An Overview of Cell and Gene Therapy Development in China.

China, the first country worldwide to approve a gene therapy in 2003, almost lost the advantage for a head start in cell and gene therapy (CGT) development due to a lack of clear and strict regulatory frameworks. The rapid advancements of CGTs' development worldwide as well as their therapeutic potential have triggered the government to conduct a spate of regulatory reforms to promote normative development of CGTs in China. Encouraged by policy support, the remarkable progress for CGTs in China has been observed over the past few years, thereby catapulting China back into the forefront of CGTs worldwide. This article aims to provide an overview of regulatory reforms, the current development landscape of CGTs, as well as key contributors and challenges for CGT development in China.

Gene Therapy Evidence Generation and Economic Analysis: Pragmatic Considerations to Facilitate Fit-for-Purpose Health Technology Assessment.

Gene therapies (GTs) are considered to be a paradigm-shifting class of treatments with the potential to treat previously incurable diseases or those with significant unmet treatment needs. However, considerable challenges remain in their health technology assessment (HTA), mainly stemming from the inability to perform robust clinical trials to convince decision-makers to pay the high prices for the potential long-term treatment benefits provided. This article aims to review the recommendations that have been published for evidence generation and economic analysis for GTs against the feasibility of their implementation within current HTA decision analysis frameworks. After reviewing the systematically identified literature, we found that questions remain on the appropriateness of GT evidence generation, considering that additional, broader values brought by GTs seem insufficiently incorporated within proposed analytic methods. In cases where innovative methods are proposed, HTA organizations remain highly conservative and resistant to change their reference case and decision analysis framework. Such resistances are largely attributed to the substantial evidence uncertainty, resource-consuming administration process, and the absence of consensus on the optimized methodology to balance all the advantages and potential pitfalls of GTs.

Challenges in the market access of regenerative medicines, and implications for manufacturers and decision-makers: a systematic review.

Aim: Regenerative medicines (RMs) are expected to transform the treatment paradigm of rare, life-threatening diseases, while substantial challenges impede its market access. This study aimed to present these challenges. Materials & methods: Publications identified in the Medline and Embase databases until December 2020 were included. Results: Uncertainties around the relative effectiveness and long-term benefits of RMs are most scrutinized. A new reference case for RMs is questionable, but examining impacts of study perspective, time horizon, discount rate and extrapolation methods on estimates is advised. Establishing reasonable prices of RMs requires increased transparency in the development costs and better values measurements. Outcome-based payments require considerable investments and potential legislative adjustments. Conclusion: Greater flexibility for health technology assessment and economic analyses of RMs is necessary. This comprehensive review may prompt more multi-stakeholder conversations to discuss the optimized strategy for value assessment, pricing and payment in order to accelerate the market access of RMs.

Plain language summary Regenerative medicines (RMs) potentially offered new hopes for severe diseases without effective treatments. However, substantial challenges must be overcome to make them available for patients. This systematic review aims to present these challenges. Publications identified in the Medline and Embase databases until December 2020 were included. The limited clinical evidence causes the biggest uncertainties around the relative effectiveness and long-term benefits of RMs. The current methodology for economic analysis of RMs is questionable because broader, societal values related to RMs are not sufficiently captured. The high price of RMs seems unjustified and should be lowered by balancing the development costs and values delivered. Outcome-based payments could be employed to address the long-term financial challenges, but they will require investments to implement it. More flexibility for health technology assessment and economic analysis of RMs is necessary to safeguard the accelerated patient access.

Partnership agreements for regenerative medicines: a database analysis and implications for future innovation.

Aim: Partnerships have been leveraged to advance the regenerative medicines (RMs) development. This study analyzed the evolution of partnership landscape for regenerative medicines (RMs). Methods: Partnership agreements publicly announced from January 2014 - June 2020 were described. Results: 1169 partnership agreements with total amount of US$63,496 million were identified. Most agreements concerned RMs that were for oncology (25.3%), in the discovery or preclinical phase (66.9%) and gene-based products (45.3%). The most common partnership type is collaborative agreements without licensing. The partnerships between 'biotechnology companies and not-for-profit organizations' represented the largest number (n = 416; 35.6%). 'Big Pharma' preferred collaboration and licensing agreements with a higher amount. Conclusion: Collaborations between highly specialized players with complementary expertise promote the successful translation of scientific discovery to RMs.

