Authors (including presenting author) :
Qiu C(1), Lin K(1), Chen J(1)
Affiliation :
(1)Roche Hong Kong and Macau
Introduction :
Innovative study designs are constantly emerging to investigate the effect of clinical and public health interventions. These designs allow studies to be conducted more adaptively and efficiently, but still aim to produce rigorous and insightful results. The Chief Executive’s 2021 Policy Address positions Hong Kong to have world-class research capability and an outstanding public health system. Adoption and acceptance of innovative study designs in research and healthcare decision making may contribute to this ambitious vision, and put Hong Kong on par with international standards and medical advancement.
We focus this review on several innovative study designs. For clinical interventions, we focus on adaptive trial designs (or “master protocol”, including basket trials, umbrella trials, and platform trials), real-world studies (specifically, using real-world data as an external control arm). For healthcare operations and public health interventions, we focus on dynamic simulation (system dynamics and agent-based modeling). Basket trials refer to designs in which a targeted therapy is evaluated on multiple diseases that have common molecular alterations. Umbrella trials, on the other hand, evaluate multiple targeted therapies for a single disease that is stratified into subgroups by molecular alteration. An externally controlled trial compares a group of subjects receiving the test treatment with a group of patients external to the study, rather than to an internal control group consisting of patients from the same population assigned to a different treatment. The trend in the last decade is to construct an external control using real-world data. Dynamic simulations are computer modeling methods that could take the complex dynamics of a system into consideration.
In clinical medicine, adaptive trial designs and real-world evidence have accelerated clinical investigations and supported drug registration around the world, especially for uncommon disorders. In public health, there is emerging evidence globally that system thinking (empowered by dynamic simulation) could lead to better planning, monitoring and evaluation of public health interventions.
Objectives :
The first objective is to understand the adoption of innovative study designs in Hong Kong’s academic community. The second objective is to understand the acceptance of such study designs in the decision making of Hong Kong’s public health system, including in Hospital Authority drug enlistment and in public health policies.
Methodology :
TrialTrove, ClinicalTrials.gov, European Union Clinical Trial Register, Hong Kong University Clinical Trial Register were searched for adaptive trials that have any connection to Hong Kong. PubMed was searched using relevant keywords, plus author or site affiliations in Hong Kong for peer-reviewed papers. The reference lists (2019-2020) from Hospital Authority Drug Advisory Committee (DAC) meetings were obtained from DAC’s website, and all references were screened. The decision (approve, pending or reject) for an application was also obtained if an innovative study design was identified. Public policy documents on public-private partnership (PPP), healthcare vouchers, viral hepatitis action plan, voluntary health insurance scheme (VHIS) and COVID-19 were obtained from government websites, and their citations were analyzed. Basic descriptive analysis was used to summarize the findings.
Result & Outcome :
(i) Hong Kong contributed to 11 adaptive clinical trials. Four are basket trials, six are platform trials, and one is an umbrella trial. Ten trials are in the field of oncology, and one about chronic hepatitis B. Hong Kong’s participation is limited to only two leading teaching hospitals that join as study sites. There is no Hong Kong-initiated adaptive clinical trial. (ii) In the academic literature, we found no study from Hong Kong that uses real-world data as an external control arm. (iii) In the reference lists of submissions to DAC meetings, there are six cases of innovative study designs. Two out of six submissions contained external control arm studies. One (blinatumomab) of them got approved while the other (Daratumumab) was pending. One (abiraterone) out of six submissions contained a platform trial and was approved. Three submissions contained basket trials. Two (entretinib and larotrectinib) of them were rejected for “insufficient evidence to demonstrate significant clinical outcome benefits”, and one (abemaciclib) was approved for only one disease but not the other diseases in the basket. (iv) In terms of dynamic simulation, we found one system dynamics study on the Hong Kong health care voucher scheme. We also found six agent-based modeling studies, all on infectious disease modeling in Hong Kong. Four of these are about COVID-19. (v) No public policy document contains references to local or foreign dynamic simulation studies.
Outcome
The research community has started to adopt some of the innovative study designs, although the topic scope and participation scale are limited. We recommend the government and Hospital Authority encourage and support more sites to participate in a more diverse range of trials. We also recommend exploring how to leverage the data infrastructure of Hong Kong and the Greater Bay Area to conduct rigorous real-world studies that compare local with external cohorts, and could have direct impact on healthcare decision making. Due to the small number of submissions to DAC, it is too early to conclude the acceptance of these study designs among DAC members. However, there might be some concerns over the validity of basket trials, and we recommend an open multi-stakeholder discussion about it. Lastly, we recommend interactive workshops with senior healthcare executives on how to better utilize dynamic simulations to support their decision making.
