Standards and regulations behind a device investigation plan

A clinical investigation plan for a medical device is written against layers of requirement: the Declaration of Helsinki, the device good clinical practice standard ISO 14155, the EU Medical Device Regulation (MDR), the guidance documents beneath them, local law and disease-specific guidelines. How far ISO 14155 binds depends on the study. Its 2020 edition changed the standard in several respects, and the MDR sets out where the plan stands among the requirements for a clinical investigation.

The layers of requirement

The main regulations and guidelines for a clinical investigation in Europe include: ^{1, 2}

• the Declaration of Helsinki, a set of ethical principles that applies to medicinal products and medical devices ^{2, 3, 4, 5}
• ISO 14155:2020, which is similar to ICH good clinical practice E6 for medicinal products, and whose annexes include content requirements for plans, reports and investigator's brochures and give an overview of the different investigation types ²
• the MDR 2017/745, which mainly describes how to bring devices to market and how to ensure their safety and performance, and which gives details on clinical investigations and devotes its Annex XV to them ²
• the Medical Device Coordination Group (MDCG) guidance documents, which supersede the MEDDEV guidance and cover the application, modification and safety reporting of investigations and associated documents such as the post-market follow-up plan and report; they are continuously developed, so a regular check of their website is recommended ²
• local law, such as Germany's Medical Device Act, which must also be respected ²
• disease-specific guidelines, such as the Academic Research Consortium's harmonised endpoint definitions for coronary interventions, which must also be respected when designing investigations ^{2, 3}

In other regions, other regulations may apply, such as the US Code of Federal Regulations Title 21 or Japan's ministerial ordinance on good clinical practice for devices. ^{1, 6}

General guidelines relevant to medical writing, such as the CONSORT statement and Good Publication Practice (GPP3), apply to devices as well as to drugs, as does the requirement for trial registration. ⁵

A writer should always consider whether other standards, such as product-specific ones, and national guidelines also apply. ⁷ The EU is centralising guidance for collecting clinical data, but the work is not complete and additional requirements may exist. ⁷ Where standards differ, the most stringent requirements always apply. ⁷

The Declaration of Helsinki

The Declaration of Helsinki is the overarching guideline and ethical principle of clinical research. ^{3, 4} One experienced writer sums it up as patient safety first, and scientific integrity. ^{3, 4} In general, a study not conducted according to it will not be published. ⁴ It is available free on the internet. ⁸ One experienced writer finds it very easily written and very self-explanatory. ⁸

ISO 14155, the device good clinical practice standard

ISO 14155, Clinical investigation of medical devices for human subjects — Good clinical practice, is the device counterpart of the ICH E6 good clinical practice guideline that the pharmaceutical industry follows. ^{9, 10, 5, 7, 11, 12} Experienced writers differ on how close the two are: one finds that, compared side by side, they are literally the same, while another holds them very similar but with some slight differences. ^{11, 12} One experienced writer holds ISO 14155 to be the most important regulation for medical devices. ¹⁰ In the EU, several older MEDDEV guidances cover clinical investigations, but one experienced writer holds that the two guidelines a medical writer should really know are ICH E6 and ISO 14155. ^{13, 12}

ISO 14155 describes how to conduct an investigation and gives the required content of informed consent forms, case report forms, clinical investigation plans, investigator's brochures and clinical study reports. ^{5, 14, 11} It lists the minimum content requirements for a clinical investigation plan. ¹⁵ It sets the minimum requirements for an informed consent form, and its appendices those for the plan, the case report form and other documents. ^{11, 16} It also gives normative templates useful to writers on device trials, for the plan, the consent form, the investigator's brochure and other essential documents, and for the report, whereas in pharmaceutical trials ICH E6 covers the protocol and the consent form and the clinical study report falls under a separate guideline, ICH E3. ^{17, 18} One experienced writer finds the standard very nicely and easily written, and its appendices like a little recipe book: a writer who follows them has everything included and can be reasonably sure of meeting all requirements. ¹⁶

ISO standards are sold, while ICH guidelines are free on the internet. ^{17, 16} ISO 14155 costs about €150 by one estimate, and anyone who intends to work on medical devices will need to buy it. ^{16, 19}

