The Future of Drug Development Is Informed by Patient Data – Observations from China Releasing Its First Patient-Reported Outcomes (PROs) Guidance
Written by Sophie (Jui-Hua) Tsai & Na Guo
How can companies prepare themselves for a future where the market is patient-driven and regulatory agencies use patient data as evidence to inform their decisions?
Throughout the years, various regulatory guidance documents have appeared worldwide, highlighting the importance of patient data and recommending the use of methods to capture patients’ perspectives in clinical trials, such as the inclusion of patient-reported outcomes (PROs) as trial endpoints for drug development. In December 2021, China’s Center for Drug Evaluation (CDE) issued the first patient-reported outcomes (PRO) guidance in China: “Guidance for Applying Patient-reported Outcomes (PROs) in Clinical Research for Drug Development (Interim).”
In this article, we will be discussing:
- What are the changes to China’s regulatory environment for drug approvals?
- What are PROs and what are their roles in drug development?
- What does the China PRO guidance cover?
- How does China’s guidance on PRO use compare with PRO guidance from other global regulatory agencies, such as the FDA and EMA?
- What are the challenges and barriers to integrating PROs in clinical trials in China?
- What are the strategies and opportunities for firms interested in understanding and/or integrating PROs in clinical trials in the China market?
The Changing Regulatory Landscape of China’s Pharmaceutical Market
The pharmaceutical market in China has evolved significantly over the past decade. Since joining the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) in 2017, China has taken on a more integral role in global drug development and seeks to align itself with international guidelines. This includes harmonization with developed regulatory agencies and ICH members, such as the Food and Drug Administration (FDA) in the United States (US) and the European Medicines Agency (EMA) in Europe. In December 2021, China’s Center for Drug Evaluation (CDE), governed by China’s National Medical Products Administration (NMPA), issued its first patient-reported outcomes (PRO) guidance: “Guidance for Applying Patient-reported Outcomes (PROs) in Clinical Research for Drug Development (Interim).” Along with the first PRO guidance, the NMPA released multiple clinical development draft guidelines (e.g., oncology, rare disease), emphasizing clinical value and patient-focused drug development and encouraging the use, design, and development of PRO tools in the early stage of drug development to understand and accommodate patients’ needs.
PROs and Their Role in Drug Development
According to the FDA, “A PRO is any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.” Traditionally, clinical endpoints such as laboratory test results, overall survival, progression-free survival, and adverse events have been considered important and meaningful outcomes that help in evaluating drugs’ efficacy and safety and in guiding clinical and policy decision-making. PROs provide information on those aspects of health, condition, and treatment that are known only to those suffering from the condition, such as symptoms, feelings, and impact on daily life. It has been broadly agreed upon that PROs have the potential to enhance drug development and guide clinical, regulatory, and coverage decision-making.
Content Covered in the China PRO Guidance
The China PRO guidance is a 33-page document written in Mandarin Chinese. It intends to provide guidance for the appropriate use of PRO data in drug development research, applicable to clinical trials and real-world studies. It covers the following key areas:
- Definition of PROs
- Development, translation, modifications of PROs
- Selection and evaluation of PROs
- Considerations of implementing PROs in clinical trials
- Quality control of PRO data collection
- PRO data analysis and interpretation
- Considerations of using electronic PRO (ePRO) instruments
- Communications with regulatory agencies
Overall, the guidance acknowledges the increasing importance of capturing patients’ experience, perception, and needs and integrating these data into drug development and evaluation. It demonstrates that PROs can reflect patients’ experiences and are an integral part of patient-focused drug development initiatives.
A Comparison of PRO Guidance Documents Issued by Global Regulatory Agencies
Since the first guidance documents released by the EMA in 2005 to the guidance issued in early 2022 by the FDA, global regulatory agencies have been recommending the integration of PRO endpoints in clinical trials and highlighting the role of PRO data in informing regulatory decision-making. These guidance documents are evidence of the importance of patient-focused drug development perceived by regulatory agencies around the world.
Table 1 below showcases key PRO guidance documents issued by the FDA, EMA, and NMPA throughout the years.
