SHANNON GIBSON AND TRUDO LEMMENS
I. ADDRESSING PREMARKET SYNDROME
The drug-approval system in most advanced economies focuses predominantly on a review of safety and efficacy data from various premarket clinical trials. These trials are largely organized and controlled by the pharmaceutical industry—an industry with a vested and significant financial interest in demonstrating the safety and efficacy of the products tested. Once approved by regulatory authorities, prescribers and consumers often uncritically presume that drugs are reasonably safe and effective. Subsequent postmarket clinical trials are the exception rather than the rule.
The regulatory fixation on premarket activities, which we refer to as “premarket syndrome,” contributes to a range of problems that can negatively impact both patient health and the health care system. Premarket clinical trials are typically conducted under controlled conditions that generally do not reflect how a drug will be used in the real world (Ahmad 2003) and rarely assess whether a drug is actually more effective than existing therapies (Flood and Dyke 2012). These trials are often of short duration, so rare or longer-term side effects may remain hidden for many years, by which point the drug is already widely prescribed (Lasser et al. 2002). Moreover, drugs are frequently prescribed “off label” to patients and disease groups never assessed in clinical trials (Wiktorowicz, Lexchin, and Moscou 2012), as is discussed in greater depths in other chapters in this book.
Two recent trends—one in drug development and one in drug regulation—are reinforcing the importance of moving drug evaluation beyond the premarket stage. First, in recent years the pharmaceutical industry has been showing a growing interest in developing drugs for niche markets where the symptoms of premarket syndrome can be particularly acute. The narrow population base for these therapies often inherently limits the amount of safety and efficacy data available to support their approval—a fact that heightens the importance of assessing the benefits and risks of these drugs through the ongoing collection and analysis of postmarket data.
Second, as the shortcomings of the current focus on premarket activities become increasingly apparent, drug regulatory systems in various jurisdictions have proposed reforms that move away from the “artificial dichotomy” of the pre- versus postmarket stages (Eichler et al. 2012). In the United States, a 2007 report by the Institute of Medicine (IOM) recommended that the Food and Drug Administration (FDA) adopt a “life-cycle” approach to drug approval where the benefits and risks of drugs are monitored not simply based on premarket evidence but on the entire body of evidence that is collected throughout the life cycle of the drug (Committee on the Assessment of the US Drug Safety System 2007). The report endorsed such measures as aggressive assessments of drug effects throughout the product life cycle; an overhaul of adverse events reporting; greater public–private funding of postmarket studies; and authority for FDA to demand postmarketing reports. In February 2013, FDA released a draft benefit–risk framework to implement the life-cycle approach (FDA 2013a).
In this chapter, we explore both the promises and risks associated with rising interest in niche market development and, concurrently, how reform efforts toward the life-cycle approach and more postmarket evidence generation are both a response to and a driving force behind the shift toward niche markets. We argue that despite the promise of the life-cycle approach in combatting premarket syndrome, significant questions remain about whether regulatory authorities are prepared to address the attendant challenges that accompany the shift toward the life-cycle approach, particularly the concern that increasing the focus on postmarket monitoring and evaluation may lead to a softening of regulatory control at market entry.
A. Premarket Syndrome in Niche Markets
Pharmaceutical developers have traditionally shied away from smaller drug markets due to the revenue limitations presented by the reduced patient base (Woodcock 2007). However, in recent years, the pharmaceutical industry has turned more attention toward high-value niche therapies for the treatment of smaller patient populations. The orphan drug market, the main focus of Greenwood’s chapter in this volume, has expanded rapidly in recent years, largely due to legislative initiatives—most significantly the Orphan Drug Act of 1984, Pub. L. No. 97-414, 96 Stat. 2049 (ODA)—that have incentivized drug development related to orphan diseases (Coté, Xu, and Pariser 2010). The ODA offers a special designation to drugs that treat a rare disease—defined as conditions affecting less than 1 in 200,000 people in the United States—and provides a number of incentives including tax benefits on clinical trials, fast-track approval, grants, and seven years of market exclusivity. FDA now reports that almost 200 orphan drugs enter development each year, and approximately one-third of new drug approvals are for the treatment of rare diseases (Rockoff 2013).
