by Linsey Reavie
In vitro diagnostic (IVD) and companion diagnostic (CDx) tests are crucial for the rapid diagnosis, response and treatment of diseases. Their availability has the potential to significantly improve healthcare outcomes, particularly in places where the health care infrastructure is weak and access to quality medical care is suboptimal (Kuupiel, 2017).
Disease areas, like oncology and neurodegenerative disorders, have a significant unmet need for better, more rapid testing that not only helps monitor disease status but also guides earlier, more efficient treatment strategies. Many pharmaceutical companies have a keen interest in developing such CDx tests that better identify target patient populations where the efficacy of new drug products can be successfully demonstrated. These types of diagnostic tests are of high value in the age of more advanced technology (e.g. next generation sequencing) and increased knowledge of the molecular drivers of disease.
IVD and CDx developers must satisfy a diverse set of evaluators to ensure commercial success, such as regulators, health care providers, physicians, and reimbursement organizations. While these sectors have recently seen significant growth, they have also been met with an increased demand from regulatory bodies to demonstrate the clinical utility for patient treatment. With the high cost of development, it is of utmost importance for companies to have a clear, efficient development and commercialization strategy.
As per Regulation (EU) 2017/746, an IVD and CDx is defined as
‘any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, piece of equipment, software or system, whether used alone or in combination, intended by the manufacturer to be used in vitro examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information on one or more of the following:
(a) Concerning a physiological or pathological process or state;
(b) Concerning congenital physical or mental impairments;
(c) Concerning the predisposition to a medical condition or a disease;
(d) To determine the safety and compatibility with potential recipients;
(e) To predict treatment response or reactions;
(f) To define or monitoring therapeutic measures’
Start with the end in mind, know the user! Understanding the User’s real needs at the beginning of development is essential. The scientific validity of the diagnostic test can then be matched with the User’s needs to develop an appropriate diagnostic test. Spending this time at the beginning can save money, time and intellectual effort by minimizing the likelihood that the product will need modifications (large or small) at later stages of development. Making the User’s needs a priority in early stages will help to ensure that the product is used safely to:
satisfy regulatory requirements
be correctly used for its intended use to minimize errors
be fully embraced by users as a diagnostic test – a key contributor to market success
Clearly define the intended use of the product. The intended use, in this sense, is the statement found on the product label saying what the diagnostic test can do. Defining the intended use from the beginning will not only focus product development but allow proper definition of the risk class. The regulatory burden can be vastly different depending on the classification of the product. Solidifying the appropriate regulatory path from the beginning allows for an efficient development plan to minimizes extraneous work that costs time and money. Drafting a target product profile (TPP) at this stage is a useful and important document to delineate the User need, intended use and begin outlining a development plan to satisfy the identified objectives.
An integrated development plan with clear objectives is crucial for the success of an IVD or CDx. In our view, the two most important parts of a development plan that should be outlined early are the requirements and subsequent data sets needed for the:
analytical performance – design controls
The analytical performance should satisfy all regulatory requirements surrounding assay parameters of the diagnostic test (e.g. specificity, accuracy, precision etc.) as well as sample collection, handling and storage. When the User’s need(s) and intended use are clearly defined, the experiments needed to demonstrate adequate analytical performance can be easily streamlined into a set of experiments. Pre-thinking about the development of appropriate design controls is crucial to ensure this stage of development is efficient. This can really save on time and cost. Factors for further consideration at this stage are traceability, quality control and good documentation.
The clinical performance of a diagnostic test is fulfilled by clinical performance studies, scientific peer-reviewed literature and/or published experience gained by routine diagnostic testing. Clinical performance studies can be observational or interventional with regard to the patient population. The extent of clinical performance testing required by regulatory bodies is also defined by the risk classification of the product. This is of particular relevance when developing a CDx. Thus, the scope of clinical performance studies is highly context dependent. However, construction of a clear clinical performance plan can be easily achieved when all the parameters described above have been delineated.
Quality Management System
Although one of the biggest hurdles to tackle in the beginning, the developer of an IVD or CD must also plan and implement a quality management system that is compliant with regulatory guidelines. Such a system must control the quality of the product through all stages. Important considerations for a quality management system are:
Definition and documentation of roles and responsibilities
Good documentation and traceability
Risk Management plan
Implementation of mitigation measures
Spending effort and time to pre-think though these points in the beginning will save in the end and hopefully pave a smooth way towards regulatory success and approval.
If you wish to learn more about how some of these points can be implemented in your programs, please contact us!
1) Desmond Kuupiel et al., Diagnostics (Basel). 2017 Dec; 7(4): 58.
2) Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision 2010/227/EU
3) REGULATION (EU) 2017/745 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 5 April 2017 on medical devices, amending Directive 2001/83/EC, Regulation (EC) No 178/2002 and Regulation (EC) No 1223/2009 and repealing Council Directives 90/385/EEC and 93/42/EEC