Refining the impact of genetic evidence on clinical success.

The cost of drug discovery and development is driven primarily by failure1, with only about 10% of clinical programmes eventually receiving approval2-4. We previously estimated that human genetic evidence doubles the success rate from clinical development to approval5. In this study we leverage the growth in genetic evidence over the past decade to better understand the characteristics that distinguish clinical success and failure. We estimate the probability of success for drug mechanisms with genetic support is 2.6 times greater than those without. This relative success varies among therapy areas and development phases, and improves with increasing confidence in the causal gene, but is largely unaffected by genetic effect size, minor allele frequency or year of discovery. These results indicate we are far from reaching peak genetic insights to aid the discovery of targets for more effective drugs.

An urgent call to raise the bar in oncology.

Important breakthroughs in medical treatments have improved outcomes for patients suffering from several types of cancer. However, many oncological treatments approved by regulatory agencies are of low value and do not contribute significantly to cancer mortality reduction, but lead to unrealistic patient expectations and push even affluent societies to unsustainable health care costs. Several factors that contribute to approvals of low-value oncology treatments are addressed, including issues with clinical trials, bias in reporting, regulatory agency shortcomings and drug pricing. With the COVID-19 pandemic enforcing the elimination of low-value interventions in all fields of medicine, efforts should urgently be made by all involved in cancer care to select only high-value and sustainable interventions. Transformation of medical education, improvement in clinical trial design, quality, conduct and reporting, strict adherence to scientific norms by regulatory agencies and use of value-based scales can all contribute to raising the bar for oncology drug approvals and influence drug pricing and availability.

Contribution of NIH funding to new drug approvals 2010-2016.

This work examines the contribution of NIH funding to published research associated with 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010-2016. We identified >2 million publications in PubMed related to the 210 NMEs (n = 131,092) or their 151 known biological targets (n = 1,966,281). Of these, >600,000 (29%) were associated with NIH-funded projects in RePORTER. This funding included >200,000 fiscal years of NIH project support (1985-2016) and project costs >$100 billion (2000-2016), representing ∼20% of the NIH budget over this period. NIH funding contributed to every one of the NMEs approved from 2010-2016 and was focused primarily on the drug targets rather than on the NMEs themselves. There were 84 first-in-class products approved in this interval, associated with >$64 billion of NIH-funded projects. The percentage of fiscal years of project funding identified through target searches, but not drug searches, was greater for NMEs discovered through targeted screening than through phenotypic methods (95% versus 82%). For targeted NMEs, funding related to targets preceded funding related to the NMEs, consistent with the expectation that basic research provides validated targets for targeted screening. This analysis, which captures basic research on biological targets as well as applied research on NMEs, suggests that the NIH contribution to research associated with new drug approvals is greater than previously appreciated and highlights the risk of reducing federal funding for basic biomedical research.

Regulatory considerations in biosimilars: Asia pacific regions.

Biosimilars are the biological drugs that are granted after the expiry of the patent of an affirmed innovator. Asia Pacific countries are characterized by significant demand as they account for majority of the world population and poor affordability due to low per capita income in most regions. Some of these countries offer potential to emerge as global suppliers of affordable, safe and efficacious biosimilars. This article highlights the prospects of biosimilars in the Asia Pacific market. Regulatory framework in the various countries is also discussed.

Potential Life-Years Lost: The Impact of the Cancer Drug Regulatory and Funding Process in Canada.

BACKGROUND: Canada has an established publicly funded health care system with a complex drug approval and funding process. After proof of efficacy (POE; key publication/presentation) and before becoming publicly accessible, each drug undergoes a Health Canada approval process, a health technology assessment (HTA), a pricing negotiation, and finally individual provincial funding agreements. We quantified potential life-years lost during this process. METHODS: We analyzed drugs for advanced lung, breast, and colorectal cancer that underwent the HTA process between 2011 and 2016. Life-years lost were calculated by multiplying documented improvement in progression-free and overall survival, number of eligible patients, and time from POE to first public funding. For conservative calculation, we assumed all eligible patients in Canada had access at the time of first public funding, whereas in reality provinces fund at different time points. RESULTS: We analyzed 21 drugs. Of these, 15 have been funded publicly. The time from POE to first public funding ranged from 14.0 to 99.2 months (median 26.6 months). Total overall life-years lost from POE to first public funding were 39,067 (lung 32,367; breast 6,691). Progression-free life-years lost from POE to first public funding were 48,037 (lung 9,139, breast 15,827, colorectal 23,071). CONCLUSION: The number of potential life-years lost during the drug regulatory and funding process in Canada is substantial, largely driven by delays to funding of colorectal cancer drugs. Recognizing that interprovincial differences exist and that eligible patients may not all receive a given drug, if even a fraction does so, the impact of delays remains substantive. Collaborative national initiatives are required to address this major barrier to treatment access. IMPLICATIONS FOR PRACTICE: Patients may spend lengthy periods of time awaiting access to new and effective cancer drugs. Patients with private drug insurance or personal funds or who reside in certain Canadian provinces may obtain some drugs sooner than others, potentially creating a two-tiered access system. The cancer drug access and public funding system must be expedited to improve equity.

