, Dilip R. Karnad2 and Snehal Kothari3
(1)
Cardiac Safety Services Quintiles, Durham, North Carolina, USA
(2)
Research Team, Cardiac Safety Services Quintiles, Mumbai, India
(3)
Cardiac Safety Services Global Head, Cardiac Safety Center of Excellence Quintiles, Mumbai, India
If our patient is older than, younger than, sicker than, healthier than, ethnically different from, taller, shorter, simply different from the subjects of a study, do the results pertain? The art of clinical decision-making is judgment, an even more difficult concept to grapple with than evidence (Katz 2001).
15.1 Introduction
Previous chapters have focused on cardiovascular safety in drug development and therapeutic use. In this final chapter, we provide a flavor of safety considerations in other aspects of integrated biopharmaceutical medicine, a discipline that encompasses drug development, commercial-scale manufacture, prescription by physicians, dispensing by pharmacists, and the administration of medicines (both by patients themselves and by caretakers, hospital staff, and residential care staff).
Six areas are discussed. While these have been chosen arbitrarily, each one allows additional commentary on the general topic of drug safety. These areas include regulatory science, rare diseases, precision medicine, pain medication, adherence, and the reporting of randomized clinical trials.
15.2 Regulatory Science
In addition to biological, clinical, statistical, and manufacturing sciences, regulatory science is a key component of medical product development. In a talk given on October 6, 2010, in Washington, DC, FDA Commissioner Dr Margaret Hamburg announced the release of a White Paper entitled “Advancing Regulatory Science for Public Health: A Framework for FDA’s Regulatory Science Initiative.” She noted that regulatory science refers to “the science and tools needed to assess and evaluate a product’s safety, efficacy, quality and performance. Regulatory science involves the development of new methods, standards and models we can use to speed the development, review, approval and ongoing oversight of medical products” (Hamburg 2010). In August 2011, the agency released its document entitled “Advancing Regulatory Science at FDA: A Strategic Plan” (FDA 2011). The plan identified eight priority areas of regulatory science where new or enhanced engagement in regulatory science research was considered essential to the continued success of FDA’s public health and regulatory mission. A ninth strategic priority was added in 2013. These priorities are presented in Table 15.1.
Table 15.1
Priority areas of regulatory science at FDA
1. Modernize toxicology to enhance product safety |
2. Stimulate innovation in clinical evaluations and personalized medicine to improve product development and patient outcomes |
3. Support new approaches to improve product manufacturing and quality |
4. Ensure FDA readiness to evaluate innovative emerging technologies |
5. Harness diverse data through information sciences to improve health outcomes |
6. Implement a new prevention-focused food safety system to protect public health |
7. Facilitate development of medical countermeasures to protect against threats to USA and global health and security |
8. Strengthen social and behavioral science to help consumers and professionals make informed decisions about regulated products |
9. Strengthen the global product safety net |
15.2.1 Contributors to the Development of Regulatory Science
In addition to regulatory agencies, other stakeholders play major roles in advancing regulatory science. Academic medical centers have considerable scientific expertise, and interaction between regulators and academicians can help shape “the regulatory science agenda” (Meyer 2014). Experts from industry also play an important role. As a result of the contributions and collaborations of experts from this triumvirate of stakeholders, consortia are playing a particularly significant role in the advancement of regulatory science. Since its launch in Europe in 2008, the Innovative Medicines Initiative “has catalyzed the formation of many consortia to address challenges in drug development and regulation” (Goldman et al. 2015). These authors highlighted key outcomes and lessons learned to date.
Consortia are also important to the FDA’s involvement in the advancement of regulatory science (Woodcock et al. 2014). Since their Critical Path Initiative was launched in 2004 (FDA 2004), FDA’s Center for Drug Evaluation and Research is now participating in more than 20 science-driven consortia to improve the science of drug development and regulation (Woodcock 2014). One of these, the Cardiac Safety Research Consortium, was introduced in Chap. 1.
