Project 2 - Clinical Investigation Plan

Introduction

What is clinical investigation?

A clinical investigation is defined as “any systematic investigation or study in or on one or more human subjects, undertaken to assess the safety and/or performance of a medical device.” (SG5/N1:2007). The undertaking of a clinical investigation is a scientific process that represents one method of generating clinical data.

What is the objective of a clinical investigation?

The objective of a clinical investigation is to assess the safety and performance/efficacy of the device in question and evaluate whether the device is suitable for the purpose(s) and the population(s) for which it is intended (ISO 14155-1:2003).

How is a clinical investigation conducted?

ISO 14155-1:2003 Clinical Investigation of Medical Devices for Human Subjects - General Requirements details the general requirements for the conduct of clinical investigations and ISO 14155-2:2003 Clinical Investigation of Medical Devices for Human Subject - Clinical Investigation Plan contains detailed information about the procedure and contents of a clinical investigation plan. Clinical investigations must take into account scientific principles underlying the collection of clinical data along with accepted ethical standards surrounding the use of human subjects. The clinical investigation objectives and design should be documented in the clinical investigation plan.

Scope

The primary purpose of this document is to provide guidance in relation to:

• when a clinical investigation should be undertaken for a medical device to demonstrate compliance with the relevant Essential Principles (see GHTF/SG1/N041 – “Essential Principles of Safety and Performance of Medical Devices”); and
• the general principles of clinical investigation involving medical devices.

Given the wide diversity of medical devices and their associated risks, this document is not intended to provide comprehensive guidance for clinical investigations of specific medical devices. The guidance contained within this document is intended to apply to medical devices generally and combination products regulated as medical devices. It is not intended to cover in vitro diagnostic medical devices. Additionally, this document was drafted primarily to address the use of Clinical Investigations to support a marketing authorization application. Some aspects of this document may apply to studies conducted following commercial release of a device. Future GHTF documents will specifically address post-market clinical follow-up studies.

Clinical Data: Safety and/or performance information that are generated from the clinical use of a medical device.

Clinical Evaluation: The assessment and analysis of clinical data pertaining to a medical device to verify the clinical safety and performance of the device when used as intended by the manufacturer.

Clinical Evidence: The clinical data and the clinical evaluation report pertaining to a medical device.

Clinical Investigation: Any systematic investigation or study in or on one or more human subjects, undertaken to assess the safety and/or performance of a medical device.

Clinical Investigation Plan: Document that states the rationale, objectives, design and proposed analysis, methodology, monitoring, conduct and record-keeping of the clinical investigation.

Clinical Performance: The ability of a medical device to achieve its intended purpose as claimed by the manufacturer.

Clinical Safety: The absence of unacceptable clinical risks, when using the device according to the manufacturer’s Instructions for Use.

Conformity Assessment: The systematic examination of evidence generated and procedures undertaken by the manufacturer, under requirements established by the Regulatory Authority, to determine that a medical device is safe and performs as intended by the manufacturer and, therefore, conforms to the Essential Principles of Safety and Performance for Medical Devices (SG1/N041:2005).

Endpoint: Indicators measured or determined to assess the objectives of a clinical investigation, prospectively specified in the clinical investigation plan. (ISO 14155, modified)

Residual Risk: Risk remaining after risk control measures have been taken (ISO 14971).

Risk Management: The systematic application of management policies, procedures and practices to the tasks of analysing, evaluating, controlling and monitoring risk (ISO 14971).

Ethical Considerations for Clinical Investigations

As a general principle, “the rights, safety and wellbeing of clinical investigation subjects shall be protected consistent with the ethical principles laid down in the Declaration of Helsinki” (ISO 14155). It is ethically important in deciding to conduct a clinical investigation that it should generate new data and answer specific safety and/or performance questions that remain unanswered by the current body of knowledge. The desire to protect human subjects from unnecessary or inappropriate experimentation must be balanced with the need to protect public health through the use of clinical investigations where they are indicated. In all cases, however, care must be taken to ensure that the necessary data are obtained through a scientific and ethical investigational process that does not expose subjects to undue risks or discomfort. The rights, safety and well-being of subjects are paramount, and appropriate trial design and conduct is essential to generate meaningful data.

