The world of RWE and RWD is in constant development, each different regulatory agency has been addressing this complementary source of information as a promising asset to clinicals trials like CDG clinical trials. Global regulators agencies such as US Food Drug Administration (FDA), Canadian Agency for Drugs and Technologies in Health (CADTH), European Medicines Agency (EMA), China’s National Medical Products Agency (NMPA) and UK National Health Service (NHS) have come to understand the benefits and downsides associated with Real World Data (RWD) and Real World Evidence (RWE), which allowed the increasing of understanding of the concepts and how the might be useful in a drug life development cycle. We now know that There are various applications of RWD/E. However, it demands a lot of regulation so as not to violate ethical issues and the quality of standard clinical trials and drugs’ approvals.Some of the most noteworthy moments for RWD/E are highlighted for each regulatory agent. One of the biggest milestones regarding RWD/E happened in 2018 when the FDA published the first framework in the world about RWD/E
United States of America
In the United States, the FDA has made drastic changes in the way RWE has been addressed in their country. In 2013, it issued guidance regarding how pharmacoepidemiologic safety studies using Electronic Health Records (EHR) data (a type of RWD) should be handled; therefore, optimizing the studies results and incentivize the usage of this type of RWD (1). In 2016, the 21st Century Cures Act was passed, which allowed the expansion of opportunities for the use of RWE in the healthcare and pharmaceutical industries (2). In the same year, a The FDA sent out a draft guidance clarifying the use of real world evidence in medical device regulatory decision making and recommendations for RWD collection.
In 2018, the FDA published an extremely straightforward framework for their RWD/E programs (3). In these guidelines, according to the FDA, RWD has to follow certain parameters of quality as it was stated. As well as offering such a degree of detail, RWD also has to be able to address the question in hand, being manageable to apply in different scales if necessary. In their framework the FDA outlines numeros applications that RWD/E has in assisting regulatory decision-making (3):
- Expanded Indications for Use
- Postmarket surveillance studies
- Post-Approval Device Surveillance as Condition of Approval
- Control Group
- Supplementary Data
- Objective Performance Criteria and Performance Goals
Spotlight to the following resources available:
- A powerpoint from FDA that walks the audience along the Real-World Evidence Guidance
- Guidance: Submitting Documents Utilizing Real-World Data and Real-World Evidence to FDA for Drugs and Biologics
- Guidance: Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices
- Guidance: Use of Electronic Health Records in Clinical Investigations
- Framework for FDA’s Real-World Evidence Program
- Real-World Evidence — What Is It and What Can It Tell Us?
- Accelerating development of scientific evidence for medical products within the existing US regulatory framework
- FDA offers real-world evidence examples with file summaries, details on real-world data source, populations, and descriptions of use
- FDA Presentation on theme: "Real World Data Use in the U.S. FDA Perspective"
For further reading move ahead to the bibliography at the end of this page.
Regarding CDG, most of these approaches are extremely helpful in improving the velocity of an orphan drug approval and its authenticity. According to the FDA (3), in order to approve a product such as an orphan drug, substantial evidence of effectiveness of that same product is required. This is crucial in order to distinguish the results from other influences and understand the importance of the product as a way of treating a certain disease. In order to do this adequate controlled trials are needed .The Code of Federal Regulations (CFR) (3) states that these clinical trials also require a control group against which the results of the study may be compared. This can consist of a concurrent placebo (group of people that receive a drug without any affect) or an active group; however, in the case of a single-arm study, it is considered a valid comparison to use a control group that incorporates Real World Evidence like natural history data, such as in the case of rare diseases, when it is usually difficult and might be unethical to create a randomized control group.
European Union (EU)
In EU, the EMA has not published any guidelines. However, it has made some improvements in the last years regarding the usage of RWE. The use of RWE and RWD is also an increasing priority for them and how it can complement Randomized Clinical Trials (RCTs) in the design and support of the results from distinct research (4). In 2014, The EMA developed an adaptive pathways pilot to accelerate the european drug development. In this pilot one of their main principles is the gathering of Real World data as a complementary source of information in clinical trials as a way to optimize the latter in terms of results and time (5). In 2016, the EMA issued guidance regarding post-authorization studies where it raised the possibility of utilizing RWE and source of information to create pragmatic trials (more heterogeneous groups of people) rather than RCTs (6). In addition, The chief medical officer of the European Medicines Agency in 2017 addressed the development of a healthcare system in order to leverage the full potential of RWD (7). Nonetheless, there are some concerns regarding the evidence’s credibility in acting without any assistance from RCTs. In comparison with the FDA, the EMA does not advise the use of RWE unaided by RCTs. According to an article issued in 2019 by the EMA officials (8), there is a need to test the possible assurance of RWE in order not to lose the credibility of today’s clinical trials. If RWE is applied without any reassurance, this can possibly jeopardise the efficiency of the drugs approved by the EMA. It is also stated that applying novel methods means that the procedure applied must be outlined and while assessing it the product-evaluation cannot be compromised by methods-evaluation but despite this it is addressed the promising asset that RWD is as a complementary source of data. Furthermore, one of EMA objectives to Regulatory science for their 2025 document is to incentivise the usage of approaches such as RWE/RWD in research decision-making as a mean to improve scientific quality evaluation (9). It was also stated that improving evidence taken out from data also would optimize cost-effectiveness of trials, which in turn would reduce the big burden that it is felt on healthcare systems.