Association Between the Use of Surrogate Measures in Pivotal Trials and Health Technology Assessment Decisions: A Retrospective Analysis of NICE and CADTH Reviews of Cancer Drugs.

OBJECTIVE: To assess whether using surrogate versus patient-relevant endpoints in pivotal trials of cancer drugs was associated with health technology assessment recommendations in England (National Institute for Health and Care Excellence [NICE]) and Canada (Canadian Agency for Drugs and Technologies in Health [CADTH]). METHODS: Cancer drug approvals from 2012 to 2016 were categorized by demonstrating benefit on overall survival (OS), progression-free survival, disease response, or having no comparator. Approvals were analyzed by benefit category and health technology assessment recommendation. The association between benefit (surrogate vs OS) and recommending a drug was examined using descriptive statistics and linear probability models controlling for unmet need, orphan designation, and cost-effectiveness. RESULTS: Of 42 cancer indications that NICE recommended, 15 (36%) demonstrated OS benefit. Cancer indications with OS benefit were less likely to receive a recommendation from NICE than those without (P = .04). In linear probability models, availability of OS benefit was no longer associated with a recommendation from NICE (P = .32). Cost-effective cancer drugs had a 55.6% (95% CI: 38.9%-72.3%) higher probability of receiving a recommendation from NICE than those that were not. In Canada, 15 of 37 (41%) cancer indications that were recommended showed OS benefit. There was no detectable association between surrogate measures and CADTH recommendations based on descriptive statistics (P = .62) or in linear probability models (P = .73). CONCLUSION: When cost-effectiveness was considered, pivotal trial endpoints were not associated with NICE recommendations. Pivotal trial endpoints, unmet need, orphan status, and cost-effectiveness did not explain CADTH recommendations.

"Stick or Twist?" Negotiating Price and Data in an Era of Conditional Approval.

BACKGROUND: Changes in the regulatory context enable faster approval of transformative medicines. They also lead to health technology assessment (HTA) agencies having to make decisions with less evidence. In response, HTA agencies have also initiated forms of conditional approval. When the evidence base for a new oncology treatment leaves substantial uncertainty, the new Cancer Drugs Fund allows the National Institute for Heath and Care Excellence to give the manufacturer two options: (1) offer a low price based on conservative assumptions and obtain immediate approval ("stick") or (2) wait until the evidence base has further matured before finalizing a potentially higher agreed price ("twist"). OBJECTIVES: The purpose of this article is to explain how, using the theoretical framework of the expected value of sample information, simulation methods can help inform a manufacturer's decisions when faced with the option to stick or twist. METHODS: We first summarize a general model to help frame the manufacturer's negotiating strategy. We then use a motivating case study, based on a hypothetical immunotherapy, to illustrate how manufacturers can use simulation methods to robustly characterize the uncertainty inherent to further data collection and incorporate this uncertainty within their decision making. RESULTS: Our approach allows us to estimate the commercial value of generating additional data (the difference between the estimated net present value of stick and twist). We test the sensitivity of the results to different assumptions via scenario analyses. CONCLUSIONS: This article shows that simulation methods can be used to help pharmaceutical managers make informed strategic decisions in contexts of uncertainty.

Clinical evidence supporting the marketing authorization of biosimilars in Europe.

