Sponsor's Roles and Responsibilities (31%-35%)

Section 4.13 Abstracting / Verification of Information from Medical Records describes:

Data abstracting/verification from medical records from investigator's standpoint.

Continuing Reviews (Sponsor):

The sponsor is required under to submit annual reports to FDA on the progress of the clinical study.

Sponsor Corrective and Preventative Action Plans (CAPA) requirement:

Sponsor is recommended to develop quality assurance and quality control system for clinical trial oversight at the sponsor, as listed in section 5.1 of the ICH GCP guideline.

Final Reports For drug studies (Sponsor):

Sponsor must submit clinical trial reports to appropriate regulatory agency as required.

A study monitor performs SDV to:

Verify whether the data / information entered on the case report form (CRF) are consistent and accurate based on the source data.

MEDWATCH (Form 3500B):

Voluntary reporting for consumers. This is a consumer-friendly version of the Form 3500 reporting form.

MEDWATCH (Form 3500):

Voluntary reporting. This is for healthcare professionals and consumers for voluntary reporting of adverse events found in the course of clinical care.

For investigational device studies, clinical investigators must retain study records for:

a period of two years after (21 CFR 812.140 (d): -The investigation is terminated or completed, or -The date that the records are no longer required for purposes of supporting a premarket approval application or a notice of completion of a product development protocol.

Final Reports for medical device studies (Sponsor):

1. A sponsor conducting a trial on significant risk device: -Notify FDA within 30 working days of the completion or termination AND -Submit a final report to FDA, all reviewing IRBs, and participating investigators within 6 months after completion or termination. 2. A sponsor that conducts a trial on non-significant risk device should: -Submit a final report to all reviewing IRBs within 6 months after completion or termination.

21 CFR 312.53 (c) lists specific information from investigator prior to clinical trial participation as:

1. A signed investigator statement (FDA form 1572) 2. Curriculum vitae 3. Clinical protocol 4. Financial disclosure information

Content of an IND?

1. Animal Pharmacology and Toxicology Studies - pre-clinical data in animal on pharmacology and toxicology and any available data on drug effect in human. 2. Manufacturing Information - information on composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. 3. Clinical Protocols and Investigator Information - detailed protocols, investigator's brochure, and information on the qualifications of clinical investigators who oversee the administration of the experimental compound (FDA Form 1571, FDA Form 1572)

Responsibilities of a study monitor in source data verification include:

1. Check the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. 2. Inform the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialed by the investigator or by an authorized personnel. This authorization should be documented.

Different types of IND?

1. Commercial IND 2. Investigator IND 3. Emergency Use IND - for the use of an investigational drug or biologic in an emergency situation that does not allow time for submission of an IND in a normal route 4. Treatment IND - for investigational drug or biologic that shows promise in clinical testing for serious or immediately life-threatening conditions while the final clinical testing and FDA review are taking place.

Study monitor's responsibilities with regard to study oversight may involve:

1. Create, maintain, and review study related documents (Protocol, CRFs, monitoring plans, trip reports, clinical study report, instructions, etc.) 2. Identify potential sites and qualified investigators 3. Assist in regulatory application submission and approvals (FDA, IRBs, etc.). 4. Prepare the trial sites for conducting the study; o Ensure that trial sites have necessary materials, equipment, including investigational product. 5. Provide necessary training 6. Monitor the trial throughout its duration from initiation to close out (both on site visits and remote inquiries) 7. Work with sites and sponsor team members to identify, capture, document, and resolve problems 8. Escalate any compliance and trial issues to appropriate personnel.

21 CFR 312.23 (a) describes the content that should be in the IB:

1. Description of the drug substance and the formulation, including the structural formula, if known. 2. The pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans. 3. The pharmacokinetics and biological disposition of the drug in animals and, if known, in humans. 4. Information on safety and effectiveness in humans obtained from prior clinical studies. 5. Possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug.