- EMA talk on “EMA’s Regulatory Science Strategy to 2025 – Human Stakeholder Workshop” named Promote use of high-quality real-world data (RWD) in decision making
- EMA presentation on “Real world evidence (RWE) – an introduction; how is it relevant for the medicines regulatory system?
- A talk by Peter Arlett (Head of EMA Data Analytics and Methods Taskforce) presents DARWIN EU (Data Analytics and Real World Interrogation Network) initiative waks you throughout the numerous Regulatory use of RWE cases
- Real world data across the product life cycle
- A presentation entitled Real World Evidence by RWD focussed Activities – Electronic Health Records HMA-EMA Joint Big Data Taskforce. It highlights Real world data across the product life cycle. in addition to opportunities and challenges around implementation of a common data model in Europe to support regulatory decision making.
- Dr Alison Cave talks named What are the real-world evidence tools and how can they support decision making? stresses the RWE - What are the Opportunities across the product life cycle. It can be complemented with Use of Real World Data in Development Programmes
For further reading move ahead to the bibliography at the end of this page.
Innovative Medicines Initiative (IMI)
IMI is an initiative created in 2008 by the European Commission in order to help in the development and improvement of pharmaceutical research (10). Throughout the years, IMI has been one example of agencies that promote awareness about RWE and its importance in the research field as well as in the pharmaceutical company. In 2014, The IMI Getreal program was launched with aim to mitigate some of the challenges of RWD such as the lack of standardized data as well as the overall optimization RWE and its appropriate use in healthcare decision-making (2). In 2015, IMI ran 5 workshops in order to discuss the use of RWE and the benefits it brings in demonstrating the effectiveness of new drugs (10). This aspect is also reflected in 2017, when this initiative tried to bring together most key stakeholder groups in order to discuss the incorporation of real-life clinical data into drug development.
The United Kingdom has made some advancements regarding the usage of RWE. In 2015, NHS addressed a solution where new cancer drugs would be given conditional approval while real world data is collected regarding their efficiency in real world settings(12). This is taking into consideration the Cancer Drugs Fund (CDF) which is a collaborative initiative with The National Institute for Health and Care Excellence (NICE). In 2020, the Medicines and Healthcare products Regulatory Agency (MHRA) has issued a draft guidance on RCTs which generates RWE to support regulatory decisions (13). Moreover in the same year, NICE has issued a statement of intent regarding the use of different types of sources of data for the development and evaluation of their guidance (14).
In this statement, it is stated a big focus of RWD sources and how they should be taken into account. The document has set certain goals:
- the evidence we currently use
- the broader types of evidence available
- when and why we’d consider using a broader type of evidence
- practical considerations
- clarification on how these ambitions link to our health technology evaluation methods review
- acknowledgement of additional data sources, including potential emerging forms and sources
- acknowledgement that we may consider international sources of data
- reference to external initiatives
- additional detail about our proposals to ensure transparency
- details about the risks associated with this work, and how we propose to mitigate them
The Health Canada and the Pan-Canadian Health Technology Assessment (HTA) Collaborative has done their own action in the implementation of RWE applications. In 2018, Health Canada has started a project regarding the optimization of RWE’s usage, this project was called ‘Strengthening the use of real world evidence for drugs’. This has the objective of creating a more equal accessibility and affordability in the canadian health care system, through the utilization of RWE. Therefore, it has different goals in order to obtain the wanted success (15):
- increased use of RWE to enhance regulatory decision-making and risk communications throughout the drug life cycle
- improved use and sharing of RWE with our healthcare system partners
- increased clarity for stakeholders on where and how RWE can be used to support regulatory decision making
- improved access to drugs through the use of new sources of evidence to support approval of drug applications
This ambitions goals are subdivided in different tasks:
- identifying opportunities for enhanced use of RWE throughout the drug life cycle
- mapping potential RWE sources
- developing and implementing a RWE strategy and implementation plan for the use of RWE in regulatory decision making for drugs
- consulting with stakeholders on the RWE strategy
It was also stated that their objective is to finish all parts until 2022. New documents were issued regarding the organization that was made in order to achieve their aim (16). In this, it was outlined the activities of the Health Canada and its collaboratives (the Canadian Agency for Drugs and Technologies in Health (CADTH), and l’Institut national d'excellence en santé et services sociaux). The information regarding the activities was extremely straightforward, stating starting and ending date, as well as the final goal, such as the development of a RWE framework and the preparation of guidance protocols (16).
