LEAKED DRAFT OFFERS PROMISES OF NEW SUPPORT FOR EUROPEAN CLINICAL TRIALS

A leaked draft of the health plans under consideration for the next stage of the European Union's Horizon research program gives some insight into what is likely to result later in the year in a formal invitation for proposals. Successful proposals are likely to be able to demonstrate the ability to sustain multi-country adaptive platform trials with adequate trial implementation capacity, laboratory analysis capacity, and a harmonized approach to the collection, storage, sharing, and analysis of data. Proposals should consider the coordination of adaptive platform trials addressing diverse trial target populations (such as primary care or hospitalized patients) as well as different possible medical countermeasures (including therapeutics and vaccines), within or across networks, which could include performance study plans for diagnostics, says the leaked draft.

NEW STRUCTURES TO TACKLE NEW CHALLENGES IN EUROPEAN HEALTHCARE

At the official level, the EU has already acknowledged the need for some closer alignment between its distinct but overlapping institutions, with the emergence of declarations of intent to create a European Health Union and promises of a radical review of EU rules on pharmaceuticals-all predating the arrival of COVID's additional impact of concentrating minds. [...]there is support within the European Parliament and the European Commission for more ambitious official EU engagement in health policy and a corresponding extension of EU competences into traditionally national government territory-although as a telling demonstration of the sort of divisions that dominate Europe, this is viewed by many of the member states in the EU's Council with extreme caution and has even provoked some downright resistance. According to its just-released manifesto, collaboration is needed between European policymakers, member states, and all other actors across the health community-and even more so in the wake of COVID.

IS COVID A GAMECHANGER FOR WIDER DRUG DEVELOPMENT POLICY?

[...]while the scientific panel notes with satisfaction that "research and innovation have been one of the few bright spots" in the COVID response, with "unprecedented advancements in record time," it laments the lack of a global strategy at the outset of the crisis "to optimize and coordinate research and development efforts." Countries need to have more capacities for data collection and analysis, including thorough genome sequencing for early detection, pathogen characterization, surveillance of pathogen spread, and assessment of disease dynamics. [...]the ideas are formally backed by G20 countries, heads of international and regional organizations, and representatives of global health bodies, after co-hosting by European Commission President Ursula von der Leyen and Italian Prime Minister Mario Draghi.

HERA, A MATRIACH'S DEVICE TO SAVE EUROPEANS FROM THE NEXT COVID

At the end likely to be of most interest to readers of ACT, it will "support the development of cross-cutting technologies and solutions sustaining multiple potential future threat responses (e.g. vaccine platform technologies, or the application of digital tools and artificial intelligence) as well as the development of specific countermeasures, including through clinical trials and data infrastructure." [...]in practical terms it will monitor and pool production capacity and development facilities, raw material requirements and availability, and ensure that supply chain vulnerabilities are addressed. [...]it is working towards the 'EU FAB' project, a network for single or multi-user, single or multi-technology emergency response production capacity for vaccine and medicine manufacturing at the European level. To accelerate approval of adapted vaccines, the incubator is exploring the introduction of emergency authorization of vaccines at EU level, providing guidance on data requirements, and supporting research to include children in clinical trials.

EUROPE'S ETERNAL STRUGGLE WITH SAFETY AND INNOVATION

Amid the heated COVID-driven controversies over vaccination that are ruffling Europe, a specialized European advisory group on ethics has just issued a cautious opinion on the use of gene editing-including a call for a global guarantee that heritable human genome editing is not prematurely clinically applied. The European Group on Ethics in Science and New Technologies (EGE) is tasked with advising the European Commission with "high quality, independent advice on all aspects of EU legislation and policies, where ethical, societal and fundamental rights issues intersect with the development of science and new technologies." With a view to promoting broad alignment, the group has asked the European Commission to engage in global discussions on regulation of this emerging field with the World Health Organization and the World Medical Association, covering universal adoption of standards on the ethical use of genome editing in human beings. [...]within Europe it wants to see the creation of a specifically European platform to exchange information and promote "a broad and open public debate" on the ethical and social implications of germline genome editing in human beings.

