Sources of innovation for new medicines: questions of sustainability.

The biopharmaceutical industry has undergone remarkable changes over the past half century, driven largely by a need to offset the ever-rising costs of developing new medicines. In this report, we aggregated information about the creation and fate of all clinical-stage biopharmaceutical companies, assessing trends over time. These results reveal that the rate of new company formation has been declining at the same time that industry consolidation has been accelerating at an unprecedented rate. Consequently, the number of companies involved in biopharmaceutical research and development has declined by one-third over the past decade, while those able to achieve at least one FDA approval has dropped by more than half. These findings raise important questions about the sustainability of an industry that is vital for both public and economic health.

Achieving equal and timely access to innovative anticancer drugs in the European Union (EU): summary of a multidisciplinary CECOG-driven roundtable discussion with a focus on Eastern and South-Eastern EU countries.

The Central European Cooperative Oncology Group (CECOG) and 'ESMO Open-Cancer Horizons' roundtable discussion brought together stakeholders from several European Union (EU) countries involved in drug development, drug authorisation and reimbursement or otherwise affected by delayed and unequal access to innovative anticancer drugs. The approval process of drugs is well established and access delays can be caused directly or indirectly by national or regional decision-making processes on reimbursement. The two key aspects for those involved in reimbursement decisions are first the level of evidence required to decide and second pricing, which can be challenging for some innovative oncology compounds, especially in Eastern and South-Eastern European countries. Other important factors include: available healthcare budget; the structure and sophistication of healthcare authorities and health technology assessment processes; societal context and political will. From the point of view of the pharmaceutical industry, better alignment between stakeholders in the process and adaptive pathway initiatives is desirable. Key aspects for patients are improved access to clinical trials, preapproval availability and reports on real-world evidence. Restricted access limits oncologists' daily work in Eastern and South-Eastern EU countries. The roundtable discussion suggested considering the sequencing of regulatory approval and reimbursement decisions together with more flexible contracting as a possible way forward. The panel concluded that early and regular dialogue between all stakeholders including regulators, payers, patient stakeholders and industry is required to improve the situation.

Fight Against Antimicrobial Resistance: We Always Need New Antibacterials but for Right Bacteria.

Antimicrobial resistance in bacteria is frightening, especially resistance in Gram-negative Bacteria (GNB). In 2017, the World Health Organization (WHO) published a list of 12 bacteria that represent a threat to human health, and among these, a majority of GNB. Antibiotic resistance is a complex and relatively old phenomenon that is the consequence of several factors. The first factor is the vertiginous drop in research and development of new antibacterials. In fact, many companies simply stop this R&D activity. The finding is simple: there are enough antibiotics to treat the different types of infection that clinicians face. The second factor is the appearance and spread of resistant or even multidrug-resistant bacteria. For a long time, this situation remained rather confidential, almost anecdotal. It was not until the end of the 1980s that awareness emerged. It was the time of Vancomycin-Resistance Enterococci (VRE), and the threat of Vancomycin-Resistant MRSA (Methicillin-Resistant Staphylococcus aureus). After this, there has been renewed interest but only in anti-Gram positive antibacterials. Today, the threat is GNB, and we have no new molecules with innovative mechanism of action to fight effectively against these bugs. However, the war against antimicrobial resistance is not lost. We must continue the fight, which requires a better knowledge of the mechanisms of action of anti-infectious agents and concomitantly the mechanisms of resistance of infectious agents.

The Impact Of Price Regulation On The Availability Of New Drugs In Germany.

The 2011 German Pharmaceutical Market Restructuring Act subjected brand-name drugs for nonrare diseases to price regulation based on an assessment of their clinical benefit. Indication-specific assessment outcomes range from major added benefit to less benefit than the appropriate comparator(s) and affect price negotiations beyond the first year on the market. Using data on drugs that entered the market in the period 2012-16, we evaluated benefit assessment findings, subsequent drug exits, and their correlates. We considered 171 drug-indication pairs, corresponding to 138 different drugs. Of these, 66 drug-indication pairs (55 different drugs) were found to have added benefit. Almost all drugs with a positive benefit assessment (98 percent) remained on the market, while drugs without a positive benefit assessment were over ten times more likely to exit (25 percent versus 2 percent). US policy makers considering how to address rapidly increasing drug costs may draw valuable lessons from the German experience.

Patterns of alternative access: Unpacking the Slovak extraordinary drug reimbursement regime 2012-2016.

