Over the past two years, RWE has demonstrated a significant trend, going from academic research to regulatory decision-making. The Chinese government has started to build a regulatory and technical-level system and have improved the active drug warning systems to build a framework for health technology assessments in China.

Considering that RWE development faces many technological, ethical and regulatory limitations and challenges, pharmaceutical companies should adopt a common-sense approach in formulating development strategies and use RWE to support value and results-oriented strategic transformation.

What is Real World Evidence?

Real World Data (RWD) refers to routine medical data related to patients’ health that is collected from a variety of sources outside of clinical trials. These sources of medical information can include hospital electronic medical records (such as blood pressure, blood glucose, blood oxygen and lung volume data generated by medical monitoring equipment), medical insurance reimbursement information, genetic data and patient-reported health data from sources such as online reports and apps.

Based on RWD, the US Food & Drug Administration (FDA) defines Real World Evidence (RWE) as “clinical evidence derived from analysis of real world data, with regards to the usage, potential benefits or risks of a medical product”. The true impact of a course of treatment on a patient’s health is assessed through a variety of data obtained in the real environment to meet post-market regulatory requirements related to drug safety.

These days, the application range of RWE goes far beyond the scope of pharmaco-vigilance. In addition to drug regulatory agencies, other stakeholders including medical insurance payers, pharmaceutical companies, doctors, patients and commercial insurance companies, have started to participate in a healthcare ecosystem built with RWE at its core.

The importance of RWE applications

In a traditional clinical design test scenario, a randomised control trial (RCT), the gold standard for clinical trial designs, is conducted in a strictly controlled, conditionally optimised environment. Despite its many advantages, RCTs to some extent, limit the developers’ and regulators’

understanding of the safety and efficacy of drugs in a broader context during the review and approval phase. In contrast, RWE and real world research can:

1. Effectively assess whether the safety and true efficacy of the listed drugs are consistent with that at the review and approval stage;

2. Solve data blind spots in the use of new drugs;

3. Evaluate whether the cost-effectiveness ratio of drugs justifies its inclusion in the list of health insurance policies under increasing cost pressures;

4. Assess the improvements in quality of life of patients under ongoing medication;

5. Help regulatory authorities better meet their obligations to inform patients about the true efficacy of medical products.

We can see from this that the application of RWE has far-reaching implications for the science-based decision-making of regulatory authorities.

In addition, the application of RWE has become the focal point of attention for the entire healthcare ecosystem, mainly due to the rise of value-based medicine and technological advancements. In light of the development of tailored healthcare methods and the observational research conducted in real world, it is easier for stakeholders to understand the complex issues such as complications, burden of disease, and compliance of medication. Meanwhile, new treatments such as genotyping have greatly solved difficult problems like recruiting patients in the development of anti-cancer medicines. At the same time, the rapid advancement of IT technologies and research methods such as electronic

Jia Xu

Lead Consulting Partner of Pharma & Healthcare, PwC China

devices and social media, as well as the widespread penetration of social media, have offered new sources for data and technology development tools in the study of RWD and RWE. Driven by these trends, the entire health ecosystem, including regulatory agencies, medical insurance departments and enterprises, must strengthen their understanding of RWE and accelerate their research and applications in this field to optimise on medical value.

Part I: Healthcare ecosystem built with RWE at its core

Drug regulatory agencies

The U.S was one of the first countries to apply RWE in drug regulation. Under the FDA’s regulatory system, the application of RWE can be traced back to a Sentinel Initiative carried out in 2007. Using patient electronic health and insurance claims data, an Active Risk Identification and Analysis (ARIA) database was established to actively monitor adverse drug reactions (ADRs) on the market.

As a milestone document in FDA regulatory reform, the “21st Century Cures Act” was approved by the US Congress in December 2016. This further clarified the role of RWE in supporting the pre-market safety and effectiveness evaluations of drugs to encourage basic medical innovations, reform the FDA regulatory processes and accelerate the listing of innovative drugs. This act has had far-reaching implications on the healthcare industry in the U.S and globally. It clearly stipulates that the FDA should establish a framework to assess RWE in drug safety and effectiveness evaluations; offer clear legislative protections for the application of RWE; recognise RWE as a supplement for traditional clinical trial designs; and support the approvals of new indications for listed drugs.