How far ISO 14155 binds a study

Device investigation protocols must follow ISO 14155 for good clinical practice. ⁷ The standard addresses good clinical practice for the design, conduct, recording and reporting of clinical investigations of medical devices carried out for regulatory purposes. ¹⁰ Its principles also apply to all other clinical investigations, and should be followed as far as the nature of the investigation and national requirements allow. ¹⁰ The standard applies fully to investigations for regulatory purposes, which must meet every item, while other studies meet the items as far as they apply. ^{16, 19} A registry of an approved, commercially available product with no additional invasive assessment, for instance, needs no device accountability, because the product used is the commercial one. ¹⁹

The 2020 edition of ISO 14155

ISO 14155 has existed since 1996, and its 2011 version aligned it with ICH E6 and with two ISO standards on risk management and quality management systems. ¹² ISO 14155:2020, the third edition, was published in July 2020 and replaces the second, of 2011. ²⁰ Accounts of how often the standard has changed differ: one has it revised many times by its 2011 version, while another counts the 2020 edition as the third. ^{12, 20} Like ICH E6(R2) for medicines, the 2020 edition governs the design, conduct, recording and reporting of clinical investigations in human subjects that assess the clinical performance and safety of a device. ²⁰ In line with the Declaration of Helsinki, its overriding purpose is to protect the rights, safety and wellbeing of the subjects. ²⁰ The edition is held to bring improved harmonisation and clearer guidance to manufacturers in the middle of the transition to the MDR, and the standard to be an asset for every professional working in the medical device industry. ²¹

Its main changes from the 2011 edition are: ^{22, 20}

• a summary section of good clinical practice principles, aligned with ICH E6 ²²
• reference to registering investigations in a publicly accessible database, in line with the Declaration of Helsinki ²²
• a new requirement for clinical quality management ^{22, 23, 24}
• risk-based monitoring ^{22, 25}
• statistical considerations in Annex A, which covers the plan ²²
• guidance for ethics committees in Annex G ²²
• risk management reinforced throughout the investigation, with Annex H describing in detail how ISO 14971:2019 applies to investigations and how ISO 14971 and ISO 14155 interact ^{22, 25}
• clarification, in Annex I, of which requirements apply at which clinical development stage ^{22, 20}
• guidance on auditing investigations in Annex J ²⁰

The edition's thirteen principles of good clinical practice, aligned with the Declaration of Helsinki and ICH E6, require that: ²³

1. investigations are conducted according to the ethical principles that originate in the Declaration of Helsinki and are consistent with ISO 14155 ²³
2. before an investigation starts, foreseeable risks and inconveniences are weighed against the anticipated benefit for the subject and for society, and the investigation starts and continues only if the anticipated benefits outweigh the risks ^{23, 22}
3. the rights, safety and wellbeing of subjects are the most important considerations and prevail over the interests of science and society ²²
4. the available non-clinical and clinical information on the device is adequate to support the investigation ²²
5. the investigation is scientifically sound and described in a clearly detailed plan ²²
6. the investigation is conducted in compliance with a plan that has the ethics committee's prior approval or favourable opinion and, where applicable, the regulator's approval or non-objection ^{22, 26}
7. medical care for subjects, and medical decisions made on their behalf, are always the responsibility of a qualified healthcare professional ²⁶
8. everyone who designs, conducts, records or reports the investigation is qualified by education, training and experience for their task ²⁶
9. freely given informed consent is obtained from every subject before participation ²⁶
10. all investigation information is recorded, handled and securely stored so that it can be accurately reported, interpreted, monitored, audited and verified ²⁶
11. the confidentiality of records that could identify subjects is protected, respecting privacy and confidentiality rules ²⁶
12. investigational devices are designed, manufactured, handled and stored according to the essential principles, and used according to the approved plan, the investigator's brochure and the manufacturer's instructions for use ²⁶
13. systems with procedures that ensure the quality of every aspect of the investigation are implemented ²⁶

The new requirement for clinical quality management obliges the use of quality management principles aligned with ISO 13485:2016. ^{24, 23} It aims to ensure that the investigation is designed, conducted and monitored, and its data documented, evaluated and reported, according to the regulatory requirements, ISO 14155, the plan and other applicable standards. ²⁴ The sponsor must document the implementation of these procedures in writing. ²⁴