A second trend that is contributing to burgeoning interest in niche markets is the advent of pharmacogenomics, the study of the influence that genetic factors have on drug response. Pharmaceutical products are now being developed in combination with companion diagnostic tests that can stratify patient populations based on genetic predisposition to respond to drug therapies (Collier 2011)—thereby dividing more common diseases into rarer disease genotypes. The number of pharmacogenomic products on the U.S. market has increased steadily over the past decade from thirteen prominent examples of personalized medicine in 2006 to seventy-two in 2011 (Personalized Medicine Coalition 2011). Likely the two best-known examples are the breast cancer drug Herceptin (trastuzumab) and the leukemia drug Gleevec (imatinib), both of which have already achieved billions of dollars in annual sales (Keeling 2007). Further, a growing number of products in clinical development rely on biomarkers, presaging their increasing importance in drug development.
Premarket syndrome may be particularly acute in niche markets since these therapies present a number of evidentiary challenges that increase the imperative to continue to monitor drug use during the postmarket phase. First, clinical trials for niche markets often prove difficult to organize as a result of the inherently limited number of patients with the disease (Boon and Moors 2008) and “encounter a disadvantage compared with more widely used drugs, as large-scale clinical trial data are usually unavailable” (Owen et al. 2008:236). Consequently, drugs for niche markets may be approved on the basis of safety and efficacy data that are less robust than the data produced in larger-scale clinical trials. A second factor is enrichment strategies, the “prospective use of any patient characteristic…to select patients for study to obtain a study population in which detection of a drug effect…is more likely than it would be in an unselected population (FDA 2012a:2). Genetic biomarkers represent a powerful new tool that researchers can use to refine the study population. Yet while enrichment increases the power of a study to detect a clinical effect in some populations, questions remain around whether these results are generalizable to other populations, as well as around the level of data needed to establish selection criteria for enrichment. Moreover, as noted by Ioannidis, “the large majority of proposed genetic associations (including pharmacogenetics) made in the past…have not been replicated with larger-scale evidence and stringent statistical criteria” (2013:413). FDA notes that when enrichment strategies are employed, “post-market commitments or requirements may be requested to better define the full extent of a drug’s effect” (FDA 2012a:32). Overall, a consequence of both smaller clinical trials and enrichment strategies, to the extent that they are justifiable, is a heightened need to assess the benefits and risks of these drugs through the ongoing collection and analysis of data after market entry.
II. THE LIFE-CYCLE APPROACH TO DRUG APPROVAL
Hamburg and Sharfstein, the commissioner and former deputy commissioner of FDA, respectively, once noted that “it has been said that the FDA has just two speeds of approval—too fast and too slow” (2009:2494). In making approval decisions, regulators in all jurisdictions face the fundamental dilemma of balancing the need for robust evidence on safety and efficacy with demands for timely access to promising new therapies. Decision makers face an apparent catch-22, as they are torn between demands from those who insist that patients facing life-threatening conditions need earlier access to treatments and those that fear drugs are often approved too soon on the basis of small clinical trials that do not accurately reflect drug use in the real world (Hamburg and Sharfstein 2009). Industry interests in getting products to market as fast as possible often intermingle with or hide behind the rhetoric of the need to provide access to life-saving medicines, and industry-funded advocacy groups may be used as a front in lobbying efforts. As we discuss in the following sections, while the objectives of reform efforts toward the life-cycle approach appear reasonable, it is important to remember that the devil is often in the details of implementation.
A. Expedited Access to Promising New Therapies
Over the past few decades, growing patient demands for early access to promising new therapies and for greater autonomy in drug treatment decisions have pushed regulatory authorities to adopt more flexible approval programs to speed the development and availability of drugs that treat serious diseases. In 1992, FDA introduced two new programs: the Priority Review designation, which shortened the review time for drugs that treat serious conditions and represent a significant improvement in safety or effectiveness; and the Accelerated Approval program, which allowed drugs for serious conditions that meet unmet medical need to be approved faster based on surrogate endpoints. Subsequently in 1997, FDA introduced Fast Track approval, which offers applicants more frequent interactions with the FDA review team and allows for “rolling reviews” of applications (FDA 2013).