The impact of COVID-19 on the cell and gene therapies industry: Disruptions, opportunities, and future prospects.

Coronavirus 2019 (COVID-19) has caused significant disruption to the cell and gene therapy (CGT) industry, which has historically faced substantial complexities in supply of materials, and manufacturing and logistics processes. As decision-makers shifted their priorities to COVID-19-related issues, the challenges in market authorisation, and price and reimbursement of CGTs were amplified. Nevertheless, it is encouraging to see that some CGT developers are adapting their efforts toward the development of promising COVID-19-related therapeutics and vaccines. Manufacturing resilience, digitalisation, telemedicine, value-based pricing, and innovative payment mechanisms will be increasingly harnessed to ensure that market access of CGTs is not severely disrupted.

Reinforcing Collaboration and Harmonization to Unlock the Potentials of Advanced Therapy Medical Products: Future Efforts Are Awaited From Manufacturers and Decision-Makers.

Some advanced therapy medicinal products (ATMPs) hold great promises for life-threatening diseases with high unmet needs. However, ATMPs are also associated with significant challenges in market access, which necessitates the joint efforts between all relevant stakeholders to navigate. In this review, we will elaborate on the importance of collaborations and harmonization across different stakeholders, to expedite the market access of promising ATMPs. Manufacturers of ATMPs should proactively establish collaborations with other stakeholders throughout the whole lifecycle of ATMPs, from early research to post-market activities. This covered engagements with (1) external developers (i.e., not-for-profit organizations and commercial players) to obtain complementary knowledge, technology, or infrastructures, (2) patient groups and healthcare providers to highlight their roles as active contributors, and (3) decision-makers, such as regulators, health technology assessment (HTA) agencies, and payers, to communicate the uncertainties in evidence package, where parallel consultation will be a powerful strategy. Harmonization between decision-makers is desired at (1) regulatory level, in terms of strengthening the international standardization of regulatory framework to minimize discrepancies in evidence requirements for market authorization, and (2) HTA level, in terms of enhancing alignments between regional and national HTA agencies to narrow inequity in patient access, and cross-border HTA cooperation to improve the quality and efficiency of HTA process. In conclusion, manufacturers and decision-makers shared the common goals to safeguard timely patient access to ATMPs. Collaboration and harmonization will be increasingly leveraged to enable the value delivery of ATMPs to all stakeholders.

Allocating treatment resources for hepatitis C in the UK: a constrained optimization modelling approach.

Background and objective: Although the treatment of chronic hepatitis C (CHC) has significantly evolved with the introduction of direct-acting antivirals, the treatment uptake rates have been low especially among marginalized groups in the UK, such as people who inject drug (PWID) and men who have sex with men (MSM). Cutting health inequality is a major focus of healthcare agencies. This study aims to identify the optimal allocation of treatment budget for chronic hepatitis CHC among populations and treatments in the UK so that liver-related mortality in patients with CHC is minimized, given the constraint of treatment budget and equity issue. Methods: A constrained optimization modelling of resource allocation for the treatment of CHC was developed in Excel from the perspective of the UK National Health System over a lifetime horizon. The model was designated with the objective function of minimizing liver-related deaths by varying the decision variables, representing the number of patients receiving each treatment (elbasvir-grazoprevir, ombitasvir-paritaprevir-ritonavir-dasabuvir, sofosbuvir-ledipasvir, and pegylated interferon-ribavirin) in each population (the general population, PWID, and MSM). Two main constraints were formulated including treatment budget and the issue of equity. The model was populated with UK local data applying linear programming and underwent internal and external validation. Scenario analyses were performed to assess the robustness of model results. Results: Within the constraints of no additional funding over original spending in status quo and the consideration of the issue of equity among populations, the optimal allocation from the constrained optimization modelling (treating 13,122 PWID, 160 MSM, and 904 general patients with ombitasvir-paritaprevir-ritonavir-dasabuvir) was found to treat 2,430 more patients (relative change: 20.7%) and avert 78 liver-related deaths (relative change: 0.3%) compared with the current allocation. The number of patients receiving treatment increased 4,928 (relative change: 60.1%) among PWID and 42 (relative change: 35.8%) among MSM. Conclusion: The current allocation of treatment budget for CHC is not optimal in the UK. More patients would be treated, and more liver-related deaths would be avoided using a new allocation from a constrained optimization modelling without incurring additional spending and considering the issue of equity.