Many countries employ "alternative access schemes" (e.g. compassionate use, early access programs, off-label use) that seek to provide patients with access to drugs not included on a positive drug list. These schemes offer flexibility to policy-makers but often lack transparency and clear rules. This ambiguity allows for dynamic responses to weaknesses in the main drug approval and reimbursement systems, but also opportunistic use by the health professionals, industry or patients. Yet, most descriptions of these schemes focus on the de jure rather than the de facto situation, presenting a potentially misleading picture. We describe one such scheme in practice: the Slovak "extraordinary reimbursement regime" (ERR), using semi-structured interviews with 18 experts and a new dataset of ERR drugs. The ERR expanded rapidly, doubling between 2012 and 2016. It combined features of four reimbursement schemes: (1) a backdoor market access for expensive drugs; (2) a compassionate use scheme for investigational drugs combined with a "legacy drugs" scheme for older unlicensed drugs; (3) a disease-specific scheme for cancer and orphan drugs; and (4) a scheme for off-label and "off-indication" drugs. These four features reflect broader challenges facing the Slovak reimbursement system. We conclude that detailed study of the type, size and evolution over time of alternative access schemes can serve as indicators of health policy objectives neglected by standard reimbursement systems.

Retrospective pharmaceutical financial benefits and cost avoidance analysis of clinical trial participation in the Australian haematology setting.

BACKGROUND: Clinical trial participants receiving investigational new drugs, which subsequently become approved by a medicines regulatory authority for its trialled indication, effectively gain free early access to efficacious treatment. Participants may also benefit from receiving approved, but unsubsidised medicines. These financial benefits of clinical trial participation have not previously been defined or quantified. Additionally, there are limited Australian pharmaceutical cost avoidance studies quantifying government savings through sponsored clinical trials. AIMS: To calculate pharmaceutical financial benefits and cost avoidance of clinical trial participation at a single Clinical Research Unit. METHODS: Recruiting clinical trials between 1 January 2006 and 31 December 2017 conducted at the Haematology Clinical Research Unit, Concord Repatriation General Hospital, Sydney were reviewed. Dispensing records were used to quantitate the pharmaceuticals dispensed to every participant. Financial calculations were based on Pharmaceutical Benefits Scheme (PBS) pricing, or from UpToDate for non-PBS listed agents. RESULTS: Thirty-six eligible clinical trials involving 245 participants accrued AU$3 971 357 in financial benefit from early access to subsequently approved investigational new drugs, AU$12 209 538 in financial benefit from accessing approved medications not PBS listed, and AU$6 728 576 in government cost avoidance. These findings totalled AU$22 909 471, 89% of which was derived in the past 5 years. CONCLUSION: Pharmaceutical financial benefit is a previously unquantified aspect of clinical trial participation, its assigned value reflecting a measure of the quality and quantity of life delivered to patients. These data, albeit from a single discipline and institution, suggest that financial benefit represents a greater value than cost avoidance, and that its inclusion in cost-analyses may better reflect the monetary benefits of accessing efficacious pharmaceutical agents through clinical trials.

Access to innovative medicines for metastatic melanoma worldwide: Melanoma World Society and European Association of Dermato-oncology survey in 34 countries.

According to data from recent studies from Europe, a large percentage of patients have restricted access to innovative medicines for metastatic melanoma. Melanoma World Society and European Association of Dermato-oncology conducted a Web-based survey on access to first-line recommended treatments for metastatic melanoma by current guidelines (National Comprehensive Center Network, European Society for Medical Oncology [ESMO] and European Organization for Research and Treatment of Cancer/European Association of Dermato-oncology/European dermatology Forum) among melanoma experts from 27 European countries, USA, China, Australia, Argentina, Brazil, Chile and Mexico from September 1st, 2017 to July 1st, 2018. Data on licencing and reimbursement of medicines and the number of patient treated were correlated with the data on health expenditure per capita (HEPC), Mackenbach score of health policy performance, health technology assessment (HTA), ASCO and ESMO Magnitude of clinical benefit scale (ESMO MCBS) scores of clinical benefit and market price of medicines. Regression analysis for evaluation of correlation between the parameters was carried out using SPSS software. The estimated number of patients without access in surveyed countries was 13768. The recommended BRAFi + MEKi combination and anti-PD1 immunotherapy were fully reimbursed/covered in 19 of 34 (55.8%) and 17 of 34 (50%) countries, and combination anti-CTLA4+anti-PD1 in was fully covered in 6 of 34 (17.6%) countries. Median delay in reimbursement was 991 days, and it was in significant correlation with ESMO MCBS (p = 0.02), median market price (p = 0.001), HEPC and Mackenbach scores (p < 0.01). Price negotiations or managed entry agreements (MEAs) with national authorities were necessary for reimbursement. In conclusion, great discrepancy exists in metastatic melanoma treatment globally. Access to innovative medicines is in correlation with economic parameters as well as with healthcare system performance parameters. Patient-oriented drug development, market access and reimbursement pathways must be urgently found.