PURPOSE: To review the marketing authorization of biosimilars and provide a critical analysis of the pivotal trials supporting their approval by the European Medicines Agency (EMA). METHODS: EMA website to identify the biosimilars approved up to July 2019 and the European Public Assessment Report for information on pivotal trial design, duration, intervention and control, primary outcome, data on immunogenicity, and comparability margins. RESULTS: The EMA has approved 55 biosimilars (62% in 2017-2019) of 16 biologic products, used in several clinical indications. Some biosimilars were licensed as multiple products, with different commercial names, by the same or different companies. The comparability exercise and subsequent approval of 49/55 (89%) biosimilars were based on one or more pivotal phase III trials testing their clinical efficacy. In all, biosimilars were approved on the basis of 55 trials, mostly phase III (42/55, 76%) assessing clinical efficacy; these were mainly equivalence trials (31/55, 56%). The pivotal phase III trials assessed surrogate measures of clinical effect, and 71% reported immunogenicity data. CONCLUSION: Analysis of the approval of biosimilars in Europe depicts a complex and heterogeneous scenario. The requirement for showing similarity in terms of clinical efficacy and safety provides a robust demonstration of comparable clinical outcomes but lays a burden on biosimilar manufacturers and may delay the introduction of the drugs. The development, licensing, and monitoring of biosimilars would benefit from new strategies to accelerate access to these drugs while reducing uncertainties about their use in practice.

Estimated costs of pivotal trials for U.S. Food and Drug Administration-approved cancer drugs, 2015-2017.

BACKGROUND: Pivotal clinical trials provide critical evidence to regulators regarding a product's suitability for marketing approval. The objectives of this study are (1) to characterize select features of trials for oncology products approved by the U.S. Food and Drug Administration between 2015 and 2017; and (2) to quantify the costs of these trials and how such costs varied based on trial characteristics. METHODS: We identified novel oncology therapeutic drugs, and their respective pivotal trials, approved between 2015 and 2017 using annual summary reports from the Food and Drug Administration. Cost estimates for each pivotal trial were calculated using IQVIA's CostPro, a clinical trial cost estimating tool based on executed contracts between pharmaceutical manufacturers and contract research organizations. Measures of drug and trial characteristics included trial design, end point, patient enrollment, and regulatory pathway. We also performed sensitivity analyses that varied assumptions regarding how efficiently each trial was conducted. RESULTS: A total of 39 pivotal clinical trials provided the basis for Food and Drug Administration approval of 30 new oncology drugs from 2015 to 2017. Among these trials, primary end points were objective response rate in 20 (51.3%), progression-free survival in 13 (33.3%), and overall survival in 6 (15.4%). Twenty trials (51.3%) were single-arm studies. The median estimated cost of oncology pivotal trials was $31.7 million (interquartile range = $17.0-$60.4 million). Trials with objective response rate as primary end point had a median estimate of $17.7 million (interquartile range = $11.9-$27.1 million), compared with trials examining progression-free survival ($42.3 million, interquartile range = $34.6-$101.2 million) or overall survival ($79.4 million, interquartile range = $56.9-$97.7 million) (p < 0.001). Estimated costs for single-arm trials ($17.7 million, interquartile range = $11.9-$23.7 million) were less than for trials with a placebo-controlled ($56.7 million, interquartile range = $40.9-$103.9 million) or active control arm ($67.6 million, IQR = $35.5-$93.5 million) (p < 0.001). CONCLUSIONS: Relative to the estimated costs of drug development, the costs of these oncology pivotal trials were modest, with trials that produced more valuable scientific information costing more than their counterparts.

FDA Approval and Regulation of Pharmaceuticals, 1983-2018.