Sponsors are responsible for selecting qualified investigators and providing them with the information that they need to conduct the investigation properly. They must also ensure proper monitoring of the investigation and IRB review and approval, submit an IDE application to FDA for significant risk device studies, and inform the IRB and FDA promptly of any significant new information about the investigation.

FDA and IRB approval

A sponsor cannot begin an investigation or any part of an investigation until an IRB and FDA have both approved the application or supplemental application.

Selecting Investigators

A sponsor is responsible for selecting investigators qualified by training and experience to investigate the device.

Selecting Monitors

A sponsor must select monitors qualified by training and experience to monitor the investigational study in accordance with the IDE and other applicable FDA regulations.

Device Control

A sponsor can ship investigational devices only to qualified investigators participating in the investigation.

Investigator Agreements

A sponsor must obtain a signed agreement from each participating investigator that includes:

• the investigator's curriculum vitae,
• a statement of the investigator's relevant experience, including the dates, location, extent, and type of experience, where applicable,
• an explanation of the circumstances that led to termination of a study if the investigator was involved in an investigation or other research that was terminated,
• a statement of the investigator's commitment to:
  • conduct the investigation in accordance with the agreement, the investigational plan, the IDE and other applicable FDA regulations, and conditions of approval imposed by the reviewing IRB or FDA,
  • supervise all testing of the device involving human subjects. and
  • ensure that the requirements for obtaining informed consent are met.
• sufficient accurate financial disclosure information to allow the sponsor to submit a complete and accurate certification or disclosure statement as required under 21 CFR 54, Financial Disclosure by Clinical Investigators. The sponsor shall also obtain a commitment from the clinical investigator to promptly update this information if any relevant changes occur during the course of the investigation and for one year following completion of the study. (The financial certification or disclosure is submitted in the PMA or Premarket Notification 510(k) application. It should not be submitted in the IDE application.)

Informing investigators

A sponsor must supply all investigators participating in the investigation with copies of the investigational plan and a report of prior investigations of the device.

Monitoring

• Securing Compliance: A sponsor who discovers that an investigator is not complying with the signed agreement, the investigational plan, the IDE requirements, any other applicable FDA regulations, or any conditions of approval imposed by the reviewing IRB or FDA must promptly either secure compliance, or discontinue shipments of the device to the investigator and terminate the investigator's participation in the investigation. A sponsor must also require that the investigator dispose of or return the device, unless this action would jeopardize the rights, safety, or welfare of a subject.
• Unanticipated Adverse Device Effects: The sponsor must immediately conduct an evaluation of any unanticipated adverse device effect. A sponsor who determines that an unanticipated adverse device effect presents an unreasonable risk to subjects must terminate all investigations or parts of the investigations presenting that risk as soon as possible. Termination must occur no later than 5 working days after the sponsor makes this determination and no later than 15 working days after the sponsor first received notice of the effect.
• Resumption of Terminated Studies: For significant risk device investigations, a sponsor may not resume a terminated investigation without IRB and FDA approval. For a nonsignificant risk device investigation, a sponsor may not resume a terminated investigation without IRB approval. If the nonsignificant risk study was terminated for unanticipated adverse device effects, the sponsor must also obtain FDA approval.

Sponsor records

The sponsor must maintain accurate and complete records relating to the investigation. These records include:

• all correspondence including required reports,
• records of shipment of the device,
• records of disposition of the device
• signed investigator agreements including financial disclosure information,
• records concerning complaints and adverse device effects whether anticipated or not,
• any other records that FDA requires to be maintained by regulation or by specific requirement for a category of investigation or a particular investigation.