Chinese guidelines related to novel coronavirus pneumonia.

Background and Objective: China has managed to control the coronavirus disease (COVID-19) with confinement measurements and treatment strategies, while other countries are struggling to contain the spread. This study discusses the guidelines related to COVID-19 in China in order to provide important references for other countries in the fight against COVID-19. Methods: Chinese guidelines relevant to COVID-19 were systematically searched via the China National Knowledge Infrastructure database, YiMaiTong database, and World Health Organization (WHO) COVID-19 database on March 20th, 2020. Guideline information was extracted, including date of publication, source, objectives and the target population. Guidelines specific to the pharmacological treatment of COVID-19 were further investigated to identify the types of antivirus drugs recommended and to report on how treatment recommendations for COVID-19 have evolved overtime. Results: A total of 100 guidelines were identified, of which 74 were national guidelines and 26 were regional guidelines. The scope of included guidelines consisted of: the diagnosis and treatment of COVID-19, the management of hospital departments and specific diseases during the outbreak of COVID-19. Fifty-one of the included guidelines targeted overall COVID-19 patients, while the remaining guidelines concentrated on special patient populations (i.e. geriatric population, pediatric population, and pregnant population) or patients with coexisting diseases. Fifteen guidelines focused on the pharmacological treatments for all COVID-19 patients. Interferon, Lopinavir/Ritonavir, Ribavirin, Chloroquine, and Umifenovir represented the most recommended antivirus drugs. Among them, 7 Chinese guidelines have recommended Chloroquine Phosphate or Hydroxychloroquine for the treatment of COVID-19. Conclusions: China has generated a plethora of guidelines covering almost all aspects of COVID-19. Chloroquine, as one widely affordable treatment, was recommended by Chinese national guidelines and provincial guidelines. Considering the continuous debates around Chloroquine, confirmatory studies with robust methodology are awaited to address the unanswered questions on its potential benefits and risks on COVID-19.

A critical analysis and review of Lancet COVID-19 hydroxychloroquine study.

Purpose A international registry analysis led by Mehra et al. to investigate the use of hydroxychloroquine (HCQ) and chloroquine (CQ) with or without a macrolide in 96,032 hospitalised COVID-19 patients were published on Lancet, which has raised considerable discussions in the public health community. This study aimed to critically review the quality and limitations of the Mehra et al. publication and discuss the potential influences on the use of HCQ/CQ worldwide. Method A critical review of this publication was conducted to examine the potential study bias in the study objectives, methodology, confounding factors and outcomes and summarise the external reviews. Results The very high homogeneity of the patients' characteristics at baseline was inconsistent with region specific epidemiology and several critical confounding factors. The results indicated that angiotensin converting enzyme inhibitors were associated with a hazard ratio of 0.5, which suggested a technical problem in the estimation of the propensity scores. Several major risk factors for mortality identified in the analysis were treated as a minor risk or neutral or even protective factors. Antiviral treatments were recognised as an effective method to reduce mortality and were neither further studied nor integrated in the multivariate Cox model. Conclusion This research appeared to carry multiple biases. An extensive audit of the study, conditions of review and acceptance for publication in the Lancet of that study are requested to avoid damage to the publics' trust on the scientific community at this critical time of COVID-19 pandemic.