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W2152624596 abstract "Since starting my life as a hepatologist in 1968, I have witnessed marked improvements in the design, conduct, and analysis of clinical trials—thanks to such pioneers as David Sackett and Gordon Gyatt, just two of the North American scientists devoted to studying clinical epidemiology and evidence-based medicine. The Cochrane Collaboration, first established in the United Kingdom, now with centers worldwide, has focused on systematic reviews of published clinical trials.1 This was a timely development, because randomized, controlled trials (RCTs) designed to evaluate new therapeutic agents for liver disease have multiplied, particularly over the last 15 years (Fig. 1). RCTs are needed to evaluate the efficacy of new drugs, procedures, dietary modifications, and so on. This process remains incomplete unless translated to healthcare providers. Published RCTs in hepatology. Total versus trials for ascites and for CHC (PubMed Medline). As a busy intern on a ward caring for 30 patients with liver disease, my armamentarium consisted of the following: vasopressin for “presumed” bleeding varices, lasix and aldactone for fluid retention, corticosteroids and azathioprine for autoimmune hepatitis, neomycin for hepatic encephalopathy, and a very small selection of antibiotics for sepsis. The only radiologic tests available were a flat plate of the abdomen, angiography, and splenic venography! There were no endoscopic procedures, aside from rigid sigmoidoscopy! The discovery of, and then testing for, hepatitis B2 and C3 identified many clinically silent, yet chronically infected, individuals. Some had received another diagnosis for their “hepatitis.” The scientists whose identification of hepatitis B and C revolutionalized hepatology were honored with a Nobel prize and the Lasker award, respectively. Their discoveries changed the focus for many scientists and put the pharmaceutical industry into “top gear.” Clinical trials in hepatitis B and C became big business (see Fig. 2) to the virtual exclusion of “investigator-initiated” trials in viral hepatitis. But, dilemmas remain, including the following: Who has chronic viral hepatitis?; Is it cost-effective to treat all infected?; and how do we pay for our successes? Knowing you have a potentially fatal condition, curable only at prohibitive cost, is, to me, unacceptable! Therapeutics for almost all liver diseases are entering the era of “designer” drugs, which interfere with specific targets, for example, the first antivirals targeted at the hepatitis C virus (HCV) itself or at cellular components essential to complete viral replication4 (Table 1). RCTs for CHB and CHC (1992-2008 in PubMed Medline). Many academics have adopted new research interests within hepatology, such as complex trial analyses (including meta-analyses), cost-effectiveness studies, quality analysis, and the development of management guidelines—all essential to translate the indications for new therapies to clinicians. The “takeover” by the pharmaceutical industry has translated new knowledge of antivirals to front-line physicians. However, there is no budget for the translation of investigator-initiated studies5 (mostly in liver failure)—hence the continued accumulation of such patients in the emergency room. Combining the results of RCTs provides the “power” to estimate the overall effect (i.e., good or bad). Because not all trials are conducted to the same standard, the inclusion of poorly designed or conducted studies may lead to misinterpretation of the results.6, 7 To translate specific findings to our patients, careful scrutiny of all factors relevant to patient outcome must be reported, as must adherence to recruitment criteria and/or results of the screening log (i.e., number approached of the total and proportion of those approached who consented—two items commonly found missing, but much needed to asses the generalizability of a study). Further analysis (e.g., race, percentage of those with symptomatic versus asymptomatic disease at baseline, severity of background liver disease, age, sex, comorbidities, outcome of previous treatments, drug interactions, and so on) is needed to relate the outcome to our patient population. When this information is omitted, in part because of publishers' length limitations, the trial data are inaccurately presented. Reexamination of trial data is possible now that all clinical trials must be registered online (www.clinical trials.gov), and all data generated are kept for 25 years after the study's completion. Great advances in our understanding of the treatment of liver disease have taken place during my academic career, in part because the science of designing and executing clinical trials has received great attention. A major “hidden” confounder of trials remains so long as there is no formal “reporting” system for publication of “negative” trials. Responsibility for this gross oversight—with potential to compromise patient safety—lies with