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    <recommendedItem id="20100101_19_200"
                     title="Debate Surges on Composite Endpoints"
                     score="-0.003"
                     href="http://www.medpagetoday.com/PublicHealthPolicy/ClinicalTrials/tb/18046?impressionId=1265779228680"
                     
      &lt;p&gt;Composite endpoints can obscure the real findings of clinical trials, two researchers charged in a &lt;em&gt;JAMA&lt;/em&gt; commentary this week, but others who had led trials using such outcomes defended the practice.&lt;/p&gt;
&lt;p&gt;Composite endpoints  --  where a study&apos;s main outcome is a combination of two or more different types of events, such as death and nonfatal myocardial infarction  --  can serve useful purposes, George Tomlinson, PhD, and Allan S. Detsky, MD, PhD, both of the University of Toronto, wrote in the Jan. 20 &lt;em&gt;Journal of the American Medical Association&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;But the benefits of composite endpoints come with a price, they argued  --  confusion to physicians and patients.&lt;/p&gt;
&lt;p&gt;&quot;Clinicians want to know if all events in the composite outcome are affected equally by the intervention,&quot; Tomlinson and Detsky wrote.&lt;/p&gt;
&lt;p&gt;Physicians can usually find results for the endpoint&apos;s individual components, they acknowledged, but it may &quot;result in some confusion, because the component relative risks may have broad confidence intervals and differ widely, at times even extending in opposite directions.&quot;&lt;/p&gt;
&lt;p&gt;Moreover, the Toronto researchers argued, if readers must examine results of the individual components of the composite endpoint to grasp the study&apos;s clinical implications, it defeats the composite endpoint&apos;s original purpose.&lt;/p&gt;
&lt;p&gt;&quot;While [readers] were enticed by a trial performed according to rigorous principles and based on the primary composite outcome, once the results have been reported they find that their interest has been redirected to individual outcomes of questionable importance,&quot; Tomlinson and Detsky wrote.&lt;/p&gt;
&lt;p&gt;They acknowledged that composites may sometimes make clinical sense, or are necessary because no single outcome is a natural primary endpoint by itself. Another practical rationale is to reduce the number of patients necessary in a study to detect a significant treatment effect.&lt;/p&gt;
&lt;p&gt;For example, if an outcome is expected to occur at a 5% annual rate and the trial is planned to last five years, more than 2,500 patients are needed to establish a hazard ratio of 0.75 with &lt;em&gt;P&lt;/em&gt;&amp;lt;0.05, Tomlinson and Detsky noted.&lt;/p&gt;
&lt;p&gt;But if several outcomes can be combined into a composite endpoint that has an annual rate of 20%, fewer than 800 patients will provide adequate power.&lt;/p&gt;
&lt;p&gt;That&apos;s generally fine when the individual component events occur at approximately equal rates, are of similar seriousness, and change in the same way with treatment, but that is frequently not the case, Tomlinson and Detsky contended.&lt;/p&gt;
&lt;p&gt;Steven Nissen, MD, a Cleveland Clinic cardiologist, agreed in a phone interview with &lt;em&gt;MedPage Today&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;Noting that composites of death, heart attack, and stroke are common in cardiovascular therapy trials, &quot;one would argue that all three of those outcomes are fairly grave [and] involve death or permanent injury,&quot; he said, and thus can be appropriate to combine into a single outcome.&lt;/p&gt;
&lt;p&gt;But, he added, &quot;what if the combination of endpoints is illogical, where you&apos;re combining grave endpoints with endpoints that are much less serious.&quot; In that case, the composite is much more difficult to interpret and may actually mislead readers about the study&apos;s true findings, Nissen suggested.&lt;/p&gt;
&lt;p&gt;&quot;Composite endpoints are a necessary evil, but they have to be thought through very carefully,&quot; he said.&lt;/p&gt;
&lt;p&gt;One trial with composites of serious and not-so-serious outcomes was reported last month at the American Society of Hematology meeting.&lt;/p&gt;