Sponsor Reports

The sponsor must provide the following reports in a timely manner to FDA, the IRB's, and/or the investigators.

• Unanticipated Adverse Device Effects
• Withdrawal of IRB Approval
• Withdrawal of FDA Approval
• Current List of Investigators
• Progress Reports
• Recalls and Device Disposition
• Final Report
• Informed consent
• Significant Risk Device Determination
• Other Reports

Studies involving unapproved devices that are considered to be significant risk: An IDE from the FDA is required to perform clinical research using an unapproved device that poses a significant risk to subjects. Typically, these studies are conducted to collect safety and effectiveness data used to support Premarket Approval (PMA) applications submitted to the FDA.

• Studies involving an approved device being tested for a new indication: IDE regulations also apply to significant risk studies testing an FDA-approved device for a new indication.

Example: Significant risk (SR) studies involve implantable devices such as cardiac pacemakers, orthopedic implants, and stents. SR studies can also involve products not introduced into the body, such as computer software used for prenatal risk evaluation. Each of these studies would require an IDE. For more information, see FDA guidance on Significant and non significant risk medical devices.

Example: A legally marketed coronary stent would be considered an investigational device and would require an IDE if used as part of a study to collect safety and effectiveness data for treating occlusions of other vascular sites.

General Principles When Considering the Need for a Clinical Investigation

When should a clinical investigation be undertaken?

Clinical investigations are necessary to provide the data not available through other sources (such as literature or preclinical testing) required to demonstrate compliance with the relevant Essential Principles (including safety, clinical performance and acceptability of risk/benefit ratio associated with its use). When a clinical investigation is conducted, the data obtained is used in the clinical evaluation process and is part of the clinical evidence for the device (see GHTF/SG5/N2 – “Clinical Evaluation”). For long established technologies, clinical investigation data that might be required for novel technologies may not be necessary. The available clinical data in the form of, for example, published literature, reports of clinical experience, post-market reports and adverse event data may, in principle, be adequate to establish the safety and performance of the device, provided that new risks have not been identified, and that the intended use(s)/purpose(s) has/have not changed.

What are the crucial steps in clarifying the need for clinical investigations?

1. Identifying relevant clinical Essential Principles (for example, specifics of safety, clinical performance, acceptability of risk/benefit-ratio) for the device and its intended use/purpose(s) (see GHTF/SG1/N041 – Essential Principles of Safety and Performance of Medical Devices);
2. Performing risk management (ISO 14971) activities will help in identifying the clinical data necessary to address residual risks and aspects of clinical performance not completely resolved by available information e.g. design solutions, preclinical and material/technical evaluation, conformity with relevant standards, labelling, etc.;
3. Conducting a proper clinical evaluation will demonstrate which clinical data are necessary and can be adequately contributed to by sources such as literature searching, prior clinical investigations, clinical experience, or clinical data available from comparable devices, and which clinical data should be generated from clinical investigation(s). Available clinical data for comparable devices should be carefully examined for comparability and adequacy (see SG5/N2:2007 Clinical Evaluation).

What is the role of risk analysis?

A properly conducted risk analysis is essential in determining what clinical evidence may be needed for a particular device (see ISO 14971). A clinical investigation is generally required when the currently available data are insufficient to demonstrate conformity with the Essential Principles. This would be the case when the manufacturer’s risk analysis and the clinical evaluation of a medical device for a particular intended use, including new claims, shows that there are residual risks, including aspects of clinical performance, that have not been adequately addressed by the available data.

As described in ISO 14971, “residual risk” is the risk remaining after risk control measures have been taken. Risk control measures include inherent safety by design, protective measures in the medical device itself or in the manufacturing process, and information for safety. The decision to use a medical device in the context of a clinical procedure requires the residual risk to be balanced against the anticipated benefits of the procedure. A clinical investigation may be required to further elucidate the risk/benefit ratio in a defined patient population. Where uncertainty exists as to whether current data are sufficient to demonstrate conformity with the Essential Principles, discussion with the relevant regulatory authorities or conformity assessment bodies may be appropriate.