It is no coincidence that demands for expedited review are increasing alongside the growing interest in niche markets. Advances in fields such as pharmacogenomics and legislative initiatives such as orphan drug policies have made previously neglected rare disease markets much more attractive to industry. Patients are being presented with seemingly promising new treatment options and, consequently, demands for earlier access to these therapies are escalating. Moreover, since many niche market therapies treat serious or life-threatening diseases with few or no alternative treatment options, pressure on regulators to speed access to these therapies can be particularly intense.
Growing interest in niche markets is pushing drug regulators to adapt the drug approval system to accommodate the evidentiary challenges introduced by limited patient populations. Most recently, the FDA Safety and Innovation Act of 2012 (FDASIA) introduced a new “breakthrough therapy” designation and expanded the scope of the existing accelerated approval process to allow approval on the basis of both surrogate and intermediate clinical endpoints (FDA 2013). The new breakthrough designation is available to investigational drugs for the treatment of serious or life-threatening conditions where preliminary clinical evidence indicates the drug offers substantial improvement over existing therapies on at least one clinically significant endpoint. Sherman and colleagues (2013) note that the impetus for the new breakthrough designation can be traced to emerging trends in drug development and discovery, particularly targeted therapies aimed at subgroups of patients within broader disease categories who are expected to experience a much larger treatment effect, even in early trials.
While not directly included in the FDA’s 2013 draft benefit–risk framework implementing the life-cycle approach, the expansion of FDA’s expedited review programs should be considered along with the life-cycle approach as part of a broader movement that is increasing the focus on postmarket evidence generation and assessment. The accelerated approval process, in particular, lowers the threshold for initial approval on the condition of more postmarket commitments by the manufacturer, thereby pushing assessment beyond the premarket phase. The convergence of early approval mechanisms and the life-cycle approach is similarly evident in reforms that have been proposed by the European Medicines Agency (EMA), which move away from the artificial dichotomy of the pre- versus postmarket phases. In particular, the “staggered”-approval model endorsed by the EMA allows earlier market entry for well-defined or restricted populations of “good responders,” followed by a broadening of the population postapproval as more “real-life” evidence becomes available (European Medicines Agency 2010). This staggered approval model combines both a more flexible approach to market entry (as under expedited approval programs such as accelerated approval) and more postmarket evidence generation and assessment (as under the life-cycle approach).
FDA claims that it has “been vigilant in assuring that reducing the time necessary for drug development has not compromised the safety and effectiveness of drugs for patients with serious conditions” (FDA 2013). Nonetheless, studies have shown that where drugs are expedited through the approval process, they are more likely to encounter problems during the postmarket phase, likely due to the faster review missing serious safety issues (Lexchin 2012a). Moreover, there are widespread concerns about approving drugs on the basis of surrogate markers or intermediate outcomes (versus long-term clinical endpoints) that may not be very informative in actual clinical practice (Ioannidis 2013). For example, a study by Berlin (2009) found that where oncology drugs are approved under the accelerated approval or priority review channels offered by FDA, drug labeling is revised significantly more frequently than the labeling for traditional drug products. Moore and Furberg (2014) note that, increasingly, innovative drugs are being approved more rapidly based on small clinical trials in narrower patient populations on the condition of expanded requirements for postmarket testing. Indeed, of the twenty drugs studied by Moore and Furberg that received expedited review, FDA required postmarket studies for nineteen of them. The authors note that this shift has made it more challenging to balance the risks and benefits of new drugs, which highlights the need for rigorous control on the rationale for expedited approval.
Another important concern is that expedited review programs could potentially be used by the pharmaceutical industry to get a foot in the regulatory door. Once a drug receives expedited approval, even if only for a very specific indication or patient group, industry may soon request label changes to expand the market. Moreover, even without explicit label change, the market for these drugs may also expand through off-label use; as earlier chapters in this volume suggest, recent case law may mean that off-label promotion becomes more routine and the rules against it less likely to be enforced. After market entry, withdrawing the drug based on subsequent information is likely to be met with strong resistance, particularly from patients who, rightly or wrongly, believe that they are benefiting from the drug. Industry may push regulators to keep the drug on the market through a variety of lobbying and pressure tactics, including the use of industry-supported patient advocacy groups (Hughes and Williams-Jones 2013). To the extent that it is appropriate to approve promising therapies based on a more limited level of evidence, there is a clear need to assess the benefits and risks of these drugs through the ongoing collection and analysis of data after market entry. However, as discussed in more detail below, there are serious questions about whether existing and proposed postmarket regulatory measures are properly equipped to counterbalance the risk posed by earlier market entry.
B. An Incremental Approach to Market Access
The dominance of the blockbuster model of drug development in recent decades has significantly impacted the nature of postmarket risk and, consequently, the risks associated with premarket syndrome. In particular, blockbuster drugs are so widely prescribed, and increasingly for prevention or the long-term treatment of chronic conditions, that even a minor change in relative risk can lead to a significant number of adverse drug reactions (Wiktorowicz, Lexchin, and Moscou 2012). Moreover, the vigorous promotion of blockbuster drugs by sponsoring pharmaceutical companies often leads to rapid market uptake that far outpaces the ability of the scientific community to develop the evidence to support such wide-scale use. The highly publicized market withdrawal of Vioxx demonstrates the risk that important safety data may only become apparent after many people start using the medication—the now-infamous drug has been associated with major adverse events, including myocardial infarctions and strokes, in tens of thousands of patients (Topol 2004).
To combat the risks posed by the rapid promotion and uptake of new drugs, the life-cycle approach involves “the pursuit and active management of emerging knowledge about the benefit-risk balance as drugs become more widely used by larger numbers of increasingly diverse patients” (Psaty, Meslin, and Breckenridge 2012:2491). Incorporating restrictions on the use of new products can help control the diffusion of drugs into the market and limit the number of patients who are exposed to these drugs before adequate data has been collected on their safety and efficacy (Ray and Stein 2006; Eichler 2012). Subsequently, access to the drug can be expanded or restricted as more evidence is generated on appropriate use. Controlling the diffusion of new drugs is particularly important when the drug is approved on the basis of a reduced evidence profile, such as based on a surrogate or intermediate clinical endpoints under the accelerated approval process. To increase the chances that only approved patients receive the drug, Eichler and colleagues argue that “[a]ppropriate targeting to the label population will need to be a high priority” and “at least after the initial approval, systemic restrictions and monitoring of prescribing may be required to prevent off-label use” (Eichler et al. 2012:429).
In recent years, as discussed in the Parasidis chapter in this volume, FDA has moved toward more proactive risk management for drug products. Perhaps most significantly, the FDA Amendments Act of 2007 (FDAAA) gave FDA the authority to require a manufacturer to develop Risk Evaluation and Mitigation Strategies (REMS) for certain products with “exceptional circumstances.” REMS can mandate that patients meet safe-use conditions when further measures beyond drug labeling are needed to ensure that the drug’s benefits outweigh its risks. For example, REMS may place restrictions on the distribution of drugs, including requiring advanced certification for prescribers and pharmacists, permitting dispensing only at authorized pharmacies, or mandating enrollment in patient registries. REMS may be imposed either before or after a drug is approved and may be associated with a single drug or a class of drugs (FDA 2012).
Pharmacogenomic drug products are well suited to an incremental approach to access because diagnostic testing could be used to identify those patients who are likely responders and therefore the best candidates to receive initial access to the drug. Indeed, REMS may specifically require the use of biomarker screening and pharmacogenomic tests before a drug is prescribed (Evans 2013). Ideally, if pharmacogenomic data can be gathered through improved pharmacovigilance systems and postmarket studies, this may allow for increasingly responsive tailoring of prescribing guidelines and the incremental expansion and tightening of approved drug indications based on evolving postmarket evidence. Indeed, FDA has acknowledged that if “new science enables us to determine that the adverse events are restricted to a small, identifiable segment of the population, public health could be improved by making the drug available to others who could benefit without undue risk” (FDA 2007:4). However, defining the appropriate target population in actual clinical practice is itself an uncertain process. In particular, Ioannidis argues that “[t]he lack of a systematic approach to the pharmacogenetic evidence and the inconsistent use of pharmacogenetic information in Food and Drug Administration labeling may create confusion in clinical practice” (Ioannidis 2013:415). Clinicians may have difficulty assessing what a label really means and how to interpret a genetic test result and its association with the effect of a drug, thus perhaps unnecessarily excluding patients who could benefit from therapy.
The effectiveness of REMS will ultimately depend on regulators having the authority, resources, and political will to police and enforce the prescribed measures. Unfortunately, a recent evaluation by the Office of the Inspector General (OIG) released in February 2013 found that FDA lacks the comprehensive data necessary to determine whether REMS are actually improving drug safety. The OIG reviewed forty-nine REMS and found that half did not contain the information requested by FDA, ten were not submitted within given time frames, and only seven achieved all of their objectives—all of which raise significant concern about the effectiveness of REMS. The report concludes that “[i]f FDA does not have comprehensive data to monitor the performance of REMS, it cannot ensure that the public is provided maximum protection from a drug’s known or potential risks” (OIG 2013:22). The OIG also recommended that FDA be given the legislative authority to take enforcement actions when drug companies do not submit all information requested in assessment plans, which the agency currently lacks. The OIG analysis also hints at a broader issue in drug regulation: the gap between well-intended and seemingly reasonable regulatory adjustments to new developments and the reality of drug regulation on the ground—a reality characterized by limited public resources and a resulting power imbalance between industry and regulatory agencies.
C. A Stronger Focus on Postmarket Evidence Generation
Another consequence of premarket syndrome is that the focus on premarket activities means that regulators often have limited measures available to ensure continued compliance with regulations once a drug has received market approval. Earlier studies showed that although drug manufacturers are often expected to conduct further studies after a drug enters the market, they often fail to do so (Avorn 2007). However, a turning point has arguably been reached in recent years as FDA expanded regulatory requirements for postmarket commitments. Most notably, the FDAAA expanded FDA’s authority to require manufacturers to conduct studies after market approval if new safety information comes to light (Evans 2010). FDA can even mandate that these studies be completed on a specific timetable. In a 2012 report on the fulfillment of postmarket requirements, FDA reported that of the 675 postmarket studies for new drug applications that had been mandated as of September 2011, 87 percent were on schedule (FDA 2012b). Nonetheless, in May 2012, the IOM issued a report on postmarket safety in which it urged FDA to be more aggressive in proactively dealing with the safety concerns that emerge following the entry of a drug into the market (Kuehn 2012).
Particularly for drugs approved based on a reduced evidence profile, the expansion of postmarket surveillance is integral to counterbalancing increased uncertainty around safety and efficacy at market entry. However, the impact of more postmarket studies and monitoring will be limited if insufficient attention is paid to how such evidence is generated. Developing the infrastructure necessary for the comprehensive, timely, and accurate collection of data on drug use in actual clinical practice remains a significant challenge (Evans 2010), as is discussed in the chapter by Parasidis. Moreover, a fundamental problem with the existing regulatory system is the pharmaceutical industry’s control over the majority of clinical trials, which studies have shown may lead to manipulation of trial results through carefully crafted research design, choices made in the context of statistical analyses, exclusion of negative findings, over-inclusion of positive findings, and even outright misrepresentation (Lexchin 2012b). These issues will only be overcome through more significant changes to pharmaceutical knowledge governance (Lemmens and Telfer 2012; Lemmens 2013).
Enhanced transparency measures are fundamental to improving the reliability of pharmaceutical knowledge production (Lemmens 2013)—not only during premarket development but also after market entry. Industry may also be driven to manipulate or obfuscate unfavorable study results in the postmarket phase if such studies demonstrate, for example, the inferiority of a drug to other therapies or the inappropriateness of a drug for widely prescribed off-label uses. Transparency is important not only for reasons of public accountability but also because problems with drug safety and efficacy have sometimes been detected by independent scientific experts rather than by regulatory agencies. FDA has already taken important steps toward improving transparency, perhaps most notably the introduction of strict registration- and results-reporting requirements for all Phase II–IV trials under the FDAAA, with associated penalties for noncompliance. Some regulatory agencies, such as the EMA, have gone further and impose transparency for all clinical trial reports. Kimmelman and Anderson (2012) have even argued for the registration of preclinical research, which would be particularly relevant for pharmacogenomic drug development where the rationale for biomarker selection is based on preclinical data. However, transparency is only a first step, and reform efforts must also be directed at deeper issues in data production that stem from industry control over the design, conduct, and reporting of clinical trials.