Abbreviations: COA, Clinical Outcome Assessment; CBER, Center for Biologics Evaluation and Research; CDE, Center for Drug Evaluation; CDER, Center for Drug Evaluation and Research; CDRH, Center for Devices and Radiological Health; CHMP, Committee for Medicinal Products for Human Use; HRQL, health-related quality of life; HRQoL, health-related quality of life; OCE, Oncology Center of Excellence; PRO, patient-reported outcome
Challenges of Integrating PROs as Endpoints in Clinical Trial Designs in China
Despite the excitement of NMPA/CDE releasing its first PRO guidance, several barriers and challenges exist for the integration of PROs in clinical trial designs in China. This includes language and context barriers, low recognition of PRO instruments, and lack of expertise and resources
Language and Context Barriers
- Most PRO instruments were originally developed in Western countries. - Chinese versions are not always available. Often, the translated versions are not well adapted to local situations, leading to misunderstandings, potential bias in data collection, and risk of incorrect data imputation. - PRO instruments developed in Western countries require further validation work among the Chinese population.
Low Recognition of PROs as Study Endpoints
- Studies in China tend not to include PROs in clinical trial and real-world study designs due to a lower recognition of PROs compared with traditional clinical outcome endpoints. - Even when the PROs are included, they tend to incur a higher rate of missing data due to their low recognition.
- The value of PRO data is not yet fully recognized and accepted among certain stakeholders (e.g., healthcare providers).
Limited Expertise and Resource
- Local clinical operation teams often lack the experience of including PROs as study endpoints, especially when it comes to using ePROs to collect patient data.
- ePROs require resources to set up. There is a dearth of international ePRO vendors offering quality and timely services in China, while local ePRO service providers are still in their early stages of development.
- Global firms can be hesitant to conduct research studies in China due to their unfamiliarity with the research and political environment in China; expertise is required to navigate the local ethics committee submission and/or meet the requirements of the Human Genetic Resources Administration of China [HGRAC] regulations.
Looking Ahead – Recommended Strategies Moving Forward
Establish Strategic Partnerships
- Collaborate with experienced research partners to implement patient insights throughout the drug development process. - OPEN Health experts have a strong local presence (e.g., a China regional office) and are experienced in PRO methods, including the selection and/or development of appropriate PRO measures, the generation of PRO evidence for regulatory submissions, and the navigation of subsequent regulatory communications.
- Consider a strategic alliance with local academic centers to develop and/or modify PRO instruments for fit-for-purpose in China.
Initiate Planning Early in the Drug Development Life Cycle
- Companies interested in exploring PROs as endpoints should consider consulting PRO experts early in the planning phase.
- One of the benefits of planning early is that companies can include PROs as exploratory endpoints in phase II trials to further inform the use of PROs as primary or secondary endpoints in phase III studies.
- OPEN Health experts can assist with developing an effective PRO strategy for the drug development life cycle and provide guidance on implementation.
Active Communication with Regulatory Authorities
- The China PRO guidance outlined standards for communicating with the local regulatory authorities. Companies should consider establishing proper communication channels (both formal and informal channels) with local regulatory authorities to ensure the PRO evidence generated meets the requirements of regulatory evidence submission.
Sophie (Jui-Hua) Tsai is a Senior Scientist in the Global Patient-Centered Outcomes and Patient Engagement and Real-World Evidence & Data Analytics Centers of Excellence. Sophie is an experienced qualitative researcher with a clinical background. She currently serves as the lead qualitative scientist and project manager of a $1.8 million grant awarded by the FDA to develop and validate a de novo patient-reported outcome (PRO) instrument for non-cystic fibrosis bronchiectasis (NCFBE) through the FDA’s Clinical Outcome Assessment (COA) Qualification Program.
Na Guo is the China lead of OPEN Health, located in Shanghai, China. Na has over 10 years of experience in Epidemiology, Patient-Centered Outcomes, Health Economics, and Real-World Data/Real-World Evidence research. Prior to joining OPEN Health, Na worked in pharmaceutical companies and CRO companies across a breadth of roles. During her time with Roche Product Development Asia-Pacific, as an EpiPRO scientist, Na provided PRO technical support to local clinical trials.