&lt;p&gt;Presented by Jeffrey Carson, MD, of the University of Medicine and Dentistry of New Jersey in New Brunswick, N.J., it tested different postoperative blood transfusion volumes. (See &lt;a href=&quot;http://www.medpagetoday.com/MeetingCoverage/ASHHematology/17418&quot; mce_href=&quot;http://www.medpagetoday.com/MeetingCoverage/ASHHematology/17418&quot; target=&quot;_blank&quot;&gt;ASH: Lower Threshold for Post-op Transfusion Proves Safe&lt;/a&gt;)&lt;/p&gt;
&lt;p&gt;Its primary outcome was a combination of death and walking ability, and a secondary endpoint was a composite of death, myocardial infarction, infection, congestive heart failure, stroke, and venous thromboembolism.&lt;/p&gt;
&lt;p&gt;In a recent phone interview with &lt;em&gt;MedPage Today&lt;/em&gt;, Carson said composites are frequently chosen to reduce the necessary sample size, but in his study the rationale was more about finding an outcome that best reflected the clinical issue.&lt;/p&gt;
&lt;p&gt;Including death alongside less serious outcomes such as inability to walk or infections was intended to capture the possibility that a transfusion regime might improve the lesser outcome but increase mortality.&lt;/p&gt;
&lt;p&gt;&quot;You wouldn&apos;t want to declare that, well, it improves your chances of walking and not consider its impact on death,&quot; Carson explained.&lt;/p&gt;
&lt;p&gt;Another study with a composite endpoint was a 2006 study of rosiglitazone (Avandia) called DREAM. Its primary endpoint combined death with incidence of new-onset diabetes. (See &lt;a href=&quot;http://www.medpagetoday.com/Endocrinology/Diabetes/4115&quot; mce_href=&quot;http://www.medpagetoday.com/Endocrinology/Diabetes/4115&quot; target=&quot;_blank&quot;&gt;EASD: Avandia Prevents Progression to Diabetes in High-Risk Patients&lt;/a&gt;)&lt;/p&gt;
&lt;p&gt;Tomlinson and Detsky held up DREAM in the very first paragraph of their &lt;em&gt;JAMA&lt;/em&gt; commentary as an example of a questionable composite endpoint.&lt;/p&gt;
&lt;p&gt;&quot;Death and diabetes are quite far apart in the spectrum of severity,&quot; they wrote, suggesting that clinicians would find the outcome  --  a 60% reduction in the two events  --  hard to interpret.&lt;/p&gt;
&lt;p&gt;&quot;Two questions arise,&quot; they wrote. &quot;Was there a 60% reduction in both death and diabetes? Are the two outcomes just as likely to occur?&quot;&lt;/p&gt;
&lt;p&gt;Nissen agreed that DREAM well illustrated the problems that can arise from composite endpoints.&lt;/p&gt;
&lt;p&gt;&quot;I do not like the situation where endpoints that have a great deal of difference in gravity and seriousness are combined,&quot; he told &lt;em&gt;MedPage Today&lt;/em&gt;. &quot;This was a great example.&quot;&lt;/p&gt;
&lt;p&gt;But the lead investigator on DREAM defended the composite outcome in a phone interview with &lt;em&gt;MedPage Today&lt;/em&gt;, insisting that sample size or other cost-based rationales never entered into the decision to use it.&lt;/p&gt;
&lt;p&gt;&quot;I&apos;ll quote from the paper,&quot; said Hertzel Gerstein, MD, of McMaster University in Hamilton, Ontario. &quot;It was to account for the possibility that diabetes might develop at a different rate in individuals who died than in individuals who survived. . . . It had nothing to do with any suggestion that the drug might prevent death. In fact, what we did in the DREAM trial, it was explicitly designed to [enroll] people at low risk of having serious outcomes including death.&quot;&lt;/p&gt;
&lt;p&gt;Gerstein continued, &quot;It was designed that way in order to be careful that we did not overestimate the benefit of the drug and provide the most conservative estimate of the benefit of the drug on diabetes prevention.&quot;&lt;/p&gt;
&lt;p&gt;Nissen, however, argued that composites chosen for legitimate scientific reasons are subject to misinterpretation when the results are published or submitted to regulators.&lt;/p&gt;
&lt;p&gt;Consider the composite of death, myocardial infarction, stroke, or hospitalization for unstable angina or revascularization, a common endpoint in registration trials for cardiovascular drugs, he said. Very often it&apos;s the hospitalizations that dominate the composite outcome, as they are far more common than the more serious events.&lt;/p&gt;