15.3 Rare Diseases
Definitions of a rare disease differ by country, being influenced by the size of the population in a given country. In the USA, a rare disease, also referred to as an orphan disease, is defined as one that affects fewer than 200,000 patients. While that number may initially seem small when compared with estimates of individuals in the USA with, for example, hypertension and diabetes (both of which affect tens of millions of individuals), the tremendous importance of this topic lies in the fact that there are thousands of rare diseases, a total of tens of millions of patients suffer from them, the majority are of genetic origin and life-threatening, and far too few have available treatments (Turner 2012a). Of the estimated 7000 rare diseases, only around 300 have medicines approved to treat them, referred to as orphan drugs: this gap represents “a huge unmet medical need” (Sasinowski et al. 2015).
In 2014 the FDA approved 41 novel new drugs, 17 of which were designated as orphan drugs (FDA 2015a). In 2015 the FDA approved 45 novel new drugs, 21 of which were designated as orphan drugs (FDA 2016). For many of them, the FDA used a combination of various approaches to bring the new drug to market as quickly as possible: the designations for these approaches include fast track, breakthrough, priority review, and accelerated approval. Table 15.2 summarizes the nature of these methods for expediting innovative novel new drugs to market.
Table 15.2
FDA methods for expediting innovative novel new drugs to market
Method designation | Description |
|---|---|
Fast track | Fast track is for drugs with the potential to address unmet medical needs. Fast track speeds new drug development and review. One example is increasing the level of communication FDA allocates to drug developers and by enabling CDER to review portions of a drug application ahead of the submission of the complete application |
Breakthrough | Breakthrough therapies are drugs with preliminary clinical evidence demonstrating that the drug may result in substantial improvement in at least one clinically significant endpoint over other available therapies. All of the fast track program features are included in addition to more intensive FDA guidance on an efficient drug development program. Breakthrough status is designed to help shorten the development time of a promising new therapy |
Priority review | A priority review designation means that CDER determined that the drug has the potential to provide a significant advance in medical care and set a target to review the drug within 6 months instead of the standard 10 months |
Accelerated approval | The accelerated approval program allows early approval of a drug for a serious or life-threatening illness that offers a benefit over current treatments. Approval is based on a surrogate endpoint or other clinical measures that are considered reasonably likely to predict a clinical benefit of the drug. Once accelerated approval is granted, the drug must undergo additional testing to confirm its therapeutic benefit. This strategy speeds the availability of the drug to patients who need it |
A pertinent question for both a regulatory agency and a patient (or, in the case of many rare diseases that afflict children, a patient’s parents or legal guardian) is: How much risk are we prepared to take to obtain the therapeutic benefit of a drug for this serious and potentially fatal disease? The statement in the FDA’s Sentinel Initiative that we first encountered in Chap. 1 is particularly pertinent here (FDA 2008):
When there is no other therapy available for a serious and potentially fatal disease, it is a perfectly reasonable decision to accept more risk than when approving (and taking) a drug for a much less serious condition, especially one for which there are already available therapies.
Although marketed medical products are required by federal law to be safe for their intended use, safety does not mean zero risk. A safe product is one that has acceptable risks, given the magnitude of benefit expected in a specific population and within the context of alternatives available.
15.4 Precision Medicine
While the term personalized medicine is used widely in the literature to refer to the tailoring of an intervention for an individual based on specific (often genetic) information pertaining to that individual, in almost all cases, the term precision medicine can reasonably and forcefully be argued to be more appropriate (an example of an exception occurs when a cancer vaccine’s manufacture incorporates the use of an individual patient’s material in preparing a treatment uniquely tailored to that individual: see Kaitin (2008). Physicians have always practiced personalized medicine to the limit of knowledge at any given point in time. Clinical care of a patient has always involved, and will continue to involve, using all available evidence concerning the patient’s unique set of characteristics and circumstances (physical, psychosocial, sociocultural, socioeconomic, environmental) and knowledge of all available treatment options to tailor optimal treatment for the patient.