Importance: US law requires testing of new drugs before approval to ensure that they provide a well-defined benefit that is commensurate with their risks. A major challenge for the US Food and Drug Administration (FDA) is to achieve an appropriate balance between rigorous testing and the need for timely approval of drugs that have benefits that outweigh their risks. Objective: To describe the evolution of laws and standards affecting drug testing, the use of new approval programs and standards, expansions of the role and authority of the FDA, and changes in the number of drugs approved from the 1980s to 2018. Evidence: Sources of evidence included principal federal laws and FDA regulations (1962-2018) and FDA databases of approved new drugs (1984-2018), generic drugs (1970-2018), biologics (1984-2018), and vaccines (1998-2018); special development and approval programs (Orphan drug [1984-2018], Fast-Track [1988-2018], Priority Review and its predecessors [1984-2018], Accelerated Approval [1992-2018], and Breakthrough Therapy [2012-2018]); expanded access (2010-2017) and Risk Evaluation and Mitigation Strategies (2008-2018); and user fees paid to the FDA by industry (1993-2018). Findings: From 1983 to 2018, legislation and regulatory initiatives have substantially changed drug approval at the FDA. The mean annual number of new drug approvals, including biologics, was 34 from 1990-1999, 25 from 2000-2009, and 41 from 2010-2018. New biologic product approvals increased from a median of 2.5 from 1990-1999, to 5 from 2000-2013, to 12 from 2014-2018. The median annual number of generic drugs approved was 136 from 1970 to the enactment of the Hatch-Waxman Act in 1984; 284 from 1985 to the enactment of the Generic Drug User Fee Act in 2012; and 588 from 2013-2018. Prescription drug user fee funding expanded from new drugs and biologics in 1992 to generic and biosimilar drugs in 2012. The amount of Prescription Drug User Fee Act fees collected from industry increased from an annual mean of $66 million in 1993-1997 to $820 million in 2013-2017, and in 2018, user fees accounted for approximately 80% of the salaries of review personnel responsible for the approval of new drugs. The proportion of drugs approved with an Orphan Drug Act designation increased from 18% (55/304) in 1984-1995, to 22% (82/379) in 1996-2007, to 41% (154/380) in 2008-2018. Use of Accelerated Approval, Fast-Track, and Priority Review for new drugs has increased over time, with 81% (48/59) of new drugs benefiting from at least 1 such expedited program in 2018. The proportion of new approvals supported by at least 2 pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017, based on 124 and 106 approvals, respectively, while the median number of patients studied did not change significantly (774 vs 816). FDA drug review times declined from more than 3 years in 1983 to less than 1 year in 2017, but total time from the authorization of clinical testing to approval has remained at approximately 8 years over that period. Conclusions and Relevance: Over the last 4 decades, the approval and regulation processes for pharmaceutical agents have evolved and increased in complexity as special programs have been added and as the use of surrogate measures has been encouraged. The FDA funding needed to implement and manage these programs has been addressed by expanding industry-paid user fees. The FDA has increasingly accepted less data and more surrogate measures, and has shortened its review times.

To HTA or Not to HTA: Identifying the Factors Influencing the Rapid Review Outcome in Ireland.

OBJECTIVES: Reimbursement systems are evolving and endeavor to balance access and affordability. One such evolution in Ireland is the compulsory rapid review (RR) process, the outcome from which is a recommendation for a health technology assessment (HTA) or no HTA. For drugs that avoid an HTA, evaluation times are shorter, lengthy price negotiations are avoided, and access is faster. In the absence of formal decision-making criteria around the requirement of an HTA, this study examines the factors influencing the outcome of the RR process in Ireland. METHODS: A database was developed combining data from publicly available sources for drug evaluations conducted by the National Centre for PharmacoEconomics (NCPE) (January 2010-June 2017, n = 296). Because Irish cost data were not publicly available for all drugs, cost data from the Scottish Medicines Consortium were employed as a proxy. Employing logistic regressions, the factors influencing the RR outcome are revealed. RESULTS: After an RR, an HTA was recommended for 55% of drugs. The regression results revealed therapeutic area (endocrine, musculoskeletal, and neoplasm), first-in-class and orphan disease increased the probability of an HTA. Furthermore, when proxy costs were included, results revealed that every €1000 increase in annual drug costs per patient increased the probability of an HTA being required by 1% and that an HTA was more likely than no HTA when annual drug costs exceeded €15 000. CONCLUSION: Given the current focus on access and affordability, this study identifies the factors influencing the requirement of an HTA in Ireland.

Conditional Financing of Drugs in the Netherlands: Past, Present, and Future-Results From Stakeholder Interviews.

BACKGROUND: Conditional financing (CF) of hospital drugs was implemented in the Netherlands as a form of managed entry agreements between 2006 and 2012. CF was a 4-year process comprising 3 stages: initial health technology assessment of the drug (T = 0), conduct of outcomes research studies, and reassessment of the drug (T = 4). OBJECTIVES: To analyze stakeholder experiences in implementing CF in practice. METHODS: Public and private stakeholders were approached for participation in stakeholder interviews through standardized email invitations. An interview guide was developed to guide discussions that covered the following topics: perceived aims of CF, functioning of CF, impact of CF, and conclusions and future perspectives. Extensive summaries were generated for each interview and subsequently used for directed content analysis. RESULTS: Thirty stakeholders were interviewed. Differences emerged among the stakeholders on the perceived aims of CF. Conversely, there was some agreement among stakeholders on the shortcomings in the functioning of CF, the positive impact of CF on the Dutch healthcare setting, and improvement points for CF. CONCLUSIONS: Despite stakeholders' belief that CF either did not meet its aims or only partially did so, there was agreement on the need for new policy to address the same aims of CF in the future. Nevertheless, stakeholders diverged on whether CF should be improved on the basis of learnings identified and reintroduced into practice or replaced with new policy schemes.