Real-World

Evidence

Issue 3

As early as the start of 2000, China began to realise that RWD and RWE could be useful complements and promoters for the clinical evaluation system in the traditional research and development of new drugs. In 2010, real-world research first appeared in the intervention design of traditional Chinese medicine. Over the past two years, the Chinese government has committed to establishing a regulatory and technical-level system, improving the active drug warning systems, and building a framework for health technology assessments in China.

In the future, with the popularisation of the licensing system, the state will launch a large-scale, post-market re-evaluation system using RWD to support more post-market research of domestic drugs. For example, the consistency evaluation of generic drugs currently advanced by the Chinese government stipulates that “this product is effective, no clinical efficacy or bioequivalence tests are required, but should be supplemented by RWE in follow-up clinical use”.

Medical insurance payers

Medical insurance departments use RWE to carry out health technology assessments mainly. At present, national and local drug price negotiations focus more on factors such as price and demand. The current development of health technology assessment as an important institutional innovation which can assist medical insurance departments in assessing the clinical and economic value of drugs and other health technologies to make real, effective and science-based pricing decisions. As the collection of RWD becomes more sophisticated, health insurance departments will be able to evaluate various medical technologies (such as vaccines, drugs, screening techniques, diagnostic and therapeutic techniques, as well as treatment schemes) from the perspective of costs and results while exporting clinical benefit and affordability data from the patient population to provide recommendations in the selection of essential drugs and health insurance catalogues. This will help to provide a more scientific basis for the allocation of administrative resources.

Commercial insurance providers

In the event of limited medical insurance resources, payments for high-value innovative drugs in the field of cancer, rare diseases and neurodegenerative diseases will require underwriting from commercial insurance providers. RWE can provide commercial insurance companies with the medical data needed to design their payment schemes. At the same time, evidence from real-world research can also help commercial insurance companies to scientifically and reasonably assess the necessity and quality of medical behaviours.

1 Using RWE/RWD to support drug effectiveness decision making The FDA currently uses RWE/RWD for drug safety evaluation This new framework indicates that the FDA’s next focus will be on drug effectiveness decision-marking, exploring the potential of using RWE to improve the efficiency of clinical research.

2 Evaluating the suitability of RWE for regulatory decision-making According to the FDA, RWE as a basis for regulatory decision-making must be sufficiently reliable. Future work therefore includes: Assessing the reliability and relevance of the data Solving the lack of existing or low reliability data resources

3 Leveraging RWD’s potential in different research designs The FDA will further explore the advantages and limitations of RWD in the following clinical studies: Randomised controlled trials Single-arm non-randomised trials, with RWD as a control group Observational studies

4 Standardising RWD acquisition methods and means At present, electronic data mining technology is widely used in the acquisition of RWD. The FDA believes that the following aspects need to be standardised: Informed consent and effective management FDA record-keeping for data verification

Establishing data standards suitable for FDA applications To better support RWE in new drug applications, the FDA will: Ensure compliance of data standards and implementation recommendations for FDA-related applications Identify the differences between the new standards and existing FDA systems Propose an action plan to address this gap

5

1. Establish a strategic cooperation plan based on product line strategy

Partners include RWE data owners (hospitals, commercial insurance providers, pharmacies and big data companies), research institutes and data experts. Large big data platform companies with mature RWE systems and analytical capabilities should be selected as early as possible to carry out real-world research.

Case 1: Choosing data companies to collaborate on RWE research

Bristol-Myers Squibb, for instance, partnered with Flatiron Health (a US FDA partner) to advance RWE research on new cancer drugs using Flatiron’s oncology-specific electronic health record software and Foundation Medicine’s Clinico-Genomic Database.

2. Planning professional recruitment and development strategies and transforming the communications service model

As the main executive body of RWE initiatives in most pharmaceutical companies, the medical affairs department should align with strategy, develop recruitment programmes and training techniques for diverse professionals (including drug economists and data scientists), and design a multi-channel medical communication model within the department (between the medical consulting, medical communications consulting, pharmaco-economics, medical information, scientific operations and drug realm teams).

At the same time, the implementation of large-scale RWE projects often involves multi-functional teams within a business unit or across multiple business units and regions. Management of pharmaceutical companies should recognise the importance of internal project communication and execution efficiencies, and design an effective organisational structure and operating model.

3. Invest in RWE technology platforms to build internally developed and extended real-world research capabilities

Within the current window of China’s development of a RWE regulatory framework, pharmaceutical companies are cooperating with regulatory authorities, industry associations, academic institutions and patient organisations to participate in the early development of a RWE technical framework, sharing mechanisms and regulatory systems at the early stage. Based on the needs of different patient groups and regulatory agencies, for instance, pharmaceutical companies need to consider the selection and integration of multi-source data platforms (with sources including regional medical databases, electronic medical records databases and cancer registries).