Throughout history, and particularly when multiple generations lived in the same town and were cared for by the same physician over the course of his or her (all too often his) career, the physician may have incorporated knowledge of health and disease states of older members of a patient’s family in the diagnostic process. In this scenario, it can be reasonably argued that genetic information was being employed, even though the molecular biology of transmission genetics was not known at the time. Now, with the completion of the Human Genome Project and the public availability of huge amounts of disease-related data, genomic technology permits highly accurate prediction of individuals who will and who will not likely benefit from a particular drug (see (Turner and Durham 2009)). In the case of some cytotoxic oncology drugs, it also predicts who cannot receive therapeutic benefit from a drug but who can certainly be harmed by it: the benefit–risk balance of treatment with the drug is therefore immediately unfavorable for that individual (Lee and Turner 2016). For example, crizotinib and vemurafenib were approved by the FDA in 2011 in combination with FDA-approved companion diagnostic tests. Crizotinib is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase (ALK) positive as detected by the associated FDA-approved test. Vemurafenib, indicated for melanoma, is only indicated for patients with a certain abnormal variant of the BRAF gene, BRAFV600E, as identified by the associated FDA-approved test (Turner 2012b).
In the context of employing pharmacogenomic biomarkers in the prediction of severe adverse drug reactions, Ingelman–Sundberg commented in an editorial piece in the New England Journal of Medicine as follows (2008, p. 637):
The editorial focused on the antiretroviral drug abacavir, used against infection with the human immunodeficiency virus and discussed in an article by Mallal and colleagues describing original research published in the same issue of the journal (Mallal et al. 2008). In white populations, about 6 % of individuals carry the HLA-B*5701 allele, a genetic variant strongly associated with hypersensitivity to abacavir (it is unknown why the association between HLA-B alleles and hypersensitivity is less clear in black populations). When a physician is considering prescribing abacavir for a patient, screening that individual for the presence of the HLA-B*5701 allele has proved successful in reducing hypersensitivity reactions to the drug.
The search for pharmacogenomic markers that could be used to identify patients at increased risk for drug-related toxic effects has often focused on variation within genes encoding drug-metabolizing enzymes. Altered enzymatic activity can lead to elevated levels of the substrate drug, or, alternatively, increased amounts of a reactive metabolite, either of which could have toxic effects.
15.5 Pain Medication: Abuse of Prescription Opioids
Pain is a ubiquitous consequence of a wide range of injuries, surgeries, and medical conditions as diverse as cancer, low-back pain, and restless leg syndrome (Ahmedzai et al. 2012; Cloutier et al. 2013; Trenkwalder et al. 2013). Both acute and chronic pain can be extremely debilitating clinical conditions, and there is a constant need for analgesics in medical practice.
Assessing pain is not as straightforward as might initially be thought: as Joffe and colleagues noted, “To effectively treat pain, it must be detected and quantified using a validated assessment tool” (Joffe et al. 2013). Pain assessment becomes even more challenging when an individual who is almost certainly experiencing severe pain is unable to self-report the pain: examples include patients in cardiovascular intensive care units and medical/surgical/trauma units (Rose et al. 2013).
Opium poppy produces benzylisoquinoline alkaloids (opiates) that are important medicinal compounds, including the analgesics morphine, codeine, and thebaine, which are used in the synthesis of various semisynthetic opioid analgesics (Pasternak and Pan 2013; Runguphan et al. 2012). These synthesized compounds include hydrocodone, oxycodone, hydromorphone, and oxymorphone. Millions of patients are treated with opioid analgesics (Alexander et al. 2014). Patients requiring chronic opioid administration often have complex medical conditions, and they do not all respond in the same manner, leading to unpredictable individual differences in effectiveness and adverse drug reactions.
Drug addiction can be described as “a chronically relapsing disorder characterized by the compulsive desire to use drugs and a loss of control over consumption” (Prud’homme et al. 2015). There are increasing concerns regarding the health consequences of long-term opioid abuse (Herzig 2015). Dennis and colleagues observed that “The consequences of opioid relapse among patients being treated with opioid substitution treatment are serious and can result in abnormal cardiovascular function, overdose, and mortality” (Dennis et al. 2015). Interventions for the management of addictive behaviors and opioid dependence are therefore important (Prud’homme et al. 2015; Soyka 2015; Reed et al. 2015).
A pharmaceutical research area of considerable current interest is the development of abuse-deterrent opioids. The FDA’s April 2015 Guidance for Industry entitled “Abuse-deterrent opioids: Evaluation and Labeling” commented as follows (FDA 2015b):
While not necessarily eliminating abuse, reducing it is a very meaningful step forward, and the development of abuse-deterrent formulations is therefore an important area of research (Alexander et al. 2014; Mastropietro and Omidian 2015).
