Clinical Investigation of Medical Device in India under Medical Device Rules 2017 (CDSCO)

Medical devices play a crucial role in healthcare, ranging from highly sophisticated systems like cardiac pacemakers and proton therapy units to simpler tools like tongue depressors and ice packs. These devices are classified into various categories based on their function: preventive care, assistive care, diagnostic, and therapeutic.

Regulatory Framework

Under the Medical Device Rules, 2017, medical devices are defined as follows:

1. Devices Listed by Government: Under the Drugs & Cosmetics Act of 1940, certain devices are listed for internal or external use in diagnosing, treating, mitigating, or preventing diseases in humans or animals.
2. Compounds: This includes substances that alter the body’s function, such as disinfectants and mechanical contraceptives (e.g., condoms, intrauterine devices).
3. Surgical Materials: Includes ligatures, staples, sutures, and dressings used for blood collection.
4. In-Vitro Diagnostic Devices: Materials used for diagnostic purposes outside the human body.

The Central Drugs Standard Control Organization (CDSCO), part of the Ministry of Health and Family Welfare (MoHFW), serves as the National Regulatory Authority for medical devices. The Medical Devices Rules, 2017, published as Gazette of India notification G.S.R. 78(E) on January 31, 2017, and effective from January 1, 2018, govern the regulation of medical devices in India, aiming to align with global standards and support domestic production.

Types of Clinical Investigations

Clinical investigations are defined by the Medical Device Rules 2017 as systematic evaluations of experimental medical devices on human subjects to assess their performance and safety. Key types of clinical investigations include:

1. Pilot Clinical Investigations: The pilot clinical investigation means clinical investigation to be carried out for the first time in human participants. (MDR 2017)
2. Pivotal Clinical Investigations: Larger studies to provide comprehensive data on the device’s safety and efficacy, often involving a significant number of participants with the condition being studied. A pivotal clinical investigation on an investigational medical device shall be made on the basis of data emerging from pilot clinical investigation (MDR 2017)

Approval process of Clinical Investigation of Medical Device

Any sponsor or individual conducting a clinical study utilizing experimental medical devices on human subjects must adhere to these guidelines and obtain the CLA's approval before beginning any such study.

A sponsor must use Form MD-22 to apply to the Central Licensing Authority for authorization to carry out clinical research for an experimental medical device. The data listed in checklist must be submitted with this application along with a fee as specified in Second Schedule of Medical Device Rules 2017.

Based on information from the pilot clinical study, a pivotal clinical investigation on an experimental medical device must be carried out with fees specified in Second Schedule of Medical Device Rules 2017.

Authorization to conduct a clinical trial for the investigational medical device must be obtained in the Form MD-23 within ninety days of verifying compliance with the regulations. If the information does not satisfy the CLA, deny the application and give a written explanation. The approval process of clinical investigation of medical device from application to approval with timeline is given in below Figure.

Conditions of approval

1. Only once the registered Ethics Committee has approved the clinical study strategy may a clinical trial begin.
2. The Central Drugs Standard Control Organization's Good Clinical Practices Guidelines, the Seventh Schedule's rules, and the approved clinical investigation plan must all be followed when conducting the clinical inquiry.
3. The clinical research needs to listed with the Clinical Trial Registry of India (CTRI) before the 1^st participant is enrolled.
4. Each clinical trial must have an annual status report from the sponsor to the Central Licensing Authority stating whether it is ongoing, finished, or terminated. If an account is terminated, the Central Licensing Authority must be informed in writing of the reasons in detail in thirty days.
5. Sponsor shall notify the Central Licensing Authority (CLA) of any suspected unanticipated significant adverse event that occurs throughout the clinical trial within fourteen days of its occurrence, after conducting a thorough analysis and adhering to the Seventh Schedule's protocol.
6. The applicant will furnish full medical treatment and compensation in compliance as per the regulations in the event of an injury or death sustained by the subject during the clinical inquiry.
7. Officers from the Central Licensing Authority may investigate the sponsor's properties, including the clinical research sites, personnel, subsidiaries, branches, agents, contractors, and subcontractors. To confirm adherence to the guidelines for carrying out clinical examinations, these officials might be joined by representatives of State Licensing Authority and independent specialists.
8. Within a year of the date the permission was granted, the clinical trial must begin by enrolling the first subject. If this isn't done, the clinical trial can't begin without first getting approval as of the Central Licensing Authority.
9. If it is deemed necessary, the Central Licensing Authority retains the right to impose or exempt any condition on permission for specific clinical investigations, including those pertaining to the investigation's goal, subject eligibility, subject population, conduct, design, assessment and treatment. 
10. CLA can suspend or cancel the permission to conduct clinical investigation, if sponsor fails to follow the conditions mentioned above.