The Promising Viral Threat to Bacterial Resistance: the Uncertain Patentability of Phage Therapeutics and the Necessity of Alternative Incentives.

Bacteriophages, or "phages," are a category of highly adept and adaptable viruses that can infect and kill bacteria. With concerns over the burgeoning antibiotic-resistance crisis looming in recent years, scientists and policymakers have expressed a growing interest in developing novel treatments for bacterial infections that utilize bacteriophages. Because of the great expense associated with bringing a new drug to market, patents are usually considered the gold standard for incentivizing research and development in the pharmaceutical field. Absent such strong protection for a developer's front end investment, pharmaceutical development remains financially risky and unattractive. Unfortunately, recent Supreme Court jurisprudence analyzing patentable subject matter under 35 U.S.C. subsection 101 has cast doubt on whether phage therapeutics would be eligible for strong patent protection. In order for the promise of phage therapeutics to become a reality, alternative protections or incentives are likely necessary. Such a framework would likely include trade secrecy, regulatory exclusivities, research support, alternative payment models, or some combination thereof.

Time to Entry for New Cancer Medicines: From European Union-Wide Marketing Authorization to Patient Access in Belgium, Estonia, Scotland, and Sweden.

OBJECTIVES: First, to quantify the median time from European Union (EU)-wide approval to first use (launch) for a sample of cancer medicines and number of launches in Belgium, Estonia, Scotland, and Sweden as of June 2015. Second, to assess whether longer times to launch or lack of launches affected medicines with high or low expected additional clinical benefit. Third, to identify possible determinants of the probability of a cancer medicine to be launched. METHODS: Correlation between time to launch and a set of variables hypothesized to affect launch was tested using a complementary log-log model for a sample of 46 cancer medicines that obtained EU-wide marketing authorization between 2000 and 2014. RESULTS: In median, for a sample of 24 cancer medicines that obtained marketing authorization between 2010 and 2014, the expected time from EU-wide marketing authorization to first use of a medicine was shortest in Sweden, 3.1 months, followed by Scotland (9.3 months), Belgium (14.8 months), and Estonia (27.8 months). Median times to launch were longer for the entire sample of 46 cancer medicines that obtained marketing authorization between 2000 and 2014. In the all-country model, medicines with shorter times to submission for reimbursement, local manufacturers headquarter (or local sales representative), and a Food and Drugs Administration priority review or a combination of expedited approval programs and medicines launched in Scotland and Sweden were associated with a higher hazard of launch. Longer times since EU-wide approval initially correlate with an increased hazard but as time further elapses they negatively affect the hazard of launch. CONCLUSIONS: Median times from marketing authorization to first use of cancer medicines were shorter for medicines launched between 2010 and 2014 versus sample-wide (2000-2014). In Estonia, more medicines than in the other countries were not yet launched at the end of the observation period. There was no correlation between Prescrire and European School of Medical Oncology Magnitude of Clinical Benefit Scale ratings of added clinical value and time to launch.

Affordability Challenges to Value-Based Pricing: Mass Diseases, Orphan Diseases, and Cures.

OBJECTIVES: To analyze how value-based pricing (VBP), which grounds the price paid for pharmaceuticals in their value, can manage "affordability" challenges, defined as drugs that meet cost-effectiveness thresholds but are "unaffordable" within the short-run budget. METHODS: Three specific contexts are examined, drawing on recent experience. First, an effective new treatment for a chronic, progressive disease, such as hepatitis C, creates a budget spike that is transitory because initial prevalence is high, relative to current incidence. Second, "cures" that potentially provide lifetime benefits may claim abnormally high VBP prices, with high immediate budget impact potentially/partially offset by deferred cost savings. Third, although orphan drugs in principle target rare diseases, in aggregate they pose affordability concerns because of the growing number of orphan indications and increasingly high prices. RESULTS: For mass diseases, the transitory budget impact of treating the accumulated patient stock can be managed by stratified rollout that delays treatment of stable patients and prioritizes patients at high risk of deterioration. Delay spreads the budget impact and permits potential savings from launch of competing treatments. For cures, installment payments contingent on outcomes could align payment flows and appropriately shift risk to producers. This approach, however, entails high administrative and incentive costs, especially if applied across multiple payers in the United States. For orphan drugs, the available evidence on research and development trends and returns argues against the need for a higher VBP threshold to incentivize research and development in orphan drugs, given existing statutory benefits under orphan drug legislation.