Prescription opioid products are an important component of modern pain management. However, abuse and misuse of these products have created a serious and growing public health problem. One potentially important step towards the goal of creating safer opioid analgesics has been the development of opioids that are formulated to deter abuse. FDA considers the development of these products a high public health priority.
Because opioid products are often manipulated for purposes of abuse by different routes of administration or to defeat extended-release (ER) properties, most abuse-deterrent technologies developed to date are intended to make manipulation more difficult or to make abuse of the manipulated product less attractive or less rewarding. It should be noted that these technologies have not yet proven successful at deterring the most common form of abuse—swallowing a number of intact capsules or tablets to achieve a feeling of euphoria. Moreover, the fact that a product has abuse-deterrent properties does not mean that there is no risk of abuse. It means, rather, that the risk of abuse is lower than it would be without such properties.
While the final manuscript of this manuscript was being prepared, Dr Robert Califf was sworn in as the new FDA Commissioner in February 2016. Shortly before, he and colleagues from the FDA published a Special Report entitled “A Proactive Response to Prescription Opioid Abuse” in the New England Journal of Medicine (Califf et al. 2016). The final paragraph commented as follows:
Nationally, the annual number of deaths from opioid overdoses now exceeds the number of deaths caused by motor vehicle accidents [reference CDC website]. Regardless of whether we view these issues from the perspective of patients, physicians, or regulators, the status quo is clearly not acceptable. As the public health agency responsible for oversight of pharmaceutical safety and effectiveness, we recognize that this crisis demands solutions. We are committed to action, and we urge others to join us.
15.6 Adherence
The goal of FDA’s Safe Use Initiative is: “to reduce preventable harm by identifying specific, preventable medication risks and developing, implementing and evaluating cross-sector interventions with partners who are committed to safe medication use” (FDA 2015c). Medication adherence is one of the areas in which collaboration by multiple stakeholders is welcomed.
As noted in Chap. 3, hypertension is commonly designated as the greatest contributor to the global burden of disease. As Dolan and O’Brien (2013) noted, “Ischaemic heart disease, ischaemic, non-ischaemic and haemorrhagic stroke, hypertensive heart disease, atrial fibrillation and flutter, peripheral vascular disease, aortic aneurysm and chronic renal disease (to which we must now add cognitive impairment and dementia) are all attributed to hypertension.” Of particular relevance to discussions here is the fact that, as Dolan and O’Brien highlighted, there are many pharmacological agents on the market that, if used appropriately, provide therapeutic benefit. Additional new drugs, particularly single-pill combinations with enhanced benefit-safety-value profiles, will always be welcome, but their development is not the limiting factor here: Nieuwlaat and colleagues (2013) observed that learning how to implement effective therapies for cardiovascular disease in a better manner will have a larger effect on patient outcomes than most single new drugs.
With regard to patients, and as noted in the previous chapter, Howren (2013) observed that “Adherence is a term used to describe the extent to which an individual’s behavior coincides with health-related instructions or recommendations given by a health care provider in the context of a specific disease or disorder.” While the negative effect of patient nonadherence has been known for decades, some authoritative sources still put average nonadherence among those with chronic diseases around 50 % (Brown and Bussell 2011), and the American Heart Association (AHA) observes that “It is estimated that three out of four Americans do not take their medication as directed” (AHA 2016).
Improving hypertension management requires improvements at both the patient and physician levels. At the patient level, considerations include patient education and empowerment. Considerations at the physician level include improving their knowledge of the cognitive and behavioral factors involved in patients’ active engagement in their own care and the manner in which they communicate with patients (Turner 2013). The interaction between patient and physician is important in improving patient adherence. In the context of statin therapy, for example, Schedlbauer and colleagues observed that increased patient centeredness, i.e., placing emphasis on patients’ perspective and engaging in shared decision-making, might be useful (Schedlbauer et al. 2010). The importance of communication between doctor and patient has been known for decades (see (Korsch et al. 1968; Roter and Hall 2013)), but it is still not optimal. Levinson and colleagues, for example, observed that patient-centered communication skills that enhance patient satisfaction, treatment adherence, and self-management “can be effectively taught at all levels of medical education and to practicing physicians,” yet most physicians receive limited training in these skills (Levinson et al. 2010).