An ethical framework for the creation, governance and evaluation of accelerated access programs.

There are increasing demands on regulators and insurers internationally to provide access to medicines more quickly, and often on the basis of less robust evidence of safety, efficacy or cost-effectiveness than have traditionally been required. These demands arise from a number of sources, including those advocating for access to medicines for patients with life-threatening diseases, rare diseases, or subsets of common diseases and where entire populations are threatened in the context of public health emergencies. In response to these demands, policymakers have instituted a number of initiatives aimed at speeding up access to medicines, which we refer to collectively as "accelerated access" programs. While there are strong arguments for accelerated access programs, these programs also raise a number of socio-political, epistemic and moral issues. Some of these issues are common to all types of accelerated access programs, while others are specific to particular types of accelerated access. Here, we offer a conceptual framework that highlights ethically relevant similarities and differences among different kinds of accelerated access processes for the purpose of enabling ethically and politically-informed policy making.

Little to lose and no other options: Ethical issues in efforts to facilitate expanded access to investigational drugs.

BACKGROUND: Today, public and private bodies around the world are trying to facilitate and increase expanded access to unapproved, investigational drugs for patients with unmet medical needs. METHODS: This paper discusses three major shifts in the field of expanded access and presents an argumentative account of ethical issues connected with those shifts, based on a literature study and unstructured interviews with 35 stakeholders in the Netherlands. RESULTS AND DISCUSSION: Traditionally, expanded access has been based on three key principles: 1) it is exceptional, 2) it is done 'out of compassion', and 3) it has a therapeutic aim. Current efforts to facilitate expanded access affect these key principles, rendering expanded access a default option, allowing companies to charge for investigational drugs and gather data on its outcomes. These shifts may generate new ethical issues, including false hope, safety concerns and funding issues, which must be anticipated by physicians, pharmaceutical companies, payers and policymakers. CONCLUSION: Healthcare systems allow for the use of promising unapproved drugs in exceptional circumstances, but do not always assist patients with unmet medical needs in getting access. It is time to replace the current patchwork of practices with systems for expanded access in which criteria are clearly described, responsibilities are assigned and arrangements are made, so that patients will know what (not) to expect from expanded access.

[Why are new drugs so expensive?] / Pourquoi les nouveaux médicaments sont-ils si chers ?

Putting an end to an innovation crisis, the reality of which is the subject of debate, recent pharmaceutical innovations, the result of a combination of scientific, industrial, financial, political and economic reasons, lead to a diversification of products and to a strong interest of pharmaceutical companies for the so-called "niche" products (targeted therapies, rare diseases, etc.). These new molecules are put on the market at much higher prices than in the past. In the absence of reliable information on the costs borne by manufacturers, and knowing that high levels of margins have been observed, these prices raise legitimate questions. These are also motivated by the lack of relationship between the price and the therapeutic benefit of these new molecules. In France, faced with levels of expenditure likely to weaken the financial sustainability of the social protection system, the public authorities have so far always favored interventions on prices or the conditions and volume of reimbursement, in accordance with the existing regulation. Other regulations (use of the statutory license, group purchase, etc.) could in the future be used in a growing concern for the efficiency of public expenditure. The difficulties encountered in regulating a deeply transformed industrial sector call for a reform of national evaluation and regulation systems.

Preclinical efficacy studies in investigator brochures: Do they enable risk-benefit assessment?

Human protection policies require favorable risk-benefit judgments prior to launch of clinical trials. For phase I and II trials, evidence for such judgment often stems from preclinical efficacy studies (PCESs). We undertook a systematic investigation of application materials (investigator brochures [IBs]) presented for ethics review for phase I and II trials to assess the content and properties of PCESs contained in them. Using a sample of 109 IBs most recently approved at 3 institutional review boards based at German Medical Faculties between the years 2010-2016, we identified 708 unique PCESs. We then rated all identified PCESs for their reporting on study elements that help to address validity threats, whether they referenced published reports, and the direction of their results. Altogether, the 109 IBs reported on 708 PCESs. Less than 5% of all PCESs described elements essential for reducing validity threats such as randomization, sample size calculation, and blinded outcome assessment. For most PCESs (89%), no reference to a published report was provided. Only 6% of all PCESs reported an outcome demonstrating no effect. For the majority of IBs (82%), all PCESs were described as reporting positive findings. Our results show that most IBs for phase I/II studies did not allow evaluators to systematically appraise the strength of the supporting preclinical findings. The very rare reporting of PCESs that demonstrated no effect raises concerns about potential design or reporting biases. Poor PCES design and reporting thwart risk-benefit evaluation during ethical review of phase I/II studies.

Paying for Cures: Perspectives on Solutions to the "Affordability Issue".