This will be useful in providing decision-making support for a variety of payment methods, including total cost control.

Patients

The essence of RWD is to bring patient-centred medical solutions to patients. As various stakeholders focus more on patient performance in the real world, patients can help doctors understand the results of clinical treatments such as side effects, in order to devise a more suitable diagnosis and treatment programme.

Part II: What should the pharmaceutical companies do?

Regulators, pharmaceutical companies, healthcare providers and payers have all come to realise that RWE can cover a wider study population. It can be used to evaluate the effectiveness and safety of interventions in a wide range of real-life medical procedures and offer more meaningful outcomes and value-based medical decisions. Consensus has also been reached through legislation to clarify and promote the application and expansion of RWE. However, the development of RWE on a global scale still faces many technical and ethical challenges, such as data security, data standardisation and data access sources.

As one of the most important drivers of innovation in the medical industry, pharmaceutical companies play a vital role in promoting the development of RWD. Considering the limitation and challenges the RWE development is facing, pharmaceutical companies should formulate rational strategies to achieve strategic transformation.

1. Forward-looking strategies focused on the application of RWE in the pre-market and commercialisation stages of medical products

In the U.S, RWE has explicitly been used for post-market research and policy development, such as Phase IV clinical trials, the development of clinical practice guidelines, optimisation of drug development strategies, the use of additional indications and changes in specifications. However, China has yet to establish a mandatory post-market research system. Most domestic enterprises lack awareness of full life cycle management of medical products. As the main bodies responsible for the entire life cycle of drugs, pharmaceutical companies from home and abroad should adopt forward-looking thinking and expand the application of RWE in the pre-market and commercialisation stages of medical products.

Taking patient needs as an example, RWE based on search records of disease keywords can help pharmaceutical

Identification of potential patient needs

Discovery of new targets

Market analysis

Influencing clinical R&D strategies

Analysis of clinical trial feasibility (including patient recruitment and enrolment conditions)

Implementation as observational study

As a control study

Support for review and approval

Feedback for patient’s continuous treatment outcomes

Auxiliary pricing and payment

Support for medical insurance catalogue applications

Support for post-market research commitments

Support for clinical practice development

Support for changes in product descriptions

Support for the use of additional indications

Support for approval of new indications

Clinical research and development

Pre-clinical development

Commercialisation Post-market research

This content is for general information purposes only, and should not be used as a substitute for consultation with professional advisors.

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2. To develop RWE research cases, the internal capabilities of pharmaceutical companies need to strengthen in terms of strategy, structure and personnel training

Pharmaceutical companies concerned with entering the Chinese market need to possess strategic adjustments and shifts in perspectives. They must conduct real-world, patient-centric research and show the market

and payers the added benefits of drugs to patients, while offering a good cost-effectiveness ratio for their products. They also need to build an economic model that can provide a basis for pricing new drugs and medical insurance payments once they enter the market.

At present, RWE-related projects are mostly the responsibility of the medical affairs department and/or R&D departments. The

medical affairs department is increasingly required to demonstrate the cost-effectiveness of pharmaco-economic research, as well as the practical effects, safety and reasonable use of drug products in the real world. At the same time, this department also needs to strengthen their internal RWE application capabilities from the standpoint of strategy, structure and personnel training, develop RWE research cases, and provide a higher-quality product evidence chain:

The newly developed RWE will have an impact on the R&D management costs of pharmaceutical companies. Considering the main goal of RWE development is to reduce the cost of drug research and development and shorten approval and go-to-market times, reducing the cost of real-world research will be a challenge that R&D departments must face in the future. In evaluating RWE research projects, the relevant departments must scientifically evaluate the economic costs that can be saved when compared against a traditional clinical trial design.

companies mine potential patients who are undiagnosed and understand the market prospects of a product and patient needs, while addressing complex research problems such as disease burden and target population exploration. In the commercialisation phase of a drug, RWE not only supports review and approval decision making, it also assists multiple parties in determining innovative payment methods based on health outcomes and values. For example, Janssen UK and the British National Health Service agreed on a payment method based on the efficacy of their hepatitis C drug capsules, simeprevir. Based on medical records generated by their visits, patients who have not been cured after 12 weeks of drug intervention would receive refunds.