Before discussing a different aspect of adherence, physician nonadherence to prescribing guidelines, it should be acknowledged that there are many hypertension specialists who are extremely conversant with prescribing guidelines, who communicate very well with their patients, and who sometimes recommend treatment for specific patients that differs from the guidelines because they genuinely believe that such action is warranted. This is certainly within the spirit of guidelines, which acknowledge the role of a physician’s expertise and clinical experience. However, the literature reveals that deviation from guideline-recommended treatment is not always a considered, deliberate action.
Awareness of prescriber nonadherence to hypertension treatment guidelines dates back at least to the 1990s (see (Cabana et al. 1999)). As one example of the financial ramifications, consider a retrospective analysis of year-2006 Medical Expenditure Panel Survey data reporting substantial costs of inappropriate hypertension management. Using year-2006 US dollars, the author noted that the “overall prevalence of hypertension was estimated at 19.7 %, with 36 % of identified patients treated inappropriately. The per-person cost for inappropriate treatment was $234.60, and the total national cost was approximately $13 billion” (Balu 2009). While human costs are harder to quantify, they are no doubt commensurately disturbing (Turner 2013).
With regard to offering suggestions regarding how adherence may be improved, we [JRT] have previously proposed several pragmatic approaches with the hopes of raising both eyebrows and interest (Richards and Turner 2012; Turner and Strumph 2012). One is that every biopharmaceutical company with one or more marketed products should appoint a chief adherence officer, affording this person the same gravitas given to all other occupants of the company’s “C-wing” (e.g., the chief executive officer and the chief medical officer). This individual should ideally be trained, or at least be willing to become rapidly immersed, in educational and behavioral sciences as well as biological and pharmaceutical sciences. A second suggestion is that schools of medicine, pharmacy, nursing, and allied health professions need to redouble attention to the adherence component of their curricula in novel ways. We readily acknowledge that there are always time pressures in professional training programs, but why not try the following: Devote a 1-h lecture slot shortly before students interact with patients for the first time to having them write, by hand, the following statement over and over: “I must discuss medication adherence with my patients at every possible opportunity.” We feel that students would not readily forget that experience. More rigorously supported suggestions for improving adherence to antihypertensive medications have been offered by Turner (2013).
As a second example, consider allergic rhinitis, one of the most common diseases affecting adults. In the pediatric population, it is the most common chronic disease in the USA, which contributes to making it the fifth most common chronic disease in the USA overall. Allergic rhinitis can impair quality of life and, through loss of work and school attendance, is responsible for as much as $2–$4 billion in lost productivity annually (Seidman et al. 2015). Bender (2015) summarized several studies on adherence to allergic rhinitis treatments, the investigation of which has some challenges. These arise from the fact that many treatments are taken as needed: the lack of an administration schedule therefore complicates assessment of adherence. Additionally, many patients take over-the-counter medication without consulting a physician. However, as intranasal corticosteroids are a prescribed daily treatment, more research has been conducted in this area: adherence rates are around 50 % or lower.
Evidence for adherence to immunotherapy interventions is no more encouraging. Three to five years of sustained immunotherapy is required for full, long-term benefits (Marogna et al. 2010), and “the cost and effort of immunotherapy are difficult to justify in the face of poor adherence” (Bender 2015). With regard to estimates of the consequences of nonadherence across multiple chronic diseases, including hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and diabetes, costs of $300 billion in excess health-care costs and 125,000 deaths per year are reasonable figures (see (Bender 2015)).