both journals and investigators. The risk of subsequent patients receiving unhelpful, perhaps even toxic, therapies could easily be prevented by a requirement that all trial results be summarized—linked to the mandatory registration website. Healthcare professionals, whose job is to promote good health and reduce illness, need access to the “complete story.” All the data are needed, including safety and conflicts of interest, and clinically relevant measures of efficacy, both while on and following withdrawal from therapy. Results must be clinically meaningful, reproducible, and understandable. Only then can organizations such as the Cochrane Collaboration reliably estimate the benefit of new therapies. Approval of new drugs is a huge commitment for government agencies. Because many are for the same disease, “cost-effectiveness analysis” has become a “business of its own” used not only by treating physicians, but also health-insurance agencies and stockbrokers. In Britain, where government promises “universal” access to treatment, the National Institute for Health and Clinical Excellence was established partly to assess cost-effectiveness of new treatments and technologies and unify access across all health districts.8 The downside of limiting access to agents not shown to be cost-effective is their unavailability to specific individuals anxious for a reprieve from fatal illness (e.g., sorafenib), if only for a few months.9 Thereby, a conflict arises between what is cost-effective for a population and that which is not cost-effective, but still has seemingly tangible benefits for an individual. Though some of these expensive medications may make only minor differences in life expectancy, with time, these small, incremental advances may eventually lead to dramatic improvements in outcome (e.g., treatments for breast cancer). This review focuses first on some mistakes and/or misinterpretations of clinical trials since the 1970s that may have interfered with the production of reliable data (for the most part, from my own experiences). An RTC is the most rigorous assessment of a new agent's therapeutic effect. Randomization is now done in blocks of 4, 6, 10, and so on, depending on expected recruit numbers. When possible, both patient and investigator should be blinded to the randomization. In terms of clinical-trial expertise, I was very naïve in 1968, when part of my job was to monitor patients in follow-up in the 5-year trial of azathioprine for primary biliary cirrhosis (PBC). Neither single nor double blinding had been considered in the trial design, and no formal patient-evaluation process had been outlined! Fortunately, there were only 45 recruits—we had not calculated the sample size needed to show a difference in outcome (i.e., death) at 5 years! All documentation was with pen and paper. Every result had to be accurately transferred from many different sheets of paper, thereby limiting the reliability of the reporting—desktop computers did not exist back then. Twenty years later, I recognized that for our RCT to be truly double blind, the unpleasant taste of ursodeoxycholic acid (UDCA) should be “matched” with an unpleasant tasting, similarly shaped, and colored placebo, to prevent patients unblinding themselves when they “compared notes” at support-group meetings. Failure to “blind” a study effectively becomes particularly relevant and, possibly, very difficult, if the side effects of the treatment under study are marked and if the primary measure of outcome is “soft,” such as patients with PBC who want very much to have their fatigue or pruritus reduced. Only with close examination of the “strange” results of our crossover trial-design to evaluate the effect of ondansetron on fatigue in PBC did we “figure out” that the results were invalidated both by patient anticipation of benefit and the near-universal side effects of odansetron! In a more recently published trial in patients with autoimmune hepatitis (AIH), one outcome marker was the combined biochemical response and the change in sense of “well-being,” the latter of which may have been compromised by different dosing regimens for the two arms of the study.10 Patients with PBC tend to be more “informed” than most. My failure to take this into account taught me that before designing, writing, submitting, and securing funding, one should, first of all, solicit the patient's interest! My RCT of hormone replacement therapy (HRT) for osteoporosis failed because the patients were either dead set against, or were already taking, HRT and few sat “on the fence.” In a more recent study of the effect of antiviral therapy for chronic hepatitis C (CHC) on central nervous system integrity,11 I learned that if measures of outcome take time to conduct or collect, it is particularly hard to encourage untreated controls to return for repeat evaluation 1 year later. These examples highlight that small omissions in planning can ruin even the best-intentioned RCT. Sadly, we are familiar with some of the past mistakes in judgement