General Principles of Clinical Investigation Design

Any clinical investigation must:

• be based on the results of the clinical evaluation process;
• follow a proper risk management procedure to avoid undue risks;
• be compliant with all relevant legal and regulatory requirements;
• be appropriately designed
• follow appropriate ethical principles

The design of the clinical investigation, including the study objectives and statistical considerations, should provide the clinical data necessary to address the residual risks, including aspects of clinical performance. Some factors that may influence the extent of data requirements include, but are not limited to, the following:

• type of device and/or regulatory classification;
• novel technology/relevant previous experience;
• clinical application/indications;
• nature of exposure to the product, e.g.: surface contact, implantation, ingestion;
• risks inherent in the use of the product, e.g.: risk associated with the procedure;
• performance claims made in the device labeling (including instructions for use) and/or promotional materials;
• component materials or substances;
• disease process (including severity) and patient population being treated;
• demographic, geographic and cultural considerations (e.g.: age, ethnicity, gender, etc.);
• potential impact of device failure;
• period of exposure to the device;
• expected lifetime of the device;
• availability of alternative treatments and current standard of care; and
• ethical considerations.

Considerations for Device Study Designs

Some of the factors that need to be considered in the study design include, for example:

• clear statement of objectives
• appropriate subject population(s)
• minimization of bias (e.g., randomization, blinding)
• identification of confounding factors (e.g., concurrent medications, co-morbidities)
• choice of appropriate controls (e.g., cohort, sham, historical), where necessary
• design configuration (e.g., parallel, crossover, factorial)
• type of comparison (e.g., superiority, non-inferiority, equivalence)

Investigations should be planned in such a way as to maximize the clinical relevance of the data while minimizing confounding factors. Possible study designs include:

• randomized controlled trials
• cohort studies
• case-control studies
• case series

In designing the study, statistical considerations should be prospectively specified and be based on sound scientific principles and methodology. Care must be taken in developing a statistical plan that includes consideration of, for example, the following:

• clinically relevant endpoints
• statistical significance levels, power
• sample size justification
• analysis methodology (including sensitivity and poolability analysis)

The design should ensure that the statistical evaluation derived from the investigation reflects a meaningful, clinically significant outcome. Discussion with the relevant regulatory authorities or conformity assessment bodies may be appropriate when there is uncertainty as to whether the proposed clinical investigational plan is sufficient.

Conduct of Clinical Investigations

A properly conducted clinical investigation, including compliance to the clinical investigation plan and local laws and regulations, ensures the protection of human subjects, the integrity of the data and that the data obtained is acceptable for the purpose of demonstrating conformity to the Essential Principles. ISO 14155 outlines good clinical practice for clinical investigations of medical devices.

Final Study Report

The outcome of a clinical investigation should be documented in a final study report. This then forms part of the clinical data that is included in the clinical evaluation process and ultimately becomes integrated into the clinical evaluation report (see GHTF SG5/N2:2007) for the purposes of conformity assessment.

References

SG1/N011:2008 Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices (STED)

SG1/N029:2005 Information Document Concerning the Definition of the Term “Medical Device”

SG1/N041:2005 Essential Principles of Safety and Performance of Medical Devices

SG1/N040:2006 Principles of Conformity Assessment for Medical Devices

SG1/N43:2005 Labelling for Medical Devices

SG5/N1:2007 Clinical Evidence – Key definitions and Concepts

SG5/N2:2007 Clinical Evaluation

https://research.virginia.edu/irb-hsr/investigational-medical-devices

https://www.nia.nih.gov/health/clinical-trials-benefits-risks-and-safety

https://clinicaltrials.gov/ProvidedDocs/78/NCT03016078/Prot_SAP_000.pdf

https://www.fda.gov/medical-devices/investigational-device-exemption-ide/ide-responsibilities