See the Regulatory Authority topic, Scope of Assessment subtopic for more information. Beltsville, MD Therapeutic Biological Products: U. Based on information provided in 21CFR , for paper IND submissions, the sponsor must submit an original and two 2 copies, including the original submission and all amendments and reports. Noncommercial INDs are exempt from this submission requirement. See USA-8 for information on how to create an account. As indicated in the G-eCTDspecs , physical media should comply with the following requirements:.
See the G-eCTDspecs for additional physical media information. The IND must be submitted in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted. According to G-PedStudyPlans , a sponsor who is planning to submit a marketing application or supplement to an application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan iPSP , if required by the Pediatric Research Equity Act PREA.
An exception to this is if the drug is for an indication granted an orphan designation. For detailed application requirements, see 21CFR Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials. Each EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies supplied and application format requirements.
Per the RevisedCommonRule , which took effect January 21, , where limited EC review applies, the EC does not need to make the determinations outlined above. Clinical studies shall not be initiated until 30 days after the date of receipt of the IND application by the FDA unless earlier notification is received from the FDA that studies may begin. Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial.
As per 21CFR , once an IND has been submitted and following the day review period, the sponsor is permitted to import an investigational product IP. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.
See also the G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial. In this case, as stated in 21CFR50 , the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation.
The US-ICH-GCPs recommends establishing a DSMB to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. The sponsor is required to submit a follow-up safety report to provide additional information obtained pertaining to a previously submitted safety report.
This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information. In each safety report, the sponsor must identify all safety reports previously submitted to the FDA concerning a similar SAR, and must analyze the significance of the SAR in light of previous, similar reports, or any other relevant information.
As part of the clinical trial results information submitted to ClinicalTrials. The tables should consist of the following summarized data:. This information must be submitted no later than one 1 year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two 2 years if the sponsor or PI submits a certification to ClinicalTrials. Additionally, as indicated in the CommonRule and the RevisedCommonRule , for HHS funded or sponsored human subjects research, the institutional EC shall ensure that, when appropriate, the research plan makes adequate provision for monitoring the data collected during the study to ensure participant safety.
DSMBs are specifically required for NIH-funded, multi-site clinical trials with interventions that involve potential participant risk. As specified in 21CFR , the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. The report must contain the following information for each study:.
There is no specific timeframe stipulated for when the report should be completed. See 42CFR11 for more detailed requirements. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization.
The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. The term does not include any person other than an individual. Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing, and those obligations not covered by the written description shall be deemed not to have been transferred.
Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR and shall be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations. As indicated in 21CFR , a sponsor may be either domestic or foreign. Per 21CFR , to complete the IND application package, the sponsor must provide the following information in paper format or electronically:.
The G-CTDiversity also provides recommendations to sponsors for increasing enrollment of underrepresented populations in their clinical trials. The United States US regulations do not require compensation for trial participants either for participation in a trial or in the event of trial-related injuries or death. The sponsor must also inform participants who suffer any trial-related injuries of any available medical treatments, what they consist of, and where further information can be obtained.
Payment amounts and schedules should be presented to the ethics committee EC institutional review board IRB in the US at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence, and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study.
Further, FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence. Per the US-ICH-GCPs , the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results.
The quality management system should use a risk-based approach that includes:. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.
In addition, the sponsor must maintain SOPs that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning.
With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training.
See G-eHealthRecords for guidance related to the use of electronic health records in clinical research. Additionally, per 21CFR , the sponsor must upon request from the FDA, permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports or copies of them to the agency.
The storage system used during the trial and for archiving irrespective of the type of media used should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor.
The sponsor should appoint auditors to review the clinical trial. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring.
The sponsor should document the rationale for the chosen monitoring strategy e. The sponsor must also notify the FDA, all institutional ethics committees ECs institutional review boards IRBs in the United States , and all investigators who have participated in the study about the termination.
According to the US-ICH-GCPs , if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions.
Further, the EC should also be informed promptly and provided the reason s for the termination or suspension by the sponsor. In the event of multicenter clinical studies, also known as cooperative research studies, which are required to comply with the RevisedCommonRule , all federally-funded or sponsored institutions that are located in the US and engaged in multicenter research must use a single EC to review that study, known as the EC policy.
The exceptions to this requirement include: when multiple-EC review is required by law including tribal law or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate. Designed to complement the RevisedCommonRule , which took effect January 21, , per the NIHNotice and the NIHNotice , the National Institutes of Health NIH , issued a final policy requiring all institute-funded multicenter clinical trials conducted in the United States be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.