Unfortunately, a review of multiple publications describing various types of intervention currently paints a collectively discouraging picture: nonadherence is truly an obdurate opponent of good health. Also unfortunately, nonadherence has multiple causes, combinations of which differ between individuals. When trying to predict nonadherence, some predictors are difficult or simply not possible to modify: these include race, age, socioeconomic status, medication costs, and treatment duration. Therefore, it is sensible to focus on modifiable factors that can be influenced by health-care providers. Bender (2015) provided practical recommendations for strategies that can improve adherence: while some are couched in terms of allergy practice, many can be generalized to other conditions. These include providing patient-centered care, adopting the chronic care model (which integrates patient-, provider-, and system-level interventions), building trusting relationships with patients, improving providers’ listening skills, providing educational opportunities for patients to learn more about their disease(s), and engaging in more comprehensive follow-up strategies. The latter can be facilitated with very minimal time demand by utilizing technologies such as text messaging and interactive voice recognition technology.
15.7 Reporting Randomized Clinical Trials
Previous chapters have described preapproval clinical trials specifically designed to investigate cardiovascular safety during drug development, with the goal of prospectively excluding unacceptable cardiovascular risk: they have also addressed examples of trials conducted in the postmarketing arena. Discussions in this section turn to the topic of how randomized clinical trials should be reported.
While it is extremely important that all clinical trials are designed appropriately, conducted meticulously, and analyzed appropriately and correctly, it is equally important that they are reported appropriately. Published reports, typically papers in peer-reviewed journals, are used by physicians practicing evidence-based medicine to decide if the treatment discussed in a paper is an appropriate one for a given patient. Physicians must therefore be given accurate and complete results addressing both efficacy and safety data that are presented in a transparent manner. Publications reporting individual studies can also be used by groups of experts representing professional societies to write treatment guidelines based on their review of all relevant study reports, again bearing witness to the need for optimal-quality reporting of the original studies.
In the early 1990s, there was concern among many researchers and journal editors that reporting of clinical trials was not as good as it should be. This concern led to various meetings that generated the Consolidated Standards of Reporting Trials (CONSORT) Statement (see CONSORT Group 2016). CONSORT is “a set of reporting recommendations – it does not make statements on how trials should be done, but asks that what was done should be fully and accurately reported” (Altman et al. 2001). First published in 1996 (Begg et al. 1996) and revised in 2001 (Moher et al. 2001), the statement includes a checklist of items that should be included in the report of a clinical trial. These items are regularly reviewed, and the CONSORT 2010 checklist is available on the group’s web site (see also (Moher et al. 2010)). The checklist addresses the following sections of a publication: Title and Abstract, Introduction, Methods, Results, Discussion, and Other Information (e.g., the trial’s registration number and sources of funding and other support). Within these sections, there are a total of 25 checklist items. Many (but certainly not all) journals now require that manuscripts submitted to them conform to the guidelines presented in the statement.
The original CONSORT statement addressed one research design that was particularly common at the time the statement was published, i.e., the randomized, concurrently controlled clinical trial employing two treatment groups. Given that other trial designs have now also become common, extension statements have been released addressing various designs including cluster trials, noninferiority and equivalence trials, and pragmatic trials. Other examples of extension statements include those addressing non-pharmacologic interventions, patient reported outcomes, and harms.
15.7.1 The CONSORT Extension Statement Addressing Drug Harms
The original CONSORT statement primarily aimed at improving the quality of reporting efficacy data. The 2001 revision saw the addition of one item regarding the reporting of adverse events, but it was later felt not to do “full justice to the importance of harms-related issues,” leading a 2004 extension statement to address this topic in considerable detail (Ioannidis et al. 2004). Before summarizing the extension statement’s recommendations, the nomenclature employed warrants our attention. The terms safety and harm were discussed in Sect. 1.2, and our rationale for using the term safety in this book was couched in terms of the overreaction of print, radio, and television media to any mention of the term “drug harm.” Ioannidis and colleagues presented an alternative argument, commenting as follows, using “RCTs” as an abbreviation for randomized clinical trials (Ioannidis et al. 2004):
We certainly respect these authors’ perspective: indeed, we noted in our discussions in Sect. 1.2 that it is actually harm that is measured, with lesser harm then being equated to greater safety in a gradated manner. Nonetheless, it is likely fair to say that the term safety continues to be predominantly used in the literature.
The terminology of harms-related issues in RCTs is confusing and often misleading or misused. “Safety” is a reassuring term that may obscure the real and potentially major “harms” that drugs and other interventions may cause. We encourage authors to use the term “harms” instead of “safety.” In addition to misused terminology, reporting of harms in RCTs has received less attention than reporting of efficacy and effectiveness and is often inadequate. In short, both scientific evidence and ethical necessity call for action to improve the quality of reporting of harms in RCTs.