The National Medical Products Agency (NMPA) was another regulatory world agency that had made changes in its usage of RWD/E. China has an intriguing history regarding its use of RWE. Since the beginning of this century China has evolved in terms of the recognition of RWE and its usage. Their dated history regarding this century with RWE starts in the early 2000, when China used RWD sources as means to do a post-approval clinical evaluation without expressing officially the term RWD (17). By 2010, the RWE terminology was officially used for the first time in a real world study as aim to assess Traditional Medical interventions by Traditional Medicine Chinese researchers (17). After this RWE has been slowly embedded as a complementary source of information that can be used in different ways. In 2012, Chinese professional society introduced the comparative effectiveness research concept which means the introduction of observational studies in the clinical trials area (18). In 2016, Chinese Evidence-based Medicine Centre organized a national workshop with the aim of raising awareness of the existence of RWE to their national audience. In more recent years, the RWE awareness in Chinese population has risen. In 2018, it was realized the first RWE congress, which had 700 participants across the country (17).
Even more recently, in January of 2020 (18), the NMPA issued a guideline in which it clarifies their definition of RWD and RWE and when this approach should be used during a drug research life cycle and registration in China. This had the objective of being a complementary source of information due to the limitations of RCTs, such as that drugs which are tested in RCTs don’t represent the same results in a real world setting.
For a better understanding, the following image of RWD timeline until 2015 is available:
The sympharma has developed a timeline named “ REAL WORLD EVIDENCE (RWE) FROM CONCEPT TO ACTION: A TIMELINE “ that is ideal to everyone who is having curiosity about how RWD/RWE is being handled. Downloaded here.
For a better understanding, the following videos are available:
- The EFPIA channel has developed a video called “Keep the Spark Alive: the Regulatory Road to Innovation” that is ideal to someone who wants to understand more about this subject.
- The channel The Evidence Base has developed a video called “Real-world evidence in regenerative medicine: an interview with Shane Shapiro” that is ideal to someone who wants to understand the importance and the regulation behind RWE more specifically in America. Dr Shane explains how real-world evidence is being applied to regenerative medicine, and the challenges of working in a precision medicine environment with small patient numbers.
- The WorldwideClinical has developed a video called “ The Key to Conducting a Successful Early Phase Clinical Trial” that is ideal to someone who wants to understand a bit more about the regulation behind the early development
- National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Forum on Drug Discovery, Development, and Translation; Shore C, Gee AW, Kahn B, et al., editors. Examining the Impact of Real-World Evidence on Medical Product Development: Proceedings of a Workshop Series. Washington (DC): National Academies Press (US); 2019 Feb 6. 10, Looking Ahead. Available from: https://www.ncbi.nlm.nih.gov/books/NBK540114/
- https://www.fda.gov/regulatory-information/selected-amendments-fdc-act/… Accessed April 2021
- https://www.fda.gov/media/120060/download Accessed March 2021
- Hildesheim, Elmar .(2018). “Real World Evidence - Impact on Regulatory Decision Making.” (Master's Thesis); Rheinische Friedrich-Wilhelms-Universität Bonn Available: https://www.dgra.de/media/pdf/studium/masterthesis/master_wegener_elmar…
- https://www.ema.europa.eu/en/human-regulatory/research-development/adap… Acessed April 2021
- https://www.ema.europa.eu/en/documents/scientific-guideline/scientific-… Acessed April 2021
- https://www.regulatoryscience.nl/editions/2017/03/interview-hans-georg-… Acessed April 2021
- Eichler, H. ‐. G., Koenig, F., Arlett, P., Enzmann, H., Humphreys, A., Pétavy, F., Schwarzer‐Daum, B., Sepodes, B., Vamvakas, S., & Rasi, G. (2019). Are Novel, Nonrandomized Analytic Methods Fit for Decision Making? The Need for Prospective, Controlled, and Transparent Validation. Clinical Pharmacology & Therapeutics, 107(4), 773–779. https://doi.org/10.1002/cpt.1638
- https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/… Acessed April 2021
- https://www.imi.europa.eu/projects-results/project-factsheets/getreal Acessed April 2021
- https://www.nice.org.uk/news/press-and-media/nice-draft-guidance-condit… Acessed April 2021
- http://www.pmlive.com/pharma_news/nhs_england_hands_over_cancer_drugs_f… Acessed April 2021
- https://www.gov.uk/government/consultations/mhra-draft-guidance-on-rand… Acessed April 2021
- https://www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/n… Acessed April 2021
- https://www.canada.ca/en/health-canada/corporate/transparency/regulator… Acessed April 2021
- https://www.canada.ca/en/health-canada/corporate/transparency/regulator… Acessed April 2021
- Sun, X., Tan, J., Tang, L., Guo, J. J., & Li, X. (2018). Real world evidence: experience and lessons from China. BMJ, j5262. https://doi.org/10.1136/bmj.j5262
- https://www.ispor.org/docs/default-source/conference-ap-2018/china-2nd-… Acessed April 2021
- https://www.accestra.com/guiding-principles-of-real-world-evidence-supp… Acessed April 2021
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