Curative therapies and other medicines considered "game-changing" in terms of health gain can be accompanied by high demand and high list prices that pose budget challenges to public and private payers and health systems-the so-called affordability issue. These challenges are exacerbated when longer term effectiveness, and thus value for money, is uncertain, but they can arise even when treatments are proven to be highly cost-effective at the time of launch. This commentary reviews innovative payment solutions proposed in the literature to address the affordability issue, including the use of credit markets and of staged payments linked to patient outcomes, and draws on discussions with payers in the United States and Europe on the feasibility or desirability of operationalizing any of the alternative financing and payment strategies that appear in the literature. This included a small number of semistructured interviews. We conclude that there is a mismatch between the enthusiasm in the academic literature for developing new approaches and the scepticism of payers that they can work or are necessary. For the foreseeable future, affordability pressures will continue to be handled by aggressive price bargaining, high co-pays (in systems in which this is possible), and restricting access to subgroups of patients. Of the mechanisms we explored, outcomes-based payments were of most interest to payers, but the costs associated with operating such schemes, together with implementation challenges, did not make them an attractive option for managing affordability.

Access to benznidazole for Chagas disease in the United States-Cautious optimism?

Drugs for neglected tropical diseases (NTD) are being excessively priced in the United States. Benznidazole, the first-line drug for Chagas disease, may become approved by the Food and Drug Administration (FDA) and manufactured by a private company in the US, thus placing it at risk of similar pricing. Chagas disease is an NTD caused by Trypanosoma cruzi; it is endemic to Latin America, infecting 8 million individuals. Human migration has changed the epidemiology causing nonendemic countries to face increased challenges in diagnosing and managing patients with Chagas disease. Only 2 drugs exist with proven efficacy: benznidazole and nifurtimox. Benznidazole has historically faced supply problems and drug shortages, limiting accessibility. In the US, it is currently only available under an investigational new drug (IND) protocol from the CDC and is provided free of charge to patients. However, 2 companies have stated that they intend to submit a New Drug Application (NDA) for FDA approval. Based on recent history of companies acquiring licensing rights for NTD drugs in the US with limited availability, it is likely that benznidazole will become excessively priced by the manufacturer-paradoxically making it less accessible. However, if the companies can be taken at their word, there may be reason for optimism.

Notable deals in the pharmaceutical industry in the fourth quarter of 2016.

During the fourth quarter of 2016, Cortellis Competitive Intelligence had 889 new deals added as part of its ongoing coverage of pharmaceutical licensing activity. This was an increase on both the last quarter (865) but a decrease from the same quarter for the previous year (915). This article will focus on highlighting a number of the most valuable and notable deals forged during the quarter, as well as a selection of deals from some of the most prolific deal makers. An update on milestones, options and terminated deals of significance will also be presented, along with an early outlook on the next quarter's pharmaceutical licensing activity.

The year's new drugs & biologics 2016: Part II - Trends and highlights of an unforgettable year.

This eagle's-eye overview of the drug industry in 2016 provides insight into some of last year's top stories, including disease outbreaks that drove R&D, orphan drug development, pipeline attrition, drug pricing, and the ongoing movement in M&A. We also consider recent political events in the U.S. and U.K. and their potential impact on the industry in the years to come, and take a glimpse into the crystal ball to anticipate the new drugs that may be approved in 2017.

How excluding some benefits from value assessment of new drugs impacts innovation.

Payers often assess the benefits of new drugs relative to costs for reimbursement purposes, but they frequently exclude some drugs' option-related benefits, reducing their reimbursement chances, and making them less attractive R&D investments. We develop and test a real options model of R&D investment that shows that excluding option-related benefits heightens drug developers' incentives to avoid high-risk (volatile) R&D investments and instead encourages them to focus on "safer" (positively skewed) investments. Our model and empirical results could partly explain the decline in the number of risky new molecular entities.

The antibiotic pipeline: reviving research and development and speeding drugs to market.

INTRODUCTION: The combination of growing antimicrobial resistance with a dry pipeline has resulted in infections that can no longer be treated. Specific reasons have led to companies' exit from the antibacterial space, however recent incentives are spurring interest to reinvigorate the pipeline. Areas covered: This article summarizes the available information on the discovery, developmental, and regulatory challenges in antibacterial development that have led to disinterest in the space, as well as ongoing incentives such as public-private partnerships and streamlined pathways to mend these challenges and bring new antibiotics to patients in need. Expert commentary: Clinicians should not only understand the reasons for the decline in antibiotic development that have resulted in the dry pipeline, but also the ongoing initiatives in place to build an appropriate supply. Doing so will result in greater appreciation and prudent use of these life-saving drugs when they become available.