993; 104: 1293-1301PubMed Google Scholar reported findings from a study of Pentasa that had a profound effect on clinical practice. In this dose-finding trial that evaluated 310 patients for 16 weeks, the remission rates for the placebo, 1 g/day, 2 g/day, and 4 g/day 5-ASA groups were 18%, 23%, 24%, and 43%, respectively (P < 0.0017 for the placebo vs. 4 g/day contrast). The authors concluded that high-dose 5-ASA "is a safe and effective single agent for treating and inducing remission in active Crohn's disease." On the basis of these data and an extensive and satisfactory experience with the newer 5-ASA formulations in UC, gastroenterologists abandoned their old friend SPS. By the mid-1990s, Pentasa and other new 5-ASA formulations had become treatments of choice for mild to moderately active CD, notwithstanding that none of the new agents was ever approved for this indication by the U.S. Food and Drug Administration. We now know that this evolution in clinical practice occurred in the absence of vital information. Most important were the unpublished results of 2 additional large-scale RCTs. (The existence of one of these trials was referred to in 1994 in a letter by Dr. Singleton.5Singleton J Second trial of mesalamine therapy in the treatment of active Crohn's disease.Gastroenterology. 1994; 107: 632-633PubMed Google Scholar) Thanks to Drs. Hanauer and Stromberg, we now have an opportunity to examine the data from these long lost studies. These investigators have used both meta-analysis and pooled analysis of individual patient data to combine results from all 3 trials. Given that no benefit over placebo for the 1-and 2-g/day doses was shown in the Singleton trial, only data from the 4-g/day (n = 304) vs. placebo (n = 311) arms were evaluated. The primary analysis, based on a comparison of the average change in CDAI scores, identified a significantly greater improvement with active treatment. However, important heterogeneity of treatment effect was identified in that the published study was primarily responsible for the observed difference in favor of Pentasa. Drs. Hanauer and Stromberg concluded that the clinical relevance of the statistically significant 18-point improvement "is not clear as, in individual trials, a 70–100 point decrease is generally required to establish clinical efficacy." In my opinion, an alternative conclusion is more plausible, namely that these data provide clear evidence that Pentasa is ineffective for the treatment of symptomatic CD. To justify this conclusion, it is necessary to provide some background regarding the CDAI. This instrument was developed in the mid-1970s as a quantitative measure of a physician's assessment of disease activity. The average change in CDAI detectable by a clinician ("slightly better" or "slightly worse") is 50 points.6Best W.R Becktel J.M Singleton J Kern Jr, F Development of a Crohn's disease activity index.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2972) Google Scholar The most robust end point for use in RCTs in active CD is remission, defined by a CDAI score of less than 150 points. Because patients who enter these studies have average CDAI scores in the range of 280–300 points, treatments that are highly effective for inducing remission (corticosteroids, infliximab) will typically show improvement in the average score of at least 100 points over placebo. Nevertheless, even if we conservatively accept that a 50-point improvement is clinically important, the change observed in the study of Hanauer and Stromberg was only 18 points, less than half that considered relevant by an experienced clinician! It is also noteworthy that for noninferiority studies ("equivalence" trials), a score of one-half that considered to be clinically important (in this case 25 points) is often used to define clinical insignificance. Thus, the 18-point "benefit" observed with high-dose Pentasa therapy is not clinically meaningful. This results in the conclusion that reasonable evidence now exists that Pentasa is ineffective for the treatment of active CD. Because high-dose 5-ASA is widely used as a first-line induction therapy, this conclusion will be unsettling to many clinicians. However, several other even more disturbing issues are raised by this report. Results from the 2 negative studies included in this analysis were available as internal corporate reports in 19917Marion Merrel Dow IncStatistical report. 1991Google Scholar and 1997.8Hoechst Marion Roussel IncClinical study report. 1997Google Scholar Why did it take so long for these important data to enter the public domain? An extensive literature exists describing the phenomenon of publication bias, in which the results of trials with positive findings are more likely to be published than those with negative results. Publication bias is a serious problem because clinicians require unbiased estimates of efficacy and safety to make informed treatment decisions. What are the origins of this bias? One hypothesis, popular among disgruntled academics, is that journal editors selectively accept studies with positive findings because they are of greater interest to readers. Recently Olsen9Olsen J.H Interpretation in drug epidemiology.Lancet. 