EUROPE SEEKING CLARITY IN ADVANCED TRIALS

EU officials acknowledge that the trial landscape in response to the pandemic has been fragmented, with a multitude of small, national trials, struggling to generate robust and actionable clinical data, with great duplication of efforts and direct competition for shared resources and participant populations. The European drug industry worked on complex clinical trials in 2020 with researchers in the European Organization for Research into Treatments for Cancer and specialists in the Association of Clinical Research Organizations, as well as with the European Union's Clinical Trial Expert Group, composed of national health ministry officials. [...]the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) is developing guidelines on Adaptive Clinical Trials with a timeline of 2023, and on Good Clinical Practice Renovation to address the increasing diversity of clinical trial designs and data sources.

EMA's COOKE REVIEWS EUROPEAN CANCER PROSPECTS

Late January saw Emer Cooke, the new executive director of the European Medicines Agency, fresh from a tough debate on vaccines in the European Parliament's health committee, switch her attention to cancer, with an appearance at another of the parliament's specialized committees. [...]she had some clear ideas on how this should be done, with a powerful emphasis on patient benefit as a priority. "To do this we need to leverage the resources for conducting high quality research in Europe." Better communication could also decrease time lags and differences of view between approval decisions by regulators and access decisions by health technology assessment bodies.

EMA: A CHANGE IN CHARACTER AS WELL AS POWERS?

[...]the latest development crosses a new frontier: "Pharma companies need to focus more on R&D for innovative medicines against infections," it tweeted in mid-November. "Pharma companies need to boost research and development." EHU, as a brand, has yet to achieve enthusiastic endorsement from member states, who are suspicious of a stealthy power grab.

MONEY AND GOODWILL, BUT WHAT HAPPENS NOW ON COVID THERAPIES?

The international pledging conference that the European Union hosted in May has surpassed its target of $8 billion, in cooperation with the United Nations, the World Health Organization (WHO), the International Labour Organization, the G20, the G7, the International Monetary Fund, and the World Bank. Many nations have rallied round the beleaguered World Health Organization (WHO) after Donald Trump announced he would withdraw U.S. funding for it. [...]the EU announced a coronavirus recovery plan in late May with a budget close to $2 trillion-which included a new €10 billion health program and additional projected spending on medicines to combat COVID-19.

HOW FAR WILL EUROPEAN DRUG INDUSTRY 'COMMITMENTS' ON COVID RESONATE?

According to Jean-Christophe Tellier, EFPIA president and CEO of UCB Pharma, the industry is "continuing to donate money and in-kind support to health systems, governments, and organizations on the ground, pulling out every stop to ensure the safe supply of medicines to the patients that need them," and "working around the clock to find new vaccines, diagnostics and treatments." Industry is expanding its manufacturing capabilities and sharing available capacity to ramp up production "once a successful medicine or vaccine is developed," and in the meantime, it is directly linking with regulatory authorities to provide information about stock, manufacturing capacity, and market tensions so as to head off potential disruptions or shortages. [...]the industry commitment most likely to strike a chord with many of the industry's inveterate critics, who have not ceased to push for patent limitations and price controls in a post-COVID world, is "working with governments and health systems to ensure that when new treatments and vaccines are approved they are available and affordable."

GERMANY'S HTA AGENCY SEEKS SUPPORT ON TRANSPARENCY ABOUT COVID-19 AGENTS

"EMA should support the international research community by publishing clinical study reports on medicine and vaccine trials at the time of marketing authorization and to inform treatment decisions." [...]Weiseler and Kaiser are acutely aware of the pressures that regulators are under in the face of a rising death toll, soaring infection and morbidity, and the wideranging economic and social consequences of extensive lock-downs. "Because of the severity of the current situation, regulators are aiming to accelerate the marketing authorization process," IQWiG comments, noting that first treatments have already been evaluated by regulators, as recently seen with the fast emergency use authorization of the antiviral remdesivir by the FDA, and that EMA has also started a "rolling review" of remdesivir. Data-sharing push The international research community is already undertaking coordinated efforts- IQWiG cites the living mapping and living systematic review of COVID-19 studies-to compile all emerging information on medicines and vaccines for the virus, it says, with a view to ensuring the optimal planning and conduct of research.

