In vitro diagnostics under the IVDR
In vitro diagnostic medical devices examine specimens taken from the human body to inform diagnosis and therapy decisions, and in the EU they are regulated by the In Vitro Diagnostics Regulation, a shorter counterpart of the Medical Device Regulation. The two regulations differ mainly in their clinical chapter and their annexes. The diagnostics regulation classifies devices by risk where the directive before it classified them by a list, and the documents and study terms of the device regulation have diagnostics counterparts, several of them under other names.
What an in vitro diagnostic is
In the EU, in vitro diagnostic medical devices (IVDs) are regulated under the In Vitro Diagnostics Regulation 2017/746 (IVDR). The regulation defines an in vitro diagnostic medical device as any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, piece of equipment, software or system, used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens derived from the human body, including blood and tissue donations, solely or principally to provide information on one or more of six things: a physiological or pathological process or state; congenital physical or mental impairments; the predisposition to a medical condition or disease; safety and compatibility with potential recipients; the prediction of treatment response or reactions; and the definition or monitoring of therapeutic measures.
IVD tests are considered non-invasive and are meant to support the physician in identifying the patient's underlying disease. They analyse human samples such as blood, saliva, urine or tissue, either by measuring the concentration of a specific substance such as cholesterol or sodium, or by detecting the presence or absence of a particular marker such as DNA, RNA or a protein. The blood a doctor usually collects to evaluate basic parameters such as biochemistry, haematology and biomarkers is analysed with IVDs, and a high C-reactive protein level, for example, indicates an infection, while a high blood glucose level hints towards diabetes. Such basic information can give the physician general information on the patient's health status, and taken together with a physical examination the test results can guide the physician's treatment decisions.
Diagnostics in therapy decisions
Besides diagnosing conditions, clinicians now use IVD tests to provide important information for therapy decisions. Screening tests help to stratify patients into drug-responsive and non-responsive populations according to the biomarkers they express, whether protein-, DNA- or RNA-based, to ensure that patients benefit from the appropriate or future therapies. For example, the OncoBEAM RAS CRC Kit, a PCR-based test, detects rat sarcoma (RAS) gene mutations in plasma from patients with late-stage colorectal cancer; patients with wild-type RAS genes have been shown to benefit from antibodies targeting the epidermal growth factor receptor such as cetuximab or panitumumab, while patients carrying RAS mutations do not respond to that therapy. Likewise, patients with breast cancer overexpressing the HER2 gene benefit from anti-HER2 therapy and those overexpressing the oestrogen receptor alpha 1 gene from oestrogen-receptor antagonists, and gene expression assays such as the Mamma Typer, an in vitro molecular diagnostic test, measure the expression levels of biomarkers in surgical breast cancer samples to guide the right therapy.
The diagnostics industry
IVDs occupy only a very small segment of the healthcare market, yet they play a vital role in it, as the COVID-19 pandemic showed. The in vitro diagnostics industry develops and supplies test systems, solutions and rapid tests. Its products range over instruments, reagents and kits, services and software; its therapeutic areas over oncology, cardiology, infectious diseases and reproductive medicine, among others; its applications over blood tests, drug testing and epidemiology; and its users over hospitals, laboratories, academics and patients testing themselves, and none of these lists is exhaustive.
The developmental life cycle of the IVD industry is fast-paced compared with that of the pharmaceutical industry. The COVID-19 pandemic showed how suddenly a need for IVDs can arise and how fast it can be met: within months several companies had developed a plethora of tests, some of them CE-marked in the EU and others for research use only.
