EDITORIALS ClinicalTrials.gov: What the Numbers Don’t Tell Us Every NIH funding conversation includes the words “return on investment,” “leverage,” “impact,” and “bang for the buck.” In no conversation are these words used more than when discussing the large programs, which include clinical trials. An enhanced analysis by Todd and coworkers in this issue of AnnalsATS (pp. 411–417) of the interventional clinical trials in Pulmonary, Critical Care, and Sleep Medicine (PCCSM) registered in ClinicalTrials.gov provides insight into the balance of clinical trials across diseases, the basic characteristics of clinical trials, and the role of stakeholders, regulatory agencies, and funders in shaping PCCSM interventional trials (1). The authors conclude that PCCSM trials are underrepresented relative to the current and future disease burden, unevenly distributed across PCCSM diseases, small and rely heavily on pulmonary function endpoints, and that the dominant funding role of industry shapes the PCCSM interventional trial landscape. From the perspective of the Division of Lung Diseases (DLD) of NHLBI, the largest government funder of pulmonary clinical trials, the article provides food for thought on how the Division is spending its dollars. During the period 2007–2010, PCCSM comprised only 5.4% of all interventional studies, compared with 21.9% for oncology (that is all of oncology, not just lung cancer) and 8.4% for cardiovascular disease. The authors posit that this number is low relative to disease burden. But, is having 21.9% of the interventional trials market a sign of public health, or even research health? Would having more trials or larger trials necessarily translate into better or more treatments for the U.S. public? Further, Todd and colleagues found that NIHfunded trials comprised 5.4% (119/2,226) of all the PCCSM trials, versus the 43.5% (969/2,226) funded by industry globally. What is the appropriate balance of industry- to governmentsponsored research, and who is responsible for achieving the balance? DLD has a history of initiating and funding large trials, like Intermittent Positive Pressure Breathing, Nocturnal Oxygen Treatment Trial, Lung Health Study, Childhood Asthma Management Program, and the National Emphysema Treatment Trial. These trials have been very high impact, fill a niche that industry will not address, and would never have been done without government leadership. In addition, DLD has invested substantially in clinical research networks as a way to foster trials efficiently in certain disease areas. The charge to these networks has traditionally been to conduct management trials. These networks have conducted very high–impact trials that also would not have been done by industry and may have even been outside of FDA jurisdiction, like the Respiratory Management in ARDS and Fluid and Catheter Treatment Trials (low versus high tidal volume and fluid and catheter management in mechanically ventilated patients) (2–4) in the ARDS network; how to use approved asthma medications in the asthma clinical research networks; or testing current standard of care, like prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis in the IPF network (5). However, a review of the trials in ClinicalTrials.gov from September 2007 to September 2010 show that more than 490
two-thirds of NHLBI-sponsored trials are investigator initiated. Having a platform for investigators to initiate trials is NIH’s traditional way of allowing the most pressing questions across any disease to be considered for funding. NHLBI’s planning grant program (R34) was designed to help investigators who are close to submitting an application overcome the last hurdle in preparing for peer review. The system is elastic and could allow funding of more trials in more diseases if worthy and cost-effective questions were favorably reviewed by peers. Besides clinical trials, NIH funds the full spectrum of science from molecular and -omics research to implementation science and public education campaigns as well as training and education, an investment essential to the future of discoveries and clinical trials. The balance of basic to applied funding at NIH has remained constant over time. The percent spent on basic research was 57% in 1994 (6); since 2003, the amount of funding spent has ranged from 53–57%, and was 54% in 2012 (7). NIH’s role has traditionally been to supply discoveries through the funding of basic research, providing promising opportunities for industry to develop. In fact, NIH’s long-standing Small Business Innovation Research and Small Business Technology Transfer programs are designed to encourage this kind of hand-off (http://grants.nih. gov/grants/funding/sbir.htm). Furthermore, NIH-funded observational studies have been hypothesis generating on how to prevent disease or disease progression. NIH considers it a success that these observational studies have led industry to invest in prevention, both at the bench and in clinical trials. Rightfully, NIH might claim some contribution for many industry-sponsored trials. Strikingly, only 11.6% of the 73.2% Todd and coworkers report as intervention trials using a drug or device were Phase I studies. Particularly difficult to treat diseases, like interstitial lung disease and sarcoidosis, together comprise less than 3% of the total PCCSM clinical trials. As Todd and colleagues note, the lack of Phase I trials and the few trials in the difficult-to-treat diseases suggest that more discovery research may be what is needed. Free-ranging support of investigator-initiated research without a clear short-term return on investment allows for novelty and innovation. As Dr. Collins notes in his editorial: “.it is impossible to predict whence the next treatment may