When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:

1. Ensure and document that the electronic data processing system(s) conforms to the sponsor's established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation). 2. Maintains SOPs for using these systems. 3. Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data (i.e. maintain an audit trail, data trail, edit trail). 4. Maintain a security system that prevents unauthorized access to the data. 5. Maintain a list of the individuals who are authorized to make data changes 6. Maintain adequate backup of the data. 7. Safeguard the blinding, if any (e.g. maintain the blinding during data entry and processing).

Sponsor Investigational Product Accountability requirements:

1. Ensure timely delivery of investigational product(s) to the investigator(s) 2. Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s) 3. Maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, and expired product reclaim) 4. Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition. Section 5.14.5 of ICH GCP guideline also states that the sponsor should: 1. Take steps to ensure that the investigational product(s) are stable over the period of use. 2. Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. 3. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.

Medical Device reports (Sponsor):

1. For medical device trials, the sponsor is required to maintain records of adverse device effects (whether anticipated or unanticipated) and complaints [21 CFR 812.140 (b)(5)]. 2. A sponsor shall immediately conduct an evaluation of any unanticipated adverse device effect [21 CFR 812.46 (b)].

Annual Report includes:

1. Individual study information. A summary of status of study in progress and completed study that include: -Title, protocol number, purpose, patient population, and status -No. of subjects planned, enrolled, completed, withdrawn (list by age group, gender, and race) -Any available interim results. 2. Summary information. Information from clinical and nonclinical investigations, including: -A narrative or table showing most frequent and most serious adverse events by body systems -Summary of IND Safety Reports submitted -List of subjects who died and the cause of death -List of subjects who dropped out due to adverse events (regardless of relatedness to drug) -Any new understanding of drug's actions (e.g. dose response, bioavailability, etc.) -List of pre-clinical studies completed or in progress and major findings -Any significant manufacturing or microbiological changes. 3. General investigational plan. A description on the investigational plan for the coming year that includes: -Rationale for the drug or the research study -Indication(s) to be studied -General approach to be followed in evaluating the drug -Clinical trials to be conducted in the first year following the submission (if plans are not developed for the entire year, the sponsor should so indicate) -Estimated number of patients to be given the drug in those studies -Any risks of particular severity or seriousness anticipated on the basis of the toxicological data in animals or prior studies in humans with the drug or related drugs.

FDA form 1572 (Investigator statement) contains:

1. Investigator's name and address 2. Protocol name and code number 3. Name and address of facility(ies) 4. Name and address of clinical laboratory 5. Name and address of the IRB 6. A commitment by the investigator that he or she will: -Follow the current protocol(s) and will only make changes in a protocol after notifying the sponsor, except when necessary to protect the safety, the rights, or welfare of subjects -Comply with all FDA requirements for clinical investigators -Personally conduct or supervise the investigation(s) -Inform potential subjects that the drugs are being used for investigational purposes -Follow informed consent and institutional review board review and approval requirements -Report adverse events to the sponsor -Read and understands the information in the investigator's brochure -Ensure that all clinical trial staff are informed about their obligations -A commitment by the investigator that the reviewing IRB complies with 21 CFR 56 -Names of the sub-investigators

Complete list of records that study monitor should review / verify:

1. Investigator's qualification: -Updated and current curriculum vitae (CV), medical license, training, lab license and accreditation, etc. -Human subject protection and / or GCP training records -Signed financial disclosure 2. Institutional review board (IRB) initial approval and annual review approval 3. Signed protocol and amendments 4. Verify that latest version of IRB approved informed consent form is being used 5. Screening and enrollment list 6. Inclusion / exclusion criteria 7. Case report forms (CRFs) are being completed consistently and accurately 8. Investigational product accountability (receipt, usage, return, or discard) 9. Adverse events (AEs) and serious adverse events (SAEs) reporting 10. Relevant communication (letters, meeting minutes, telephone call notes, emails, etc.)