The IVDR and the MDR
The Medical Device Regulation 2017/745 (MDR) is widely known in healthcare, while the IVDR is less known but equally important, especially during the COVID-19 pandemic, and can be considered the MDR's shorter "younger sibling". The two regulations are quite similar in structure, content and requirements. Their chapter headings are identical for making devices available on the market and the obligations of economic operators; identification, traceability and registration and the European database; notified bodies; classification and conformity assessment; post-market surveillance, vigilance and market surveillance; cooperation between member states, the coordination group, expert panels, laboratories and device registers; confidentiality, data protection, funding and penalties; and the final provisions. The chapter that differs is the clinical one, which the MDR heads clinical evaluation and clinical investigations and the IVDR clinical evidence, performance evaluation and performance studies. The MDR has 17 annexes and the IVDR 15.
The key differences between the two regulations are detailed in their annexes.
| Category | MDR | IVDR |
|---|---|---|
| General safety and performance requirements (Annex I) | Requirements 1 to 23 | Requirements 1 to 20 |
| Technical documentation structure (Annex II) | Less granular | More granular, with detail on specimen types, assays, accuracy, sensitivity, specificity, shelf life and stability |
| Classification rules (Annex VIII) | 22 rules: four for non-invasive, four for invasive and five for active devices, and nine special rules | Seven rules |
| Device classes (Annex VIII) | Class I, IIa, IIb and III | Class A, B, C and D |
| Clinical evidence | Based on clinical evaluation, post-market clinical follow-up and clinical investigations (Annexes XIV and XV) | Based on performance evaluation, post-market performance follow-up and clinical performance studies (Annexes XIII and XIV) |
From the directive to the IVDR
Like the MDR, the IVDR was a much-needed reform of the outdated In Vitro Diagnostic Directive 98/79/EC of 1998. The directive classified IVDs by a prescriptive list, List A and List B of its Annex II, and under it the majority of IVDs were self-certified and had easy access to the EU market. The IVDR classifies them by risk-based rules, and under it the majority of the IVDs that fell under neither list require notified body approval and more complex and costly approaches to clinical evidence.
IVDR documents and their MDR counterparts
The terminology may differ between mainstream medical devices and IVDs, but the principles governing the two sets of products and the requirements for compliance are very similar. The key documents a medical writer may develop as each regulation requires correspond as follows.
| Purpose | MDR | IVDR |
|---|---|---|
| Clinical evidence | Clinical evaluation plan; clinical evaluation report | Performance evaluation plan; performance evaluation report |
| Clinical studies | Clinical investigation plan; clinical investigation report; investigator's brochure; informed consent | Clinical performance study plan; clinical performance study report; investigator's brochure; informed consent |
| Post-market surveillance | Post-market surveillance plan; post-market surveillance report; periodic safety update report | Post-market surveillance plan; post-market surveillance report; periodic safety update report |
| Post-market clinical follow-up plan | Post-market performance follow-up plan | |
| Post-market clinical follow-up evaluation report | Post-market performance follow-up evaluation report | |
| Disclosure for the lay public | Clinical investigation results summary understandable by the end user | Clinical investigation results summary understandable by the end user |
| Summary of safety and clinical performance | Summary of safety and performance |
A medical writer developing these documents needs to draw on knowledge and competencies that include, but are not limited to, scientific writing, good clinical practice, data analysis or data fluency, safety surveillance, public disclosure and plain-language writing. This skill set is very similar to the one medical writers use in other healthcare sectors, such as mainstream devices and medicinal products.
In 2020 the Medical Device Coordination Group was expected eventually to provide clear guidance on the structure and content of these documents, in addition to what the IVDR lays down. IVD companies should nonetheless start the preparatory work to comply with the IVDR as soon as possible, and the role of medical writers should be considered seriously.
Clinical performance study terms
A clinical performance study of an IVD has its own terms for those of a device clinical investigation.
| Medical device | IVD medical device |
|---|---|
| Clinical investigation | Clinical performance study |
| Intervention | – |
| Investigational medical device | IVD medical device under investigation |
| Performance or effectiveness | Performance |
| Investigational design | Clinical performance study design |
| Clinical investigation plan | Clinical performance study protocol |
| Clinical investigation report | Clinical performance study report |
| Adverse device effect | Adverse device effect |