As set forth in 21CFR and the US-ICH-GCPs , the sponsor is responsible for selecting the investigator s and the institution s for the clinical trial and for ensuring that the investigator s are qualified by training and experience. Prior to permitting an investigator s to conduct a study, the sponsor must obtain the following:. Although not specified as a sponsor requirement, the US-ICH-GCPs states that a Data and Safety Monitoring Board may be established to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.
Per the RevisedCommonRule , which took effect January 21, , for each clinical trial conducted or supported by a federal department or agency, one 1 EC-approved informed consent form used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs.
According to USA , two 2 federal websites have been identified to meet this requirement: ClinicalTrials. According to the RevisedCommonRule , if the federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a federal website e. The ICF must be posted on the federal website after the clinical trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol.
ICF content should be briefly and clearly presented orally and in writing, in a manner that is easy to understand and commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial.
Furthermore, the RevisedCommonRule requires that the informed consent, except for broad consent, must begin with a concise and focused presentation of the key information and organized to facilitate comprehension. Broad consent may be obtained in lieu of a full informed consent only with respect to the storage, maintenance, and secondary research uses of private identifiable information and identifiable biospecimens.
See USA for additional information regarding informed consent and broad consent requirements. See G-ElectronicIC for further guidance related to electronic informed consent. The communication of this information should be documented. The G-IRBFAQs indicates that the FDA does not require re-consenting of participants who have completed their active participation in the study, or of participants who are still actively participating when the change will not affect their participation.
One such case is when the change will be implemented only for subsequently enrolled participants. Language Requirements. The EC must review and approve all English and non-English language versions of consent documents. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available. Documentation Copies. The RevisedCommonRule explicitly allows electronic signatures for consent documentation.
The RevisedCommonRule also adds that the EC may waive the requirements to obtain a signed ICF if the participants are part of a distinct cultural group or community in which signing the form is not the norm, the research presents minimal risk, and there is an alternative approach to document informed consent.
Based on the protocol being reviewed, subject matter experts may be invited to offer their views and recommendations. Members who are independent of the trial and the sponsor should provide opinions or vote during the EC deliberations. All the members shall sign a declaration to the effect that there is no conflict of interest with respect to the protocol reviewed by them. In case there is conflict of interest, the members shall voluntarily withdraw from the EC meeting.
Please refer to Table 2. These inspection visits are generally conducted to ensure compliance with applicable Rules, GCP, etc. Accreditation of an Ethics Committee is recommended optional at present. It is advisable that the EC makes an effort to seek recognition or accreditation or certification from a national or international body.
Some other optional accreditation bodies are:. No deviations or changes from the approved protocol can be implemented without the prior written approval of the EC and the CDSCO in case of a regulatory clinical trial or EC for an academic clinical trial. Exceptions to this are circumstances when there is an urgent requirement to eliminate immediate hazards to the trial participant s or when the changes involve only the logistic or administrative aspect of the trial.
Clinical Trials Toolkit — India. The regulation introduces a single approach for the application and maintenance of a CT authorization, and applies to both single or multiple member state trials.
In addition, the regulation defines procedural timelines, harmonizes document requirements, and aims to reduce the administrative burden of applications. Note: This article does not cover notifications of milestones or unexpected events that are required by the new regulation.
The application content and assessment are divided into two parts: Part I contains scientific and medicinal product documentation; Part II contains the national and patient-level documentation see Table A. There is provision for cross-referencing to existing applications, which will further reduce the current administrative burden of EU CT applications. For many sponsors, the application process may require internal administration to support sponsor registration and role allocation where required by the CT arrangements e.
User training will be essential; it is expected that the EMA will offer system training. We will learn more as development of the portal and database progress, but we do know that there will be provision for both compiling an application within a workspace facility and for uploading an application that has been compiled outside of the system.
The application is submitted via the portal to all concerned member states CMSs in which the sponsor intends to conduct the CT Figure 1. At the time of application, the sponsor proposes a reporting member state RMS , who will be confirmed by day 6 following submission. Following submission, there is a validation period to assess whether the application is complete and whether the application is in scope of the regulation. During this period the member states may request additional information from the sponsor.
Member state requests for information during validation should be sent within 10 days of the submission. The regulation requires strict adherence to the maximum timelines for each phase of the application procedure and has provisions to ensure that delays from any party do not hold up the process. If the RMS does not provide validation feedback within the defined time frame, for example, this will be considered a tacit validation of the application. If a sponsor fails to reply to a request for information by the deadline, this will lead to the automatic tacit withdrawal of the application in all CMSs.
The portal will determine when the milestones such as the validation date have been met. This means that if the benefit-risk balance is not positive at the time of the authorisation, the application should be rejected. Usually a single round of RFI is expected with a short time for providing an answer. All critical issues raised in the RFI are expected to be solved in the answer to it, including submission of the corresponding updated documents e.
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