Post Marketing Clinical Investigation

Post-marketing clinical investigation is a term used to describe a study—as opposed to surveillance—that is carried out once the medical device has received marketing approval for the designated indication. The Central Licensing Authority may mandate this inquiry in order to maximize the medical device's intended use, even if it may not have been thought required at the time of licensing. Post-marketing clinical inquiry includes a range of studies, including safety studies, extra evaluations of drug-device interactions, and investigations intended to bolster the use of medical device within permitted indication, such as studies on mortality or morbidity⁵⁸.

Periodic Safety Update Reports (PSURs) should require to be provided by applicants every 6 months for the first 2 years afterward the medical device's marketing approval. PSURs are then needed to be submitted yearly for the following two years. However, if it is thought necessary to protect the public's health, the Central Licensing Authority retains the power to extend the deadline for submitting PSURs. PSURs for a given time frame have to be turned in no later than thirty calendar days following the conclusion of the reporting period. Within fifteen days after the applicant's initial notification of the licensing body, incidents involving suspected unanticipated major adverse events must be reported.

Data relating to PSURs must be submitted on a deferred basis, beginning since the moment medical device was marketed, if the applicant decides to postpone selling the device after receiving approval.

Every medical device must have a Periodic Safety Update Report (PSUR) that includes the following information in order to track clinical safety:

1. Report any new information that is pertinent and from reliable sources.
2. Connect patient exposure to these data.
3. List the various countries' market authorization statuses along with any notable safety-related differences.
4. State whether the product's information will be altered to maximize its use.

Any notable modifications to the reference safety data that occur during the reporting interval are likewise recorded in the PSUR. Information on contraindications, cautions, adverse events (AE), warnings, and significant nonclinical results are among the changes that fall under this category. Additionally, noteworthy findings from ongoing and completed clinical investigations are included.

The Indian Pharmacopoeia Commission oversees the Materiovigilance Program of India (MvPI) to ensure the oversight of medical devices in order to reduce risk and maintain a favorable risk-benefit ratio. Through ongoing monitoring, this program aids in evaluating and identifying adverse effects of medical devices, as well as malfunctions, which may lead to mortality and morbidity. Since its inception, the MvPI has been instrumental in preventing the circulation of unsafe products.

Regulatory Pathways for Clinical Investigations in India

In India, clinical investigations for medical devices are governed by distinct regulatory pathways based on the device’s classification and novelty. For voluntary clinical investigations, manufacturers may choose to conduct studies to gather supplementary data on the safety and efficacy of their devices, even though such investigations are not mandated by Indian regulations. This voluntary pathway can enhance market acceptance and provide additional validation. Conversely, mandatory clinical investigations are required for devices that lack a predicate device, ensuring that new or innovative devices meet safety and performance standards before market approval.

Voluntary Clinical Investigation

Manufacturers may opt for voluntary clinical investigations to collect additional data on the safety and effectiveness of their medical devices, even if not mandated by regulations. This can aid in obtaining market approval, enhancing product performance, or gaining a competitive edge.

Voluntary Clinical Investigations are always subjected to Pivotal Clinical Investigation.

Reference Rule 51 - Sub-rule (5) Medical devices requiring clinical investigation but claiming substantial equivalence to a predicate device shall not be marketed unless the Central Licensing Authority has approved it.

A claim of substantial equivalence does not mean that the proposed medical device and predicate device are identical. Substantial equivalence shall be established with respect to intended use, design, energy used or delivered, materials, chemical composition, manufacturing process, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics, as applicable. (MDR 2017)

Mandatory Clinical Investigation

For devices lacking a predicate device (i.e., no existing similar device in the market), mandatory clinical investigations are required to demonstrate safety and efficacy before market approval.

Regulatory Basis:

• Regulatory Framework: Mandated by the Medical Device Rules, 2017.
• Guidelines: Compliance with CDSCO requirements and Good Clinical Practice (GCP) is essential.

Clinical Investigation Application (CIA):

• Submit a detailed CIA to CDSCO, including clinical investigation protocol, pre-clinical data, and risk assessments.

Ethics Committee Approval:

• Obtain approval from a registered Ethics Committee to ensure the investigation adheres to ethical standards.

Clinical Trial Agreement:

• Enter into agreements with clinical trial sites and investigators, specifying roles, responsibilities, and compliance requirements.

Conduct of Investigation:

• Carry out the investigation following the approved protocol and GCP guidelines. Ensure rigorous monitoring and documentation throughout the study.

Data Collection and Reporting:

• Compile and analyze investigation data. Submit a detailed report to CDSCO for evaluation and approval.