apid development of personalized (also known as precision) medicine has made separating patients into different groups and customizing treatments or products based on their genomic information an important trend.

Development of companion diagnostics (CDx) as powerful tools in precision medicine typically follows one of three pathways: co-development, bridging, and follow-on. Co-development is the most ideal and cost-effective CDx pathway: It is conducive to screening target patients specifically and identifying drug targets accurately, reducing development cost and cycle times for pharmaceutical companies. The DIA China 2020 session Driving Co-Development of Therapeutic Drugs and Companion Diagnostics for Precision Medicine and Optimizing the Clinical Trial Design reviewed the regulatory framework for drug and diagnostic co-development and how to overcome the inevitable hurdles to quickly delivering innovative drugs and diagnostics to patients.

Key Takeaways

• The US, EU, and China each have their own CDx regulatory policies. The US entered the global CDx market earlier than the other two, and also has the most established CDx regulatory documentation and history. Regulatory policy in the US is established by the FDA. Regulatory policies for CDx in the EU are in a transition period.
• Although CDx regulation in China is less advanced than in the US, the National Medical Products Administration (NMPA) has paid increasing attention to regulatory guidelines for CDx development and encourages co-development based on the Technical Review Guideline of Clinical Trial for Co-Development of CDx Reagents and Anti-Tumor Drugs, which China’s Center for Medical Device Evaluation (CMDE) announced on June 3, 2020.
• Drug and CDx co-developers need early planning and engagement to accelerate regulatory approvals and reduce costs.

Data available from FDA show that 25 percent (11 of 44) of therapeutic NME medicinal product approvals in 2019 are considered personalized medicines; NMEs as personalized medicines increased from 21 percent in 2014 to 42 percent in 2018. In Europe, approximately 30 percent of NMEs approved from January to August 2020 required a diagnostic test for patient identification. Pairing diagnostic tests that can determine an individual patient’s responsiveness to therapeutic options can improve the drug development process. Drug and CDx efficacy are essential to the practice of precision medicine.

CDx are defined by the FDA as tests that are required for the safe and effective use of a drug. In 2014, FDA issued Guidance for Industry: In Vitro Companion Diagnostic Devices to inform diagnostic developers that CDx can be indicated for a group of therapeutic products, instead of one particular drug, if there is sufficient data to support such labeling. In 2016, FDA issued the draft guidance Principles for Co-Development of an In Vitro Companion Diagnostic Device with a Therapeutic Product as a practical guide to assist therapeutic product sponsors and in vitro diagnostic device (IVD) sponsors in developing a therapeutic product with an accompanying IVD companion diagnostic (a process referred to as co-development). In April 2020, FDA published a final guidance Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products, which lists several key FDA considerations for CDx manufacturers considering a class-based label and clarifies the process required to apply for and be granted one.

CDx regulatory policies in the EU are in transition. Regulation 2017/746 on in vitro diagnostic medical devices (IVDR) entered into force in Europe and will be fully effective on May 26, 2022. This regulation establishes the first European regulatory link between the approval of drugs and CDx.

Despite the fast-growing market for CDx products, China has no published CDx-specific regulatory guidelines and no clear regulatory definition of CDx-related products. Most of these types of related products have been registered as Class III medical devices and approved based on current medical device and IVD regulations. China’s CMDE (a division of NMPA) announced the preparation of the Technical Review Guideline of Clinical Trial for Co-Development of CDx Reagents and Anti-Tumor Drugs in June 2020. This encouraged co-development between discovery research laboratories and pharmaceutical companies. In July 2020, China’s CMDE published the draft version of Guidelines for Package Insert Update and Technical Review of CDx for the Same Kind of Therapeutic Drug. In August 2020, CMDE issued the draft Guidance for Clinical Study of CDx for the Marketed Oncology Drugs. These national guidelines and regulations continue to create favorable conditions for development of drug–CDx reagents in China.

Co-developing drugs and diagnostics can accelerate their respective regulatory approvals while reducing costs. However, many pharmaceutical companies seem to ignore the registration of CDx. Because this CDx application and registration period will take approximately three years, the best practice is for drug and diagnostic developers to pair up early and develop a strategy that considers the policies of global regulatory bodies as well as each stage in the process, from development through testing, up to access and adoption.

Unlike drug products, CDx products have not fully entered the Chinese market; as a result, real world CDx studies, such as bridging studies and follow-on pathways, are often not suitable in these situations. However, real world studies may offer a new pathway for CDx development as more products enter the market in China.

Drug–diagnostic co-development integrates the biopharmaceutical and diagnostic landscapes and is at the forefront of ongoing work by discovery research laboratories, pharmaceutical companies, and regulatory bodies. Development and improvement of regulatory policies will present more options for drug–diagnostic co-development and bring a more promising future for pharmacotherapy and patient care in China.

References available upon request.