EUROPE'S COVID VACCINE BIDS STILL VEILED IN SECRECY

[...]just after the autumn equinox, Europe is still a long way from finding vaccines to fight back-as a hearing in the European Parliament on Sept. 23 confirmed. Members of European Parliament (MEPs) wanted to make sure that drug firms were not being given a blank check from public funds, while charging what they wanted for their products and dodging responsibility for any side effects. [...]she said, there are issues of competition that must be respected until all the contracts are complete. Since the European Commission has already indicated that prices will be in the range of €5 to €15 (about $6 to $18 USD) a dose, that is sufficient for the moment, she added, and "it is right" that the exact prices are not yet available.

EU REPORT

[...]in March it created the COVID-19 pandemic task force, to manage and coordinate discussions on relevant product development, authorization and surveillance, and to conduct post-authorization follow-up of relevant authorized products. In particular, it is helping to meet the new challenges of the current health threat in the complexity of the disease, the variety of potential or repurposed medicinal products for prophylaxis or treatment, and the need for rapid clinical trials across Europe. "EMA will be flexible and pragmatic during the assessment of affected clinical trial data submitted as part of marketing authorization applications", it adds, encouragingly.

EU PLANNING TO RESPOND EU PLANNING TO RESPOND SMARTER REGULATION BY 2025

The results should be greater leverage of non-clinical models and optimized capabilities in modeling, simulation, and extrapolation, as well as investment in initiatives for special populations, and the conduct of environmental risk assessments in line with the latest scientific knowledge. "Developments in basic science, in medicine, in information technology, and data analytics in particular, continue to pour forth at an astonishing rate," the agenda says, and the network "must have the capacity and knowledge to regulate new types of medicine, making them available to pa- tients with unmet needs while continuing to ensure that any risks are outweighed overall by the benefits." Inevitably, the experience of the pandemic will play into the planning-as will the EU's specific health plans announced in recent months, including its new "EU4Health" health program and the so-called "rescEU" program to build a strategic European reserve of critical medicines and to encourage production of active pharmaceutical ingredients in Europe.

EU MAKES MORE VACCINE DEALS AS QUESTIONS MOUNT OVER TERMS

The allegations from many health activists of drug industry profiteering from blank checks in emergency procurement programs has also been given a new twist by controversy over AstraZeneca's reported request for protection from liability in the event of late-discovered side effects of its vaccine. Thierry Vansweevelt, professor of medical law at the University of Antwerp, was quoted in Belgian media as calling the request "very exceptional" and even "slightly shocking," in light of existing EU regulations on companies' liability for what they put on the market. Yannis Natsis of the European Public Health Alliance, who is also a member of the management board of the European Medicines Agency (EMA), has accused companies of "pushing for unprecedented liability exemption for COVID-19 vaccines."

COVID-Related Changes Have Implications for Public Acceptance of Innovation

In Europe, deep concerns have been raised about the arrangements granting immunity from liability for the half-dozen manufacturers that have forged supply deals with the European Union for vaccines they have in development, and the still-confidential aspects of these deals leave many unresolved questions for the coming months and years. [...]a wider range of trained personnel will be authorized to administer COVID-19 or flu vaccines, with a view of ensuring that vaccines and treatments for specific types of public health threat, such as a COVID-19 vaccine, can be promoted as part of national vaccination or treatment campaigns. "The existing Human Medicines Regulations contain a provision (regulation 174) that enables the temporary authorization of the supply of an unlicensed medicine (including vaccines) in response to a public health emergency," it says.

Antibody and T cell responses to COVID-19 vaccination in patients receiving anticancer therapies.