The risk management process of an investigation allows the hazards and hazardous situations associated with the investigational device to be identified. ²⁵ Risks are first identified and estimated in a risk analysis, then evaluated in a benefit-risk analysis, and where necessary reduced to an acceptable level in risk control. ²⁵ This process, which includes risk analysis, risk-to-benefit assessment and risk control, is also described in ISO 14971. ²⁷ The effectiveness of risk control is evaluated throughout the product's lifecycle and during investigations. ²⁵ Information on acceptable and anticipated risks should be part of the plan, the investigator's brochure, the instructions for use and the consent forms. ²⁵ Risks should be monitored against acceptability thresholds throughout the investigation, an unanticipated safety concern should prompt a thorough risk assessment to determine whether the risk is acceptable, and an investigation should be terminated as soon as its risks are no longer acceptable. ²⁵

The results of the device risk assessment must be used to develop a risk-based monitoring plan, whose extent and nature must be based on the investigation's objective, design, complexity, size, critical data points and endpoints, and on how far it departs from normal clinical practice. ²⁵ The sponsor must ensure that unanticipated adverse device effects are identified and investigated rapidly, so that further risk control can be added where necessary. ²⁵

ISO 14155:2020 stresses risk management in every phase of product development, including investigations, and the beneficial interplay with ISO 13485 and ISO 14971. ²⁸ Adherence to the standard is important for complying with ethical requirements and human rights, and contributes to high-quality clinical data, regulatory compliance and the acceptance of a study's conduct and outcomes across countries. ²⁸

Clinical investigations under the Medical Device Regulation

The MDR calls clinical trials clinical investigations and addresses them in Article 2(45), Articles 62 to 82 and Annex XV. ²⁹ Its requirements on investigations are based on the 2011 edition of ISO 14155 and go into much more detail than the Medical Device Directive did. ²⁹ The MDR states that clinical investigations should be conducted in line with international guidelines, such as ISO 14155 on good clinical practice and the Declaration of Helsinki. ³⁰

Articles 62 to 80 cover: ²⁹

• general requirements for investigations conducted to demonstrate the conformity of devices ²⁹
• informed consent ²⁹
• investigations on subjects requiring special consideration ²⁹
• the application process and its assessment by member states ²⁹
• the conduct of the investigation ²⁹
• the electronic system on clinical investigations, and other aspects ²⁹

An investigation to demonstrate conformity under Article 62 can be considered a pivotal trial that proves the device's intended performance, clinical benefits and clinical safety. ²⁹ Annex XV requires it to run in a clinical environment representative of the intended normal conditions of use of the device in the target patient population. ²⁹ The MDR neither favours nor specifies particular trial designs, but applies the principle of proportionality and a risk-based approach, to be read alongside ISO 14155:2020 Annex I. ²⁹

The plan must address the safety of users as well as patients, under Articles 2, 62 and 72. ²⁹ The requirements of MEDDEV 2.7.1/4 for the plan are still relevant: it must state the rationale, objectives, design and proposed analysis, methodology, monitoring, conduct and record-keeping of the investigation. ²⁹

As in drug trials, device investigations require informed consent in line with ISO 14155 and the Declaration of Helsinki, under Article 63. ²⁹

Disease-specific guidelines

A writer should also know the disease-specific guidelines. ³ In coronary artery studies these include the Academic Research Consortium guidelines and society guidelines such as the European Society of Cardiology's, from which some of the eligibility criteria may be drawn. ³ Guidelines for reporting outcomes exist, but they are always disease-specific. ³¹ Cutlip's Academic Research Consortium publication, believed to date from 2007, shows what such a guideline looks like, as do the Valvular Academic Research Consortium's standardized endpoint definitions for transcatheter heart valves, a publication believed to be Kappetein's. ^{31, 32} For questions such as how long a study should run, stent trials have Byrne and colleagues' EAPCI recommendations, from 2015 or 2016. ³² A number of disease-specific guidelines also give recommendations on approval pathways for medical devices, such as the recommendations of the European Society of Cardiology and European Association of Percutaneous Cardiovascular Interventions task force on the evaluation of coronary stents. ¹⁵