1998; 352: 162Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar examined 745 manuscripts submitted for publication to the Journal of the American Medical Association between 1996 and 1999 and found that studies with statistically significant positive findings were no more likely to be published than those with negative results (odds ratio, 1.30; 95% confidence interval, 0.87–1.96). This finding is inconsistent with the belief that editorial fiat is an important source of the problem. Alternatively, strong evidence exists that publication bias originates from investigator behavior. For example, Dickersin et al.10Dickersin K Chan S Chalmers T.C Sacks H.S Smith Jr, H Publication bias and clinical trials.Control Clin Trials. 1987; 8: 343-353Abstract Full Text PDF PubMed Scopus (528) Google Scholar tracked the publication record of all 737 studies submitted to the Institutional Review Boards at Johns Hopkins Health Institutions in 1980. Studies that reported positive findings were more likely to be published (odds ratio, 2.54; 95% confidence interval, 1.63–3.94). Again, editors were not responsible for the difference; only 6 of the 124 unpublished studies were reported to have been rejected by a journal. The inescapable conclusion is that investigators are less enthusiastic about negative findings and often choose not to make the effort to publish. This is a serious problem not only because of the issue of bias. We need to consider that one reason that patients participate in clinical studies is that they believe that their involvement will provide new information that will ultimately improve the health of others. Accordingly, failure of investigators to publish negative findings can be construed as a breach of public trust. Another even more unsettling possibility is that investigators and sponsors might fail to submit negative data for publication to protect their own interests. The extensive involvement of industry in all aspects of clinical investigation is a fact of modern life. Academic investigators who conduct RCTs routinely interact with multiple corporate sponsors. As a consequence, conflicts of interest might exist that lead to selective reporting of results. If this were the case, studies with negative results sponsored by industry would be less likely to be published than those with positive findings. Lexchin et al.11Lexchin J Bero L.A Djulbegovic B Clark O Pharmaceutical industry sponsorship and research outcome and quality systematic review.BMJ. 2003; 326: 1167-1170Crossref PubMed Scopus (1597) Google Scholar have recently performed a systematic review of all studies that have examined the relationship between industry sponsorship of research and publication. They also evaluated whether quality of research could explain the failure to publish negative results. Thirty studies were identified. Studies funded by pharmaceutical companies were significantly less likely to be published than those funded by other sources. Sixteen studies evaluated the relationship between source of funding and outcomes. Thirteen of these studies found that RCTs and meta-analyses sponsored by pharmaceutical companies favored the product of the sponsor. There was no relationship between source of funding and methodologic quality. The authors concluded that differences in the quality of research methodology could not account for the lower rate of publication. Publication bias is one potential explanation for these findings. In support of this hypothesis, the authors cited several high-profile examples in which unfavorable or inconclusive results regarding pharmaceuticals were suppressed by the sponsor. What can be done about this problem? There is plenty of work for everyone if publication bias is to be minimized. Academic investigators and institutions must understand the negative consequences of selectively reporting positive results. Steps should be taken to ensure that research approved by Institutional Review Boards is submitted for publication. For example, should monitoring of publication come under the auspices of these boards? Institutions should ensure that contracts with industry sponsors are not encumbered by restrictive publication clauses, and investigators should vigorously defend their right to publish data. Industry needs to be aware of the negative consequences associated with suppression of data and to develop policies that mandate publication of all clinically relevant information. Editors need to continue to publish important negative findings. Governments and regulatory authorities should work with researchers to develop prospective registries of all RCTs so that unpublished studies can be identified. The latter proposal is almost 20 years old12Simes R.J Publication bias the case for an international registry of clinical trials.J Clin Oncol. 1986; 4: 1529-1541Crossref PubMed Scopus (605) Google Scholar; it is time to take action so that the "Pentasa problem" does not recur! Returning to the clinic, the take away message from the study by Drs. Hanauer and Stromberg is a simple one. If you are currently using the newer 5-ASA formulations to induce remission in patients with mild to moderately active CD, you should reconsider this practice. Strong and consistent evidence exists that SPS is modestly effective for the treatment of active disease; it is now clear that this is not equally true for the newer 5-ASA compounds. We have treated our old friend SPS poorly. Perhaps it is time to get reacquainted.