Section 5.18.4 of ICH GCP guideline lists monitor's responsibilities as:

1. Maintain communication between the sponsor and the investigator. 2. Verify investigator's qualifications and make sure that resources, facilities, and staff are adequate to safely and properly conduct the trial throughout the trial period. Manage the investigational product(s) 3. Verify protocol compliance. 4. Verify that written informed consent was obtained before each subject's participation. 5. Ensure that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed. 6. Ensure that the investigator and the investigator's trial staff are adequately informed about the trial. 7. Verify that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals. 8. Verify that the investigator is enrolling only eligible subjects. 9. Report the subject recruitment rate. 10. Verify that source documents and other trial records are accurate, complete, kept up-to-date and maintained. 11. Verify that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial. 12. Check the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. 13. Inform the investigator of any CRF entry error, omission, or illegibility. 14. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialed by the investigator or by an authorized personnel. This authorization should be documented. 15. Determine whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s). 16. Determine whether the investigator is maintaining the essential documents 17. Communicate deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action to prevent recurrence of the detected deviations.

21 CFR 312.56 requires that the sponsor review ongoing investigations with the focus on:

1. Monitor the progress of all clinical investigations under its investigational new drug (IND) application. 2. A sponsor who discovers that an investigator is not in compliance should either secure compliance or discontinue shipments and end the investigator's participation. If the investigator's participation is ended, the sponsor should require that the investigator destroy or return the investigational drug (following 21 CFR 312.59 and should notify FDA). 3. Review and evaluate the safety and effectiveness of the drug and reports to FDA any safety issues as required under 21 CFR 312.32. The sponsor should make annual reports on the progress of the investigation following 21 CFR 312.33 4. A sponsor who determines that its investigational drug presents an unreasonable and significant risk to subjects shall discontinue those investigations that present the risk, notify FDA, all institutional review boards, and all investigators who have at any time participated in the investigation of the discontinuance, assure the disposition of all stocks of the drug outstanding as required by 21 CFR 312.59 and furnish FDA with a full report of the sponsor's actions. The sponsor shall discontinue the investigation as soon as possible, and in no event later than 5 working days after making the determination that the investigation should be discontinued. Upon request, FDA will confer with a sponsor on the need to discontinue an investigation.

Ways that an IND Safety Report can be submitted:

1. Narrative document (overall findings or pooled analyses from published and unpublished in-vitro, animal, epidemiological, or clinical studies) 2. FDA form 3500A 3. An electronic format that FDA can process, review, and archive 4. Council for International Organizations of Medical Sciences (CIOMS) I Form - for foreign suspected adverse reactions.

Steps that can help a sponsor ensure that informed consent regulations are followed:

1. Obtain signed FDA form 1572. One of the commitments by the investigator listed on FDA form 1572 Investigator Statement is that informed consent (21 CFR 50) requirement will be followed 2. Provide a sample informed consent form with all the required elements to investigator and work with investigator to formulate final version 3. Ensure that appropriate monitoring is done. Informed consent documentation review is a part of monitor's responsibilities listed in section 5.4.1 Monitoring.

A Quality System approach may be designed and implemented by sponsors that include:

1. Personnel roles and responsibilities 2. Training 3. Policies and procedures 4. Quality assurance and auditing 5. Document management, record retention, and reporting 6. Corrective and preventive action (CAPA). *In addition to above, a risk analysis may be used to allocate resources to activities that present a greater risk to human subjects and data integrity.

General responsibilities of a sponsor from 21 CFR 312.50:

1. Selecting qualified investigators 2. Providing the information and training the investigators need to conduct an investigation properly 3. Ensuring proper monitoring of the investigation(s) 4. Ensuring that the investigation(s) is conducted following the general investigational plan and protocols contained in the IND 5. Maintaining an effective IND 6. Promptly informing the FDA of significant new adverse effects or risks.

Items that should be reported in an IND Safety Report:

1. Serious and unexpected suspected adverse reaction. The sponsor must report any suspected adverse reaction that is both serious and unexpected (with causal relationship between the drug and the adverse event), such as: -A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure -One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug -An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group. 2. Findings from other studies that may suggest significant risk in humans exposed to the drug. 3. Findings from animal or in-vitro testing that may suggest significant risk in humans exposed to the drug. 4. Increