Sarah Garner

adaptive Licensing: Taking the Next Step in the Evolution of Drug approval

Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL.

Disinvestment from low value clinical interventions: NICEly done?

Over the past 10 years NICE has identified over 800 clinical interventions for potential disinvestment. But Sarah Garner and Peter Littlejohns report that although disinvestment will increase efficiency and quality, the opportunity for cash saving is unlikely to meet the necessary targets

From Adaptive Licensing to Adaptive Pathways: Delivering a Flexible Life-Span Approach to Bring New Drugs to Patients

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life‐span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade‐off, help de‐risk drug development, and lead to better outcomes for patients.

Reducing ineffective practice: challenges in identifying low-value health care using Cochrane systematic reviews

Objectives: Despite international agreement that stopping low value practices will increase efficiency, identifying them is difficult and controversial. Opponents of centralized lists of low value practices stress that the actual problem is inappropriate low value use, and better targeting and implementation of treatment thresholds is needed. Our objective was to use Cochrane Reviews to identify low value practices to support local disinvestment decisions. Methods: New or updated reviews were included if the authors concluded that the uncertain effectiveness of an intervention meant it should only be used in research, or that it was ineffective or harmful and should not be used. The reviews go through a production and quality assurance process, and are published as ‘Cochrane Quality and Productivity topics’ through the NHS Evidence website (http://www.library.nhs.uk/qipp/). Results: Over a six-month period, 65 Cochrane reviews were processed by the National Institute for Health and Clinical Excellence (NICE). Of these, 28 identified potentially low value practices in the UK context. This was primarily due to a lack of randomized evidence of effectiveness, rather than robust evidence of a lack of effectiveness, or evidence of harm. Conclusions: Identifying low-value health care practices for local disinvestment (total or partial) is both practically and politically challenging, yet it is necessary to manage health budgets. This project identified that Cochrane Reviews can potentially identify low value health care practices. However, each review has to be reinterpreted for the UK context and additional analysis has to be undertaken to facilitate local implementation. Recommendations to improve the usability of systematic reviews are made.

10 years of NICE: still growing and still controversial

The National Institute for Health and Clinical Excellence (NICE) will have existed for 10 years on April 1, 2009. Over the past decade, the institutes methodological approach to the development of guidance and assessment of the value of health-care interventions has received international interest and acclaim. Furthermore, individual decisions, in particular those made on new cancer drugs, have generated enormous controversy. An early example was the appraisal of irinotecan and oxaliplatin for colorectal cancer in 2002. In 2003, NICE described the rationale behind its decision making. The 10th anniversary of the institute provides an opportunity to review some of the key issues affecting cancer appraisals and to explain the development of other NICE guidance programmes relevant to the provision of cancer services.

Disinvestment and value-based purchasing strategies for pharmaceuticals : an international review

Pharmaceutical expenditure has increased rapidly across many Organisation for Economic Cooperation and Development (OECD) countries over the past three decades. This growth is an increasing concern for governments and other third-party payers seeking to provide equitable and comprehensive healthcare within sustainable budgets. In order to create headroom for increasing utilisation, and to fund new high-cost therapies, there is an active push to ‘disinvest’ from low-value drugs. The aim of this article is to review how reimbursement policy decision makers have sought to partially or completely disinvest from drugs in a range of OECD countries (UK, France, Canada, Australia and New Zealand) where they are publicly funded or subsidised. We employed a systematic literature search strategy and the incorporation of grey literature known to the authorship team. We canvass key policy instruments from each country to outline key approaches to the identification of candidate drugs for disinvestment assessment (passive approaches vs. more active approaches); methods of disinvestment and value-based purchasing (de-listing, restricting treatment, price or reimbursement rate reductions, encouraging generic prescribing); lessons learnt from the various approaches; the potential role of coverage with evidence development; and the need for careful stakeholder management. Dedicated sections are provided with detailed coverage of policy approaches (with drug examples) from each country. Historically, countries have relied on ‘passive disinvestment’; however, due to (1) the availability of new cost-effectiveness evidence, or (2) ‘leakage’ in drug utilisation, or (3) market failure in terms of price competition, there is an increasing focus towards ‘active disinvestment’. Isolating low-value drugs that would create headroom for innovative new products to enter the market is also motivating disinvestment efforts by multiple parties, including industry. Historically, disinvestment has mainly taken the form of price reductions, especially when market failures are perceived to exist, and restricting treatment to subpopulations, particularly when a drug is no longer considered value for money. There is considerable experimentation internationally in mechanisms for disinvestment and the opportunity for countries to learn from each other. Ongoing evaluation of disinvestment strategies is essential, and ought to be reported in the peer-reviewed literature.

Issues relating to selective reporting when including non‐randomized studies in systematic reviews on the effects of healthcare interventions

BACKGROUND Selective outcome and analysis reporting (SOR and SAR) occur when only a subset of outcomes measured and analyzed in a study is fully reported, and are an important source of potential bias. KEY METHODOLOGICAL ISSUES We describe what is known about the prevalence and effects of SOR and SAR in both randomized controlled trials (RCTs) and non-randomized studies (NRS), and the effects of SOR and SAR on summary effect estimates and conclusions in systematic reviews of the effectiveness of healthcare interventions. GUIDANCE Review authors should always suspect SOR and SAR in reviews that include NRS, assess primary studies for the risk of bias, and make reasonable attempts to retrieve study protocols or other documentation developed before study recruitment began. There are clues that may suggest SOR or SAR in NRS, including differences between the methods and results sections of the publication, study funder, and differences between study protocol or registration information and the study report. CONCLUSION Existing evidence about reporting biases in primary studies comes almost exclusively from methodological reviews of RCTs. The prevalence and impact of SOR and SAR in NRS are likely even greater than in RCTs but it is difficult to identify and confirm selective reporting in NRS. Copyright

ART OF THE POSSIBLE

It is very fitting that the strap line for the article on reassessment (1) is derived from the quote “politics is the art of the possible” attributed to Otto von Bismarck. Bismarck was the first chancellor of the unified German Empire that preserved peace in Europe until 1914. Politically deft, he persuaded the southern German states to join with his North German Confederation by provoking hostilities with France. The article in a similar vein attempts to find a politically acceptable way to move forward with the “disinvestment” agenda. The need for disinvestment is pretty uncontroversial (2); demand is outstripping supply, and we need to ensure that healthcare resources are spent on interventions that are of clinical value. In some jurisdictions, they also need to be cost-effective. Arguably we also have a moral duty not to use things that are of no value, particularly when they expose patients to the risk of harm. If we are requiring new technologies to undergo stringent assessment then we need to apply those same rules to established technologies. But given this is all common sense, why has disinvestment proven so difficult in practice? The first thing you learn as a researcher in this area is that any discussion on disinvestment starts, and invariably finishes, with lengthy objections to the terminology. As the authors point out the term “disinvestment” is considered by some to be unpalatable and divisive. Sponsors are concerned that their intervention is even potentially considered to be of questionable value, pre-empting subsequent review. Clinicians do not like the implication that their practice could be potentially substandard and there is always the counter-argument that it could be useful for somebody. The rule of rescue is always emotive but viewed from another perspective “Pleading from subgroups and “judicious selection” is always the last refuge of a failing intervention” (3). Researchers and policy makers have, therefore, turned to terms such as optimal practice reviews, low-value health care, reinvestment, and my particular favorite, reducing ineffective practice (RIP). The authors of the article have proposed a new “valueneutral” framework for disinvestment that they have termed “health technology re-assessment.” The stated differentiating factors between assessment and reassessment are type of technology under review and their greater focus on implementation; stopping something is always more difficult that starting. The authors have not identified any differences in the actual technical methodology that will be required. However, beyond the known issues to deal with a lack of evidence, there has never been a suggestion that new HTA techniques would be required. One barrier to the adoption of “re-assessment” is that the term suggests that an initial assessment has been done, which for legacy technologies is invariably not the case. A very real consequence of the plethora of terminology is that it is very difficult to share experience and target technologies. Discussions with the NELM, the U.S. organization in charge of the MESH headings that are used to index the medical literature, have failed to get a separate sub-heading created. This, coupled with publication bias, makes it nearly impossible to proactively identify candidates through the medical literature. Indeed the concept has proven difficult to convey to U.S. audiences where there is an apparent political paranoia that even stopping technologies of no proven value could be portrayed as rationing. Researchers have, therefore, established their own network under the auspices of Health Technology Assessment International (4). The network is agreeing to a set of author-provided keywords to be submitted to journals to enable indexing. As many similar articles have done, the authors have identified the need for political support. Even between the two examples provided the contrast is quite marked. In Australia the government has provided full support and strategy with parallel academic work incorporating deliberative stakeholder engagement (5). The structure of the payment system is such that payment codes can simply be removed as one extreme or have their indications refined in a nuanced manner so that technologies are better targeted toward high-value uses. In contrast, in the United Kingdom, the only enforceable aspect of NICE’s guidance is that the NHS has to provide funding for costeffective technologies through the appraisals program within 3 months. All other recommendations are merely guidance (6). This, coupled with the lack of a reimbursement system in secondary care, means that any controls have to be put in at a local level. A call to action is presented which will resonate with the HTA community. Many of the identified needs also apply to HTA and the interplay between the two similar agenda’s needs careful management. HTA bodies are already struggling to manage the new entrants, which have a very visible potential budget impact. The paucity of evidence base for many potential disinvestment candidates presents a quandary. Most research

Interventions for hidradenitis suppurativa: a Cochrane systematic review incorporating GRADE assessment of evidence quality

More than 50 interventions have been used to treat hidradenitis suppurativa (HS), and so therapy decisions can be challenging. Our objective was to summarize and appraise randomized controlled trial (RCT) evidence for HS interventions in adults. Searches were conducted in Medline, Embase, CENTRAL, LILACS, five trials registers and abstracts from eight dermatology conferences until 13 August 2015. Two review authors independently assessed study eligibility, extracted data and assessed methodological quality. Primary outcomes were quality of life and adverse effects of the interventions. Twelve trials, from 1983 to 2015, investigating 15 different interventions met our inclusion criteria. The median trial duration was 16 weeks and the median number of participants was 27. Adalimumab 40 mg weekly improved the Dermatology Life Quality Index (DLQI) by 4·0 points, which equates to the minimal clinically important difference for the scale, compared with placebo (95% confidence interval −6·5 to −1·5 points). Evidence quality was reduced to ‘moderate’ because the results are based on only a single study. Adalimumab 40 mg every other week was ineffective in a meta‐analysis of two studies comprising 124 participants. Infliximab 5 mg kg−1 improved the DLQI score by 8·4 points after 8 weeks in a moderate‐quality study completed by 33 of 38 participants. Etanercept 50 mg twice weekly was ineffective. Inclusion of a gentamicin sponge prior to primary closure did not improve outcomes. Other interventions, including topical and oral antibiotics, were investigated by relatively small studies, preventing treatment recommendations due to imprecision. More, larger RCTs are required to investigate most HS interventions, particularly oral treatments and surgical therapy. Moderate‐quality evidence suggests that adalimumab given weekly and infliximab are effective, whereas adalimumab every other week is ineffective.

Processes, contexts, and rationale for disinvestment: a protocol for a critical interpretive synthesis

BackgroundPractical solutions are needed to support the appropriate use of available health system resources as countries are continually pressured to ‘do more with less’ in health care. Increasingly, health systems and organizations are exploring the reassessment of possibly obsolete, inefficient, or ineffective health system resources and potentially redirecting funds to those that are more effective and efficient. Such processes are often referred to as ‘disinvestment’. Our objective is to gain further understanding about: 1) whether how and under what conditions health systems decide to pursue disinvestment; 2) how health systems have chosen to undertake disinvestment; and 3) how health systems have implemented their disinvestment approach.Methods/DesignWe will use a critical interpretive synthesis (CIS) approach, to develop a theoretical framework based on insights drawn from a range of relevant sources. We will conduct systematic searches of databases as well as purposive searches to identify literature to fill conceptual gaps that may emerge during our inductive process of synthesis and analysis. Two independent reviewers will assess search results for relevance and conceptually map included references. We will include all empirical and non-empirical articles that focus on disinvestment at a system level. We will then extract key findings from a purposive sample of articles using frameworks related to government agendas, policy development and implementation, and health system contextual factors and then synthesize and integrate the findings to develop a framework about our core areas of interest. Lastly, we will convene a stakeholder dialogue with Canadian and international policymakers and other stakeholders to solicit targeted feedback about the framework (e.g., by identifying any gaps in the literature that we may want to revisit before finalizing it) and deliberating about barriers for developing and implementing approaches to disinvestment, strategies to address these barriers and about next steps that could be taken by different constituencies.DiscussionDisinvestment is an emerging field and there is a need for evidence to inform the prioritization, development, and implementation of strategies in different contexts. Our CIS and the framework developed through it will support the actions of those involved in the prioritization, development, and implementation of disinvestment initiatives.Systematic review registrationPROSPEROCRD42014013204