when subjects were not fully informed and/or may have been coerced to participate in clinical trials.12 The process of informed consent needs to be written in a clear style and appropriate language for the average adult. But, “informed consent” in 2011 seems to me to “go overboard.” Patients must read consent forms running to so many pages, it is hard to imagine that any patient reads them in their entirety. The process could indeed be perceived as coercion, particularly if participation may be that individual's only way to gain access to treatment. Meanwhile, the need to mention every “potential” side effect may deter others from entering the trial, thereby missing the benefits from the “experimental” therapy. Blame for this should not be laid just at the feet of “industry.” These aspects of informed consent are the downside of what is basically very important: equipoise in the recruitment and conduct of clinical trials.13 This argument can be taken further if we take language, culture, and circumstance into account. We need a reevaluation of the consent process to ensure that patients not only have “access” to information, but that they are able to “consume and digest” that information. AIH, autoimmune hepatitis; AH, alcoholic hepatitis; ALD, alcoholic liver disease; CHB, chronic hepatitis B; CHC, chronic hepatitis C; DAAs, direct-acting antivirals; ERCP, endoscopic retrograde cholangiopancreatography; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HRT, hormone replacement therapy; IFN, interferon; MELD, Model for End-Stage Liver Disease; MRCP, magnetic resonance cholangiopancreatography; NAFLD, nonalcoholic fatty liver disease; NIDDK, National Institute of Diabetes, Digestive and Kidney Diseases; PBC, primary biliary cirrhosis; Peg-IFNα, pegylated interferon alpha; PSC, primary sclerosing cholangitis; RCTs, randomized, controlled trials; RBV, ribavirin; SVR, sustained virologic response; TIPS, transjugular intrahepatic portosystemic shunt; UCDA, ursodeoxycholic acid; US, ultrasound. Avoiding bias in clinical trials may be close to impossible. Local issues, such as “knowing” a patient's personality or disabilities, can influence whether that individual is approached for recruitment. Some may have limited knowledge of healthcare choices and/or are not in the habit of making decisions for themselves. But were we, say, to exclude recruitment of Asian immigrants to a study on hepatitis B, that study would never be generalizable to the population in Canadian major cities! But, the patient's not fully understanding the “trial” process required for participation may promote early termination, thereby limiting the study's power. There are numerous techniques to enhance compliance (e.g., diaries and drug dispensers), yet all can fail! I would argue that ensuring 100% compliance is not evaluating an agent under “real life” circumstances. Conducting studies outside the academic environment goes a long way toward evaluating efficacy in real life. But, this option is not always acceptable to community-based physicians because they often have fewer services available to support a study. The term “requisite recruitment” refers to whether the pretrial characteristics of subjects put them at an advantage, rather than disadvantage, if they participate in a trial. Its occurrence limits the study's generalizability, yet may be missed in the interpretation of the results, their publication, and their transmission to patients. Hence, accurate, clinically appropriate “measurement” needs to be present before, during, and following completion of the study. I know of few articles that have been misinterpreted more than the REVEAL study.14 The data from this large study indicated that outcome of chronic hepatitis B (CHB) bore a relationship to both hepatitis B e antigen (HBeAg) status and HBV-DNA titer; however, usually omitted from any discussion is that individuals were not recruited unless over 30, thus this study does not apply to younger, often immune-tolerant, individuals. Partly to try and address the issue of the clinical relevance of trials of therapy, the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health have funded clinical consortia representing several specific areas of liver disease across North America (Fig. 3). Their studies are designed and orchestrated by academic centers, and the involvement of community physicians and/or their patients is encouraged. These studies are meant to answer questions never answered by other published reports and are designed to better serve our patients. Answers to a variety of clinical issues that pertain to a disease can be achieved by something as simple as recording daily coffee intake! In previous nonresponders to treatment for CHC, intake of three or more cups of coffee per day was associated with both enhanced viral clearance and a reduced rate of disease progression!15, 16 Ability to conduct ancillary studies allows for one study to provide multiple answers to several aspects of the one disease (e.g., sociocultural, immunologic, radiologic, and serologic), all of which are clinically relevant, but less likely to interest the “industry,” but nevertheless factors that may influence patient compliance and care and/or outcome. The studies emanating from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis consortium alone have, to date, resulted in 64 clinically relevant peer-reviewed publications! Data from NIDDK-funded liver disease networks and clinical network. Both hard clinical findings and blood-test results were incorporated into one of the first combined measures of outcome, the Child-Turcotte-Pugh Score, first designed to predict postoperative outcome after surgical maneuvers for portal hypertension. More recently, another combined measure of liver function, the Model for End-Stage Liver Diease (MELD) score, also specifically developed to predict the likelihood of postoperative survival after triangular intrahepatic portosystemic shunt (TIPS) insertion, is now employed universally to assess the “optimal timing” for a transplant in patients with liver failure. A recent MELD remodel, which adds serum sodium, may be even more reliable.17 It is much harder to predict outcome in patients with presymptomatic disease—those we most often see in clinics in 2011. In the 1960s, most were diagnosed only once their liver disease was advanced. For example, of patients with AIH recruited to the trials of prednisone in the 1960s, nearly all had end-stage liver disease; hence, over a relatively short period, it was possible to appreciate that those randomized to placebo had a significantly higher mortality rate than those who received prednisolone.18 Fifty years later, patients with AIH rarely present with liver failure, though some are given this diagnosis even though they are asymptomatic! This begs the question whether AIH always shortens the person's life. So, before we treat all AIH cases, we need to know if the survival of asymptomatic cases is as bad as for those with symptomatic disease. An RCT, when put to the test in the 1970s by Peter Gregory at Stanford, failed because no patient would agree to enter the study! There are data (which have all the disadvantages of being retrospective) to suggest that corticosteroid treatment may not be advantageous to those with asymptomatic AIH.19 Today, there are many techniques (particularly radiologic) in common use worldwide that were not available before the early 1970s. They include ultrasound (US), computed tomography scan, endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), and positron emission tomography scan, to name but a few. These tests, when used appropriately, are very informative. But detailed changes in serial ERCPs or MRCPs are difficult to compare over time because patient position at each “sitting” cannot be precise. Thus, currently, we have no good radiologic markers of outcome in primary sclerosing cholangitis (PSC), and we rely on standard laboratory measurements that may (or may not) imply both improvement or worsening of liver disease, including complete blood count and liver biochemistries, as well as the tests of function, such as coagulation, bilirubin, and albumin. But, they too have their limitations (e.g., a valid surrogate marker for one disease may not be suitable for another disease affecting the same tissue). For example, normalization of serum alkaline phosphatase in patients with PBC treated with UDCA is a reliable surrogate marker of good outcome,20 but this was found not to be so for patients with PSC treated with UDCA.21 Subsequently, analysis of the serum samples from participants in this latter trial showed that it was the bile-acid profile in the blood that correlated best with outcome.22 Liver histology as a reliable predictor of outcome is doubtful, but nevertheless many drug review boards, at least in North America, request it! As hepatologists, we know the risks of liver biopsy (together with its lack of reproducibility in terms of interpretation, most often because of inadequate size of specimen, i.e., <2 cm on the slide) suggest we urgently need truly valid “surrogate” markers of liver disease progression/regression. The current noninvasive measurements of hepatic texture either include scores (e.g., FibroScan) or employ a variety of blood-test results (e.g., FibroTest, and so on). The FibroTest and FibroScan, as one-time tests, are reported to be more reliable the more severe the fibrosis, but it is unknown whether they reliably measure its progression or regression.23 In addition to drug efficacy, drug toxicity is a top priority. A mandate to report all drug side effects from minor through to major events is essential, particularly for drugs seeking first-time approval. Nevertheless, reports of possible “drug” reactions or interactions must continue to be submitted even after licensing, because all untoward consequences are rarely recognized until many thousands have received the treatment. Ideally, the data should also include analysis of “at risk” individuals (e.g., effects of drug