&lt;p&gt;&quot;When these companies go to the FDA, they often ask for a label related to the composite outcome. &apos;This drug is approved to reduce the risk of death, heart attack, stroke, and hospitalization for revascularization.&apos; Is that a good regulatory decision or a bad regulatory decision?&quot; Nissen asked.&lt;/p&gt;
&lt;p&gt;Jeffrey Carson said such composites are frequently criticized, but they can be reported in such a way as to minimize the chance of misinterpretation.&lt;/p&gt;
&lt;p&gt;&quot;It&apos;s likely that readmission to the hospital is the predominant reason for an event [in the composite] in studies of that sort,&quot; he said. &quot;You shouldn&apos;t say that it affects mortality, and you shouldn&apos;t say it affects myocardial infarction. What you should say is that it looks like the predominant effect here is on readmissions.&quot;&lt;/p&gt;
&lt;p&gt;Tomlinson and Detsky suggested that one way around this problem would be for authors and readers to assign weights to the various components of a composite outcome to reflect their clinical importance, &quot;similar to the way quality of life is measured.&quot;&lt;/p&gt;
&lt;p&gt;Alternatively, they wrote, when a composite outcome is driven by effects on the most numerous but least severe component, it should be understood to have shown an &quot;effect on surrogate outcomes and not definitive ones.&quot;&lt;/p&gt;

    </recommendedItem>
    <recommendedItem id="20090101_19_924"
                     title="Lack of Efficacy Forces Halt to Shock Treatment Study"
                     score="-0.005"
                     href="http://www.medpagetoday.com/EmergencyMedicine/EmergencyMedicine/tb/13443?impressionId=1265779228680"
                     
      BETHESDA, Md., March 26 -- The National Heart, Lung, and Blood Institute (NHLBI) has terminated a clinical trial of concentrated saline for trauma patients in shock, after interim results indicated no benefit for the treatment.
              &lt;p&gt; 
              &lt;p&gt;The multicenter, randomized trial was testing hypertonic versus normal saline solution in patients with severe blood loss and consequent shock.
              &lt;p&gt; 
              &lt;p&gt;Earlier studies had suggested the high-concentration solution compensated more effectively for blood loss, reducing inflammatory responses and cerebral edema. (See: &lt;a href=&quot;http://www.medpagetoday.com/EmergencyMedicine/EmergencyMedicine/9268&quot; target=&quot;blank&quot;&gt;Thicker Blood Equals Better Recovery from Blood Loss in Animals&lt;/a&gt;)
              &lt;p&gt; 
              &lt;p&gt;A parallel study of hypertonic saline for brain-injured trauma patients without shock will be allowed to continue.
              &lt;p&gt; 
              &lt;p&gt;The NHLBI had temporarily suspended enrollment in both trials last August after the studies&apos; data and safety monitoring board found no difference in four-week mortality between treatment groups in the shock trial.
              &lt;p&gt; 
              &lt;p&gt;The interim analysis also showed that more patients receiving concentrated saline died en route to trauma centers, although more patients in the normal-saline group died during the remainder of the four-week follow-up period.
              &lt;p&gt; 
              &lt;p&gt;The institute&apos;s final decision to end the trial, announced today, came after reviewing inhospital data on 545 patients in the largest enrolling hospital at each study location.
              &lt;p&gt; 
              &lt;p&gt;The data confirmed that patients receiving hypertonic saline tended to die earlier with no advantage in overall 28-day mortality.
              &lt;p&gt; 
              &lt;p&gt;Officials allowed the other study to resume in November after first-responders were retrained to enroll only those patients with brain injuries but not in shock.
              &lt;p&gt; 
              &lt;p&gt;Study leaders have now confirmed that hypertonic saline may be of benefit in these patients, and so that study should proceed as planned.
              &lt;p&gt; 
              &lt;p&gt;NHLBI officials said the different mortality patterns between treatment groups in the shock study remained unexplained.
              &lt;p&gt; 
              &lt;p&gt;&quot;The investigators are completing analyses of these results and will submit them for publication in a peer-reviewed scientific journal,&quot; according to a statement from the Institute.