D. Downstream Impact on Funding Decisions
The movement toward niche markets and the life-cycle approach will have important downstream impacts on how drug funding decisions are made, particularly since both trends may give rise to significant pressures to fund drugs for general distribution on the basis of a reduced evidence profile. Obtaining funding coverage is an increasingly important step in the uptake of new drugs, particularly for high-cost niche market therapies that few patients can afford to pay for out of pocket. Consequently, there is increasing interest in coverage with evidence development (CED), a funding arrangement where population-level payment or reimbursement is tied to prospective data collection in an attempt to gather more evidence and reduce decision uncertainty around funding coverage (Garrison Jr. et al. 2013). The increasing number of expensive niche market therapies with uncertain evidence profiles is placing pressure on funding authorities to enter into innovative risk-sharing approaches with drug sponsors (Owen et al. 2008).
CED may prove to be a natural complement to the life-cycle approach: both systems acknowledge that drug approval decisions should not be strictly binary but rather should be managed incrementally and continuously reassessed. Both recognize the uncertainty around premarket data and contribute toward ongoing evidence generation in the postmarket phase in an effort to deal with this uncertainty. Both facilitate a more incremental approach to the diffusion of new drug products into the market by limiting or attaching conditions to approval or coverage to prevent the drug from being widely prescribed before sufficient data on safety and efficacy have been gathered. Finally, both mandate more prospective data collection in an attempt to reduce decision uncertainty and better inform approval and coverage decisions.
Nonetheless, CED is also subject to many of the same challenges that may hinder the life-cycle approach, namely uncertainty around where to set the evidentiary bar for initial approval and how to ensure effective evidence generation and compliance with conditions of coverage once approval is granted. Discontinuing funding can be politically very difficult, even in light of new evidence of increased risks or questionable efficacy (Bishop and Lexchin 2013). For these reasons, CED must also be approached with caution—arguably even more so given that funding authorities bear the financial consequences of their approval decisions in a way that regulatory authorities do not. In this vein, there is increasing criticism of the often exorbitant prices demanded for many niche market therapies and of the industry’s traditional justification that these prices reflect the need to recoup the high cost of development across a smaller population base. However, major questions are now arising about the research and development costs claimed by industry and, by extension, the prices demanded for many new drugs. Light and Warburton (2011), for example, point to various inflationary tactics used by industry to pump up estimated research and development costs and thus they reach a much lower estimate of average drug development costs than the billion-dollar-plus figures routinely claimed by industry sources—figures that are largely based on confidential industry data. Again, the importance of transparency and better oversight mechanisms also becomes apparent in the funding context.
III. CONCLUSION
Reform efforts toward the life-cycle approach are helping to reduce the signs and symptoms of premarket syndrome that have long plagued the drug regulatory system. Concurrently, the wave of new niche market therapies for serious and life-threatening diseases, coupled with rising demands for earlier access to these “promising” new therapies, has led regulators to expand exceptional access programs. Both of these trends are contributing to the increasing focus on the postmarket phase. While there are many positive aspects to this trend, such as more proactive risk management and more postmarket studies based on real-world use, significant questions remain about whether there has been concurrent lowering of the bar to market entry. Any arguments in favor of expediting the approval of drugs must be carefully weighed against the potential dangers that may arise from earlier approval. Given the widely recognized problems associated with the reliability of evidence in existing regulatory processes, transparency and data access, while not in themselves a complete solution, should be a priority of reform efforts. Ultimately, while expanding postmarket evidence generation is an important element in counterbalancing evidentiary uncertainty on drug safety and efficacy at market entry, these measures should be a complement to, not a substitute for, more rigorous premarket assessment.
NOTE
The authors would like to thank the organizers and attendees of the Petrie-Flom Center conference “The FDA in the 21st Century” at Harvard Law School on May 3–4, 2013, and of the conference “Old Markets, New Markets: Health Law After the 2012 Act” at the University of Sheffield School of Law on June 27, 2013, for useful comments and discussions. We are particularly grateful to I. Glenn Cohen, Tamara Hervey, Donald Light, Joel Lexchin, Julian Cockbain, and Sigrid Sterckx for comments on earlier versions of this and a related paper; to Kelly Tai for diligent research and work on the references; and to Brenda Robson for her editing comments. This chapter builds on the article: S. G. Gibson and T. Lemmens. 2014. “Niche Markets and Evidence Assessment in Transition: A Critical Review of Proposed Drug Reforms,” Medical Law Review 22(2): 200–20. Research for this paper was supported by a Genome Canada grant on Ethical and Legal Issues of Cancer Initiating Stem Cell Research.
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