combinations, effect on pregnancy/fetus, and interactions with common comorbidities such as diabetes). Pharmacogenetics may one day prove to be the best application of personalized medicine: Once a “library” is constructed, it may allow the prediction of drug toxicities as with ribavirin (RBV)-induced anemia.24 By using DNA samples collected from >1,000 recruits a trial comparing pegylated interferon alpha (Peg-IFNα)-2ba to Peg-IFNα-2b, the influence of genetic control of response to treatment was evaluated: Specific variations in the IL28B gene correlated excellently with sustained virologic response (SVR).25 Do I think such “personalized medicine” is the way of the future? Frankly, not soon anyway; even IL28B genotyping as currently performed seems insufficiently reliable to decide whether to fund or not fund antiviral therapy to an individual with CHC. Patients with acute alcoholic hepatitis (AH) with a Maddrey Discriminant Function test result of >32 or, as more recently reported a Glasgow AH score of 9 or more, fail to receive treatment with corticosteroids with or without reevaluation after the first week of therapy.26, 27 Patients with new-onset ascites rarely undergo ascitic tap unless overt sepsis is manifest. Then, if they are treated with antibiotics, they often do not receive simultaneous albumin, which is shown to improve survival.28 In the same vein, I find primary prophylaxis against SBP with oral norfloxacin in patients with decompensated cirrhosis and low protein ascitic fluid has rarely been investigated or considered.29 Patients with hepatic encephalopathy (acute or chronic) continue to be starved of protein, despite studies as far back as 198330 and as recently as 200431 showing benefit from a normal (better still, vegetable) protein diet. The longer the starvation, the less likely these patients are to survive the liver transplant they need! The benefit of the oral antibiotic (e.g., rifaxamin), which is not absorbed and promotes only minimal development of gut bacterial resistance, is beneficial, but whether the treatment is effective without the use of continued lactulose needs to be evaluated.32 It is rare to be referred a patient for management of ascites who has had fully explained the need to restrict salt in their diet. In this era of consumption of instant (i.e., high-salt-containing food), cessation of such a diet may be all that is needed! Before referral for the radiologic procedure of a TIPS procedure, the effect of appropriate medical management needs first to be evaluated to assess whether control of ascites is possible with few side effects.33 Prevention of variceal hemorrhage has, I believe, become one of the most contentious areas of clinical research in hepatology. Clear endpoints in this field are difficult to define, including exactly what the time boundaries are for hemoglobin drops defining an acute variceal bleed and what the effect of comorbidities are, such as current alcohol intake, which itself promotes portal hypertension! My particular concern in this area of prevention is that, apparently, regardless of the outcome of well-conducted trials, endoscopic ligation seems to be the path taken despite many older, and recent trials clearly indicating that endoscopic treatment, although perhaps marginally more effective, comes with greater risk (e.g., death) than medical therapy in preventing variceal hemorrhage.34, 35 My question is, who is making these uninformed choices (i.e., patient or clinician) and on what basis? Thus, it would appear that education in the management of liver failure is “poorly” delivered. Why is this? Could it be that most trials in this field are investigator initiated and thus their findings fail to be delivered verbally to the front-line physician? Could Web-based education be an effective alternative? We are now at the start of a very exciting era of antiviral therapy that involves directly targeting the viral lifecycle or the host machinery of viral replication. The first two agents recently licensed are telaprevir and boceprevir, which both enhance SVR rates in treatment-naïve patients and some previously treated with Peg-IFNα plus ribavirin.36-40 Shorter duration of therapy, along with enhanced efficacy for CHC, is uppermost on every infected patient's agenda. There are advantages and disadvantages to both of these drugs. The trial design of the registration trials were very different, so only time will tell which will become (albeit for a very short while) the optimal therapy; both are toxic and require new management skills both of treating physicians and their nursing assistants. Toxicity issues will doubtless become more apparent as access to these two agents becomes available worldwide. Currently, RBV appears to be indispensable in patients prescribed either new drug. But, both Peg-IFN and RBV-free strategies are what patients want. Early reports of two direct-acting antivirals (DAAs) given simultaneously to patients with CHC (genotype 1) and one DAA with RBV to those with G2/G3 infection