             
    </recommendedItem>
    <recommendedItem id="20100101_19_109"
                     title="Biomedical Research Funding Slows"
                     score="-0.007"
                     href="http://www.medpagetoday.com/PublicHealthPolicy/ClinicalTrials/tb/17914?impressionId=1265779228680"
                     
      &lt;p&gt;WASHINGTON  --  Although biomedical research funding increased from 2003 to 2007, it did so at a much slower rate than in previous years, a study has found.&lt;/p&gt;
&lt;p&gt;The slowdown is largely driven by decreased contributions from the National Institutes of Health, which accounts for about 84% of all federal biomedical research funding.&lt;/p&gt;
&lt;p&gt;For their analysis, published in the Jan. 13 &lt;em&gt;Journal of the American Medical Association, &lt;/em&gt;researchers led by E. Ray Dorsey, MD, of the University of Rochester Medical Center, tracked biomedical funding trends from 2003 to 2007, updating a previous analysis that tracked funding from 1994 to 2003.&lt;/p&gt;
&lt;p&gt;Researchers found that total funding for biomedical research increased by 14% from 2003 to 2007  --  from $92 billion to $106 billion, after adjusting for inflation. That&apos;s a growth rate of 3% a year. By comparison, the gross domestic product (GDP) increased by 12% during the same period.&lt;/p&gt;
&lt;p&gt;Data from the earlier study found that biomedical research funding had increased at a rate of about 8% each year between 1994 and 2003.&lt;/p&gt;
&lt;p&gt;The authors acknowledge that the slowdown in funding &quot;has occurred at a time of intense economic instability and financial upheaval in the world&apos;s financial markets.&quot; But they noted that the growth rate was slowing even before the current recession began in late 2007.&lt;/p&gt;
&lt;p&gt;Crucial funding from the National Institutes of Health increased just 1% from 2003 to 2007  --  a bad sign for researchers, considering that NIH funding increased by nearly 100% from 1994 to 2003.&lt;/p&gt;
&lt;p&gt;NIH funding accounts for 65% of all biomedical research dollars, according to Thomas Boat, MD, a pediatrician at Cincinnati Children&apos;s Hospital who wrote an accompanying editorial in &lt;em&gt;JAMA&lt;/em&gt;. &lt;/p&gt;
&lt;p&gt;&quot;Recent NIH funding decrements have undoubtedly affected academic institutions most seriously,&quot; Boat wrote. &lt;em&gt;&lt;/em&gt;&quot;These institutions depend heavily on federal funding for support of biomedical research.&quot;&lt;/p&gt;
&lt;p&gt;On the other hand, the economic stimulus bill in 2009 gave more than $10 billion to the NIH for medical research, and the analyses did not take that into account.&lt;/p&gt;
&lt;p&gt;Aside from federal funding, the study analyzed trends from the three other funding sources for biomedical research and found: &lt;ul&gt; &lt;li&gt; &lt;strong&gt;State and local governments&lt;/strong&gt; contributed about $5 billion in 2007. From 2003 to 2007, their spending levels increased by just 6%, while in the 1994 to 2003 time period, funding in this area grew 45%. &lt;/li&gt; &lt;li&gt;&lt;strong&gt;Not-for-profits&lt;em&gt;,&lt;/em&gt;&lt;/strong&gt; such as foundations, public charities, and medical research organizations contributed about $4 billion in 2007, an increase of 11% from 2003. There was no statistically significant change in rates of funding in the nonprofit sector since 1993. &lt;/li&gt; &lt;li&gt;&lt;strong&gt;Industry &lt;/strong&gt;funding, including money from drug, biotech, and device companies, reached nearly $60 billion in 2007, a 25% increase from 2003, after adjusting for inflation. That represents an annual growth rate of about 6%, but from 1993 to 2004, funding from industry grew at at rate of about 8% each year. In 2007, drug companies contributed the most to research, followed by biotech companies and device manufacturers.&lt;/li&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;p&gt;In addition to pinpointing where research money is coming from, the researchers also found an interesting expenditure pattern: A growing proportion of medical funding is for late-stage clinical trials, rather than early-stage drug discovery.&lt;/p&gt;
&lt;p&gt;This could be a reason for a &quot;striking&quot; decrease in the number of new drugs per year, Boat said. He said there are several explanations for the approval stagnation, including the length and cost of new product development and reduced enthusiasm for initial investments.&lt;/p&gt;
&lt;p&gt;Another trend: large companies are increasingly purchasing small biotech companies, which is &quot;clearly problematic,&quot; according to the authors, because small firms are the most common pathway for academic research to find its way to clinical practice. &lt;ul&gt; &lt;/ul&gt;&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The study was funded by a grant from the National Center for Research Resources, a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research.&lt;/p&gt;&lt;p&gt;The authors reported financial relationships with the NIH, the American Parkinson Disease Association, CHDI Foundation, Michael J. Fox Foundation for Parkinson&apos;s Research, National Parkinson Foundation, the Robert Wood Johnson Foundation, the American Academy of Neurology, Avid Radiopharmaceuticals, Lundbeck, Medtronic, Merck, Guidant, the Alerion Institutea, Amarin, Medivation, and the Boston Consulting Group.&lt;/p&gt;&lt;p&gt;Thomas Boat, MD, reported no financial disclosures.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_1_67"
                     title="Infant Botulism Drug Safe And Effective"
                     score="-0.007"
                     href="