Table 15.3 presents the recommendations of the CONSORT extension statement on harms.
Table 15.3
Recommendations of the CONSORT extension statement on harms
The title or abstract should state if the study collected data on harms and benefits |
The introduction should state if the trial assessed harms and benefits |
List monitored adverse events with definitions for each and, when relevant, classify expected events vs. unexpected events, reference to standardized and validated definitions, as well as the description of new definitions |
Clarify how the information related to harms was collected |
Describe plans for presenting and analyzing information on harms, including coding, management of recurring events, specification of time of monitoring of adverse events, management of continuous measures, as well as any statistical analysis |
Describe for each study arm the participant withdrawals due to harms and the experience with the allocated treatment |
Provide the denominators for analyses on harms |
Present the absolute risk per study arm and type of adverse effect |
Describe some analysis and exploratory analysis for subgroup harms |
15.7.2 Imperfections in Reporting Randomized Clinical Trials
Unfortunately, despite the best intentions of CONSORT, perfection is not the norm. Moher and colleagues observed that “Overwhelming evidence shows the quality of reporting of randomized controlled trials (RCTs) is not optimal” (Moher et al. 2010). More recent papers presented in the respective section of this chapter’s Further Reading list provide similar commentary. The lack of completeness in reporting compounds physicians’ difficulty in determining the generalizability of information provided in study reports to their patients. As one example in the cardiovascular domain, Magin and colleagues investigated how completely socioeconomic data were presented in studies reporting trials of stroke or transient ischemic attack published in 12 major journals subsequent to the release of the revised CONSORT statement: the journals published papers in the disciplines of general medicine, general neurology, cerebrovascular disease, and rehabilitation. Socioeconomic status is associated with access to care and with post-stroke outcomes including mortality, functional outcome, recurrent stroke, and hospital readmission. Disturbingly, only 12 % of the studies included in their review reported any measure of socioeconomic status. As the authors concluded, “Improving reporting of [socioeconomic status] could enhance clinicians’ ability to evaluate RCT findings and apply them to their patients” (Magin et al. 2013).
Maggi and colleagues took a different approach to evaluating the degree to which published reports of randomized clinical trials adhered to CONSORT recommendations with regard to adverse event reporting (Maggi et al. 2014). They chose to focus on four leading medical journals with very high impact factors: New England Journal of Medicine, Lancet, Journal of the American Medical Association, and the British Medical Journal. Using the Medline search engine, 122 randomized clinical trials published in 2009, 5 years after the publication of the CONSORT extension statement on harms, were identified. The most frequently met CONSORT recommendation was mention of harms in the papers’ title or abstract (72.1 % of the papers analyzed). The recommendation most infrequently met was the reporting of how harm information was collected (10.7 %).
A similarly bleak picture was presented by Sivendran and colleagues, who evaluated adverse event reporting in 175 reports of oncology randomized clinical trials, identified using the Medline, PubMed, and Embase search engines, published in the 3 years 2009–2011 (Sivendran et al. 2014). Of the studies, 88 % grouped together adverse events of varying severity, and 37 % did not specify the criteria used to select which events were reported. The authors concluded as follows: “Reporting of adverse events in oncology publications of randomized trials is suboptimal and characterized by substantial selectivity and heterogeneity. The development of oncology-specific standards for adverse event reporting should be established to ensure consistency and provide critical information required for medical decision-making” (Sivendran et al. 2014).
There is clearly much room for improvement by authors, manuscript reviewers, and journal editors in ensuring that readers of randomized clinical trial reports are provided with comprehensive descriptions of adverse event data.
15.7.3 Public Registration of Clinical Trials
In a 2004 perspective article published in the New England Journal of Medicine, Steinbrook (2004) commented as follows:
Registration and reporting of trials in this manner are now routine practice. ClinicalTrials.gov is “a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world” (www.ClinicalTrials.gov). On the day this sentence was written on January 1, 2016, it listed 205,641 studies, with locations in all 50 states in the USA and in 191 countries.