BACKGROUND: Patients with cancer were excluded from phase 3 COVID-19 vaccine trials, and the immunogenicity and side effect profiles of these vaccines in this population is not well understood. Patients with cancer can be immunocompromised from chemotherapy, corticosteroids, or the cancer itself, which may affect cellular and/or humoral responses to vaccination. PD-1 is expressed on T effector cells, T follicular helper cells and B cells, leading us to hypothesize that anti-PD-1 immunotherapies may augment antibody or T cell generation after vaccination. METHODS: Antibodies to the SARS-CoV-2 receptor binding domain (RBD) and spike protein were assessed in patients with cancer (n=118) and healthy donors (HD, n=22) after 1, 2 or 3 mRNA vaccine doses. CD4+ and CD8+ T cell reactivity to wild-type (WT) or B.1.617.2 (delta) spike peptides was measured by intracellular cytokine staining. RESULTS: Oncology patients without prior COVID-19 infections receiving immunotherapy (n=36), chemotherapy (n=15), chemoimmunotherapy (n=6), endocrine or targeted therapies (n=6) and those not on active treatment (n=26) had similar RBD and Spike IgG antibody titers to HDs after two vaccinations. Contrary to our hypothesis, PD-1 blockade did not augment antibody titers or T cell responses. Patients receiving B-cell directed therapies (n=14) including anti-CD20 antibodies and multiple myeloma therapies had decreased antibody titers, and 9/14 of these patients were seronegative for RBD antibodies. No differences were observed in WT spike-reactive CD4+ and CD8+ T cell generation between treatment groups. 11/13 evaluable patients seronegative for RBD had a detectable WT spike-reactive CD4+ T cell response. T cells cross-reactive against the B.1.617.2 variant spike peptides were detected in 31/59 participants. Two patients with prior immune checkpoint inhibitor-related adrenal insufficiency had symptomatic hypoadrenalism after vaccination. CONCLUSIONS: COVID-19 vaccinations are safe and immunogenic in patients with solid tumors, who developed similar antibody and T cell responses compared with HDs. Patients on B-cell directed therapies may fail to generate RBD antibodies after vaccination and should be considered for prophylactic antibody treatments. Many seronegative patients do develop a T cell response, which may have an anti-viral effect. Patients with pre-existing adrenal insufficiency may need to take stress dose steroids during vaccination to avoid adrenal crisis.

The Contribution of Pharmacogenetic Drug Interactions to 90-Day Hospital Readmissions: Preliminary Results from a Real-World Healthcare System.

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines exist for many medications commonly prescribed prior to hospital discharge, yet there are limited data regarding the contribution of gene-x-drug interactions to hospital readmissions. The present study evaluated the relationship between prescription of CPIC medications prescribed within 30 days of hospital admission and 90-day hospital readmission from 2010 to 2020 in a study population (N = 10,104) who underwent sequencing with a 14-gene pharmacogenetic panel. The presence of at least one pharmacogenetic indicator for a medication prescribed within 30 days of hospital admission was considered a gene-x-drug interaction. Multivariable logistic regression analyzed the association between one or more gene-x-drug interactions with 90-day readmission. There were 2211/2354 (93.9%) admitted patients who were prescribed at least one CPIC medication. Univariate analyses indicated that the presence of at least one identified gene-x-drug interaction increased the risk of 90-day readmission by more than 40% (OR = 1.42, 95% confidence interval (CI) 1.09-1.84) (p = 0.01). A multivariable model adjusting for age, race, sex, employment status, body mass index, and medical conditions slightly attenuated the effect (OR = 1.32, 95% CI 1.02-1.73) (p = 0.04). Our results suggest that the presence of one or more CPIC gene-x-drug interactions increases the risk of 90-day hospital readmission, even after adjustment for demographic and clinical risk factors.

EUROPE SEEKING CLARITY IN ADVANCED TRIALS

The article reports that European Union (EU)'s strategy for tackling health risks, is to work with the European Medicines Agency to create a long-term and large-scale EU platform for multi-center clinical trials and corresponding data platforms. It mentions that 'European Health Emergency preparedness and Response Authority' will incentivize advanced research, innovation and development of relevant technologies and countermeasures–including diagnostics, therapeutics, and vaccines.