suggest that an interferon (IFN)-free drug regimen may be shortly on the horizon.41, 42 I do not think it will be too long before we can reassure everyone with CHC that their infection can be cured—but at a price! Cost-effectiveness studies employing the new DAAs are required to show whether it would be beneficial to treat all infected with CHC or just those with progressive disease at diagnosis or risks for progressive disease. Sustained viral clearance of HCV-RNA eliminates the risk of liver failure in a cirrhotic; the risk of hepatocellular carcinoma (HCC) remains, but is less for the first 5 years after achieving an SVR.43, 44 Viral clearance is also associated with a reduction in rates of diabetes,45 and this benefit of viral clearance may relate to the reduction of HCC.46, 47 (Fig. 4). Entering a liver transplant while still HCV-RNA positive impairs postliver transplant survival. The rapidity of onset of the antiviral effect of the DAAs for hepatitis C may allow rapid viral clearance, so that if given just before transplant, they may prevent graft reinfection. Nevertheless, optimum treatment goals for CHC are that it should be given before the onset of cirrhosis or, at the very least, to all cirrhotics before the onset of liver failure. This will not happen without the screening of at-risk individuals. Cumulative hazard estimates for HCC and type 2 diabetes mellitus. Treatment for CHB may lead to sustained loss of hepatitis B surface antigen (HBsAg), followed by slow regression of hepatic fibrosis. To date, loss of HBsAg of those with HBeAg+ve CHB subsequent to treatment with IFN is generally, but not always, limited to those infected with genotypes A and B,48 and the genotype specificity for those who lose HBsAg on the oral agent, tenofovir, is similar, with the addition of patients with genotype D infection.49 Unfortunately, those infected with genotype C, most prevalent in the Far East, are less likely to clear HBsAg, regardless of the antiviral agent used. The benefit of the oral agent, tenofovir, is the claim that no drug resistance has, so far, been detected in phase III RTCs of this drug.50 However, patients in this trial had the option of switching to Truvada if complete viral suppression was not achieved by 72 weeks,49 so we do not know the risk of drug resistance on prolonged monotherapy. The design of the phase III trials of entecavir did not allow for complete follow-up of some patients after the first 48 weeks when those with either undetectable HBV-DNA or high HBV-DNA were dropped from the trial, and thus the rate of drug resistance could not be reliably evaluated.51, 52 A subsequent long-term study suggested a very low resistance rate of 1.5% at 3 years.53 These design flaws in the phase III trials of both the new, potent oral antivirals for CHB should have been stopped by the advisory boards—were they asked for their opinion? We need antiviral therapy with both little or no risk of drug resistance and with efficacy against all hepatitis B genotypes. Loss of HBsAg in CHB maintained after treatment is withdrawn should be the number one goal. Sustained viral suppression without loss of HBsAg arrests liver-disease progression and improves survival when prescribed to those with advanced liver disease on treatment.54 We need stronger evidence that maintained viral suppression through effective treatment reduces or eliminates the risk of HCC. These studies will be very hard to do now that so many more effective antivirals have come onto the market. Chronic infection with hepatitis B and/or C is the main risk factor for hepatocellular cancer, whose rates are rising both in the United States and in Canada (Figs. 5 and 6).55 A randomized study of HCC screening versus none would be unethical. The best data we have are from patient-monitored HCC who were compliant or who refused with US follow-up.56 But, unless chronic infection with either hepatitis B or C is identified early, infected individuals will needlessly die as a consequence of their infection. We must encourage and support appropriate public-health screening programs. Incidence of HCC among white men in the SEER database. Differences between rates from 1981 to 1985 and from 1991 to 1995 were significant for ages 40-49 and 60-69. Annual percentage change in death rates for selected cancers, 1992-2002 from among those having an age-matched mortality rate exceeding 5 per 100,000; all values are significant. Data are from the National Cancer Institute's StatBite (2005) Cancer Care Ontario. Those with progression of hepatic fibrosis caused by underlyin" @default.
W2152624596 created "2016-06-24" @default.
W2152624596 creator A5080846340 @default.
W2152624596 date "2012-07-10" @default.
W2152624596 modified "2023-09-27" @default.
W2152624596 title "Clinical trials and their translation in hepatology: Past, present, and future" @default.
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W2152624596 doi "https://doi.org/10.1002/hep.25557" @default.
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