For many years, the registration in a public data bank of all clinical trials — from start to completion and reporting of results — has seemed a quixotic quest of some academic researchers, medical-journal editors, and librarians. Within the past two months, however, a constellation of events and developments has broadened this effort and captured the attention of the medical profession, the news media, and government officials…Although uncertainties are ahead, there is a growing realization that the public registration of clinical trials is an idea whose time has come. In the long term, no one benefits from the selective release of information about trials and the selective reporting of results.
Given that trials’ results are typically presented on ClinicalTrials.gov and in journal publications, it would seem eminently reasonable to expect the presented results to be identical in both places. However, this is not always the case. Riveros and colleagues observed that “Trial results, especially serious adverse events, are more completely reported at ClinicalTrials.gov than in the published article” (Riveros et al. 2013). Hartung and colleagues observed as follows: “Reporting discrepancies between the ClinicalTrials.gov results database and matching publications are common. Which source contains the more accurate account of results is unclear, although ClinicalTrials.gov may provide a more comprehensive description of adverse events than the publication” (Hartung et al. 2014). Earley and colleagues commented as follows: “Deaths are variably reported in ClinicalTrials.gov records. A reliable total number of deaths per arm cannot always be determined with certainty or can be discordant with the number reported in corresponding trial publications. This highlights a need for unambiguous and complete reporting of the number of deaths in trial registries and publications” (Earley et al. 2013). Tang and colleagues compared the consistency between serious adverse events posted at ClinicalTrials.gov and those published in corresponding journals (Tang et al. 2015). They concluded that many trials with serious adverse events posted at ClinicalTrials.gov omit the reporting of these events in corresponding publications, or report a discrepant number as compared with ClinicalTrials.gov, commenting that “These results underline the need to consult ClinicalTrials.gov for more information on serious harms.”
While public registration and reporting of clinical trials are an excellent idea, here too it appears that we have much room for improvement.
15.7.4 Evidence-Based Medicine and the Challenge of Generalizability
Imagine that a randomized clinical study has been perfectly reported. Imagine also that a physician wishes to use the information presented to help decide if the treatment discussed will be useful for a specific patient under his or her care, where “useful” can be operationally defined as having a favorable benefit–risk balance. That is, can the information presented in the paper, which was generated from the set of participants employed in the trial, be generalized to this patient? Physician–scientist David Katz, whose work we first met in the previous chapter, addressed the issue of generalizability as follows (Katz 2001, p. xi):
While the art of clinical decision-making is of paramount importance, it is beyond the scope of this book. That said, discussions in this section are certainly relevant. This section started with the words “Imagine that a randomized clinical study has been perfectly reported,” and we then considered a physician’s use of the information presented in the publication. In conjunction with his or her patients, a decision is made as to whether or not the drug has a favorable benefit–risk balance on a patient-by-patient basis. The sentiments expressed succinctly but powerfully by Katz make it clear that, even given perfectly reported information from a trial, physicians have to use clinical judgment to arrive at their best estimation of the benefit–risk balance for each individual patient. Now consider how much more imprecise a physician’s determination of benefit–risk balance will likely be if the information in the publication is less than comprehensive with regard to both efficacy and safety. Little consideration is needed to reach the conclusion that, as for a trial’s study design, conduct, and analysis, its reporting must be of optimal quality.
The inapplicability of some evidence to some patients is self-evident. Studies of prostate cancer are irrelevant to our female patients; studies of cervical cancer are irrelevant to our male patients. Yet beyond the obvious exclusions is a vast sea of gray. If our patient is older than, younger than, sicker than, healthier than, ethnically different from, taller, shorter, simply different from the subjects of a study, do the results pertain?
15.8 Concluding Comments
As was noted in the first chapter of this book, it is an unfortunate but immutable fact that no biologically active drug is free from the possibility of causing adverse reactions in certain individuals who are genetically and/or environmentally susceptible. However, it is also a patient-centric and public health moral imperative to do everything we can to eliminate preventable adverse drug reactions, including adverse cardiovascular reactions. We hope that you have found this book to be helpful in expanding your knowledge and understanding of cardiovascular safety and that some of you may wish to become involved (or more involved) in this central component of drug safety in development and therapeutic use.
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