emerge” (7). With the decline of industry funding of pre-clinical research between 1998 and 2010 (8), NIH has sought to enhance industry research programs by developing programs to “de-risk” the investment for industry. DLD in particular has initiated the Centers for Advanced Diagnostics and Experimental Therapeutics program, the translational program project grants, and the Novel therapies in Lung Diseases in the hopes of bridging some of the gaps. We see these as a win-win for investigators and industry. With discoveries taking 15–25 years to mature to clinical application (8), the continued investment by NIH in basic and translational research now is just as essential for our future health as are clinical trials. Another impressive finding of Todd and coworkers is that only slightly over 15% of the trials used clinical outcomes to which a patient might relate, like quality of life, exercise ability, or mortality. NIH-funded trials were more likely to include mortality and quality of life than industry trials, and industry trials were more likely to depend on pulmonary function test outcomes, a measure with a high degree of reproducibility and an AnnalsATS Volume 10 Number 5 | October 2013
EDITORIALS FDA-approved endpoint, making it easier to show statistical, if not clinical, significance. While pulmonary function tests do correlate overall with well-being, quality of life, and survival, we have yet to know whether improving pulmonary function in a chronic lung disease, like IPF, is a reasonable surrogate for survival (9). Finding valid disease-specific surrogate endpoints for clinically meaningful endpoints could increase the efficiency of certain trials and a recent Institute of Medicine report calls for FDA to have the authority to assert more rigor in the evaluation of surrogate endpoints and their use (http://www.iom.edu/Reports/ 2010/Evaluation-of-Biomarkers-and-Surrogate-Endpoints-inChronic-Disease.aspx). The need for better outcomes was part of the justification for the NHLBI-initiated Subpopulations and Intermediate Outcome Measures (SPIROMICS) in COPD program, which seeks to find phenotypically meaningful surrogate endpoints and biomarkers in COPD to facilitate screening trials in this devastating disease. Closely related to the need for meaningful surrogate endpoints is the need to find more cost-effective ways of conducting trials and evaluating interventions. NIH is facilitating the adoption of pragmatic trials with its NIH Health Care Systems (HCS) Research Collaboratory supported through the NIH Common Fund (see http://commonfund.nih.gov/hcscollaboratory/). NHLBI released an initiative, Pilot Studies to Develop and Test Novel, Low-Cost Methods for the Conduct of Clinical Trials. Another new, forthcoming NHLBI initiative is to foster low-cost, clinically integrated pragmatic trials to leverage big data infrastructures and integrated health systems to enable more large-scale and low-cost trials. For untested treatments of difficult to treat diseases, we clearly need faster evaluation and more rapid turnover, so we do not spend the time and resources on a treatment that does not work. In summary, we are all responsible for the number of trials, the distribution of trials across PCCSM diseases, the trial designs, and the endpoints used. The new and thought-provoking findings by Todd and colleagues on the interventional PCCSM trials and their attributes in ClinicalTrials.gov database provide a perspective for identifying deficits and influences and contemplating solutions. However, beyond the numbers in ClinicalTrials.gov, many clinical research participants play active roles in supporting the clinical research enterprise to improve the health of the nation. NIH contributes through encouraging innovative basic research, challenging investigators to pursue the translational potential of their basic research, fostering disease prevention, developing novel clinical research tools and methods, providing an elastic path for investigators to pursue the clinical research questions of most importance to them and their communities, and training the next generation of researchers. Thus, on the surface, NIH may appear to fund only 5.4% of the PCCSM trials, when in fact it is supporting fuel to fill gaps in the clinical research enterprise, not captured in the ClinicalTrials.gov database, but essential to its overall success. PCCSM may comprise 5.4% of all trials because that is the state of the science. The pressing scientific questions that the community is positioned to ask now may not justify more trials or larger trials. The challenge for NIH is to balance creating scientific opportunity for future clinical research with urgent public health needs now. The challenge for the PCCSM communities is to think creatively how to best harvest the opportunities Editorials
provided by NIH to develop cost-effective ways to pursue treatments for currently untreatable lung diseases, and advance novel therapies for the multitude of chronic lung diseases that exert a high health and economic burden to patients and the nation. Author disclosures are available with the text of this article at www.atsjournals.org. Gail G. Weinmann, M.D. James P. Kiley, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Bethesda, Maryland
References 1 Todd J, White K, Chiswell K, Tasneem A, Palmer S. Using ClinicalTrials. gov to Understand the State of Clinical Research in Pulmonary, Critical Care, and Sleep Medicine. Ann Am Thorac Soc 2013;10: 411–417. 2 Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A; Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308. 3 Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006;354: 2564–2575. 4 Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, Wiedemann HP, deBoisblanc B, Connors AF, Hite RD, Harabin AL; Acute Respiratory Distress Syndrome Network. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213–2224. 5 Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366:1968–1977. 6 Galis ZS, Hoots WK, Kiley JP, Lauer MS. On the value of portfolio diversity in heart, lung, and blood research. Am J Respir Crit Care Med 2012;186:575–578. 7 Collins FS. NIH basics. Science 2012;337:503. 8 Dorsey ER, de Roulet J, Thompson JP, Reminick JI, Thai A, WhiteStellato Z, Beck CA, George BP, Moses H III. Funding of US biomedical research, 2003-2008. JAMA 2010;303:137–143. 9 Raghu G, Collard HR, Anstrom KJ, Flaherty KR, Fleming TR, King TE Jr, Martinez FJ, Brown KK. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med 2012;185:1044–1048. Published 2013 by the American Thoracic Society
Multimorbidity: The New Normal Despite substantial advances in our understanding of asthma, and the availability of generally well-tolerated and effective therapies, many patients with asthma continue to experience poor control of their disease (1). Surveys performed in community and clinical settings have found that a substantial proportion of patients with asthma are either not well or poorly controlled (1–4). Patients with not well or poorly controlled asthma are more likely to experience impaired quality of life and productivity, and are at significantly increased risk for asthma exacerbations (5). Poor control of asthma is a significant national burden on the U.S. health care system (6). Hospitalizations and emergency department visits for asthma are a major component of the more 491
two-thirds of NHLBI-sponsored trials are investigator initiated. Having a platform for investigators to initiate trials is NIH’s traditional way of allowing the most pressing questions across any disease to be considered for funding. NHLBI’s planning grant program (R34) was designed to help investigators who are close to submitting an application overcome the last hurdle in preparing for peer review. The system is elastic and could allow funding of more trials in more diseases if worthy and cost-effective questions were favorably reviewed by peers. Besides clinical trials, NIH funds the full spectrum of science from molecular and -omics research to implementation science and public education campaigns as well as training and education, an investment essential to the future of discoveries and clinical trials. The balance of basic to applied funding at NIH has remained constant over time. The percent spent on basic research was 57% in 1994 (6); since 2003, the amount of funding spent has ranged from 53–57%, and was 54% in 2012 (7). NIH’s role has traditionally been to supply discoveries through the funding of basic research, providing promising opportunities for industry to develop. In fact, NIH’s long-standing Small Business Innovation Research and Small Business Technology Transfer programs are designed to encourage this kind of hand-off (http://grants.nih. gov/grants/funding/sbir.htm). Furthermore, NIH-funded observational studies have been hypothesis generating on how to prevent disease or disease progression. NIH considers it a success that these observational studies have led industry to invest in prevention, both at the bench and in clinical trials. Rightfully, NIH might claim some contribution for many industry-sponsored trials. Strikingly, only 11.6% of the 73.2% Todd and coworkers report as intervention trials using a drug or device were Phase I studies. Particularly difficult to treat diseases, like interstitial lung disease and sarcoidosis, together comprise less than 3% of the total PCCSM clinical trials. As Todd and colleagues note, the lack of Phase I trials and the few trials in the difficult-to-treat diseases suggest that more discovery research may be what is needed. Free-ranging support of investigator-initiated research without a clear short-term return on investment allows for novelty and innovation. As Dr. Collins notes in his editorial: “.it is impossible to predict whence the next treatment may emerge” (7). With the decline of industry funding of pre-clinical research between 1998 and 2010 (8), NIH has sought to enhance industry research programs by developing programs to “de-risk” the investment for industry. DLD in particular has initiated the Centers for Advanced Diagnostics and Experimental Therapeutics program, the translational program project grants, and the Novel therapies in Lung Diseases in the hopes of bridging some of the gaps. We see these as a win-win for investigators and industry. With discoveries taking 15–25 years to mature to clinical application (8), the continued investment by NIH in basic and translational research now is just as essential for our future health as are clinical trials. Another impressive finding of Todd and coworkers is that only slightly over 15% of the trials used clinical outcomes to which a patient might relate, like quality of life, exercise ability, or mortality. NIH-funded trials were more likely to include mortality and quality of life than industry trials, and industry trials were more likely to depend on pulmonary function test outcomes, a measure with a high degree of reproducibility and an AnnalsATS Volume 10 Number 5 | October 2013
EDITORIALS FDA-approved endpoint, making it easier to show statistical, if not clinical, significance. While pulmonary function tests do correlate overall with well-being, quality of life, and survival, we have yet to know whether improving pulmonary function in a chronic lung disease, like IPF, is a reasonable surrogate for survival (9). Finding valid disease-specific surrogate endpoints for clinically meaningful endpoints could increase the efficiency of certain trials and a recent Institute of Medicine report calls for FDA to have the authority to assert more rigor in the evaluation of surrogate endpoints and their use (http://www.iom.edu/Reports/ 2010/Evaluation-of-Biomarkers-and-Surrogate-Endpoints-inChronic-Disease.aspx). The need for better outcomes was part of the justification for the NHLBI-initiated Subpopulations and Intermediate Outcome Measures (SPIROMICS) in COPD program, which seeks to find phenotypically meaningful surrogate endpoints and biomarkers in COPD to facilitate screening trials in this devastating disease. Closely related to the need for meaningful surrogate endpoints is the need to find more cost-effective ways of conducting trials and evaluating interventions. NIH is facilitating the adoption of pragmatic trials with its NIH Health Care Systems (HCS) Research Collaboratory supported through the NIH Common Fund (see http://commonfund.nih.gov/hcscollaboratory/). NHLBI released an initiative, Pilot Studies to Develop and Test Novel, Low-Cost Methods for the Conduct of Clinical Trials. Another new, forthcoming NHLBI initiative is to foster low-cost, clinically integrated pragmatic trials to leverage big data infrastructures and integrated health systems to enable more large-scale and low-cost trials. For untested treatments of difficult to treat diseases, we clearly need faster evaluation and more rapid turnover, so we do not spend the time and resources on a treatment that does not work. In summary, we are all responsible for the number of trials, the distribution of trials across PCCSM diseases, the trial designs, and the endpoints used. The new and thought-provoking findings by Todd and colleagues on the interventional PCCSM trials and their attributes in ClinicalTrials.gov database provide a perspective for identifying deficits and influences and contemplating solutions. However, beyond the numbers in ClinicalTrials.gov, many clinical research participants play active roles in supporting the clinical research enterprise to improve the health of the nation. NIH contributes through encouraging innovative basic research, challenging investigators to pursue the translational potential of their basic research, fostering disease prevention, developing novel clinical research tools and methods, providing an elastic path for investigators to pursue the clinical research questions of most importance to them and their communities, and training the next generation of researchers. Thus, on the surface, NIH may appear to fund only 5.4% of the PCCSM trials, when in fact it is supporting fuel to fill gaps in the clinical research enterprise, not captured in the ClinicalTrials.gov database, but essential to its overall success. PCCSM may comprise 5.4% of all trials because that is the state of the science. The pressing scientific questions that the community is positioned to ask now may not justify more trials or larger trials. The challenge for NIH is to balance creating scientific opportunity for future clinical research with urgent public health needs now. The challenge for the PCCSM communities is to think creatively how to best harvest the opportunities Editorials
provided by NIH to develop cost-effective ways to pursue treatments for currently untreatable lung diseases, and advance novel therapies for the multitude of chronic lung diseases that exert a high health and economic burden to patients and the nation. Author disclosures are available with the text of this article at www.atsjournals.org. Gail G. Weinmann, M.D. James P. Kiley, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Bethesda, Maryland
References 1 Todd J, White K, Chiswell K, Tasneem A, Palmer S. Using ClinicalTrials. gov to Understand the State of Clinical Research in Pulmonary, Critical Care, and Sleep Medicine. Ann Am Thorac Soc 2013;10: 411–417. 2 Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A; Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–1308. 3 Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluidmanagement strategies in acute lung injury. N Engl J Med 2006;354: 2564–2575. 4 Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, Wiedemann HP, deBoisblanc B, Connors AF, Hite RD, Harabin AL; Acute Respiratory Distress Syndrome Network. Pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213–2224. 5 Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366:1968–1977. 6 Galis ZS, Hoots WK, Kiley JP, Lauer MS. On the value of portfolio diversity in heart, lung, and blood research. Am J Respir Crit Care Med 2012;186:575–578. 7 Collins FS. NIH basics. Science 2012;337:503. 8 Dorsey ER, de Roulet J, Thompson JP, Reminick JI, Thai A, WhiteStellato Z, Beck CA, George BP, Moses H III. Funding of US biomedical research, 2003-2008. JAMA 2010;303:137–143. 9 Raghu G, Collard HR, Anstrom KJ, Flaherty KR, Fleming TR, King TE Jr, Martinez FJ, Brown KK. Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. Am J Respir Crit Care Med 2012;185:1044–1048. Published 2013 by the American Thoracic Society
Multimorbidity: The New Normal Despite substantial advances in our understanding of asthma, and the availability of generally well-tolerated and effective therapies, many patients with asthma continue to experience poor control of their disease (1). Surveys performed in community and clinical settings have found that a substantial proportion of patients with asthma are either not well or poorly controlled (1–4). Patients with not well or poorly controlled asthma are more likely to experience impaired quality of life and productivity, and are at significantly increased risk for asthma exacerbations (5). Poor control of asthma is a significant national burden on the U.S. health care system (6). Hospitalizations and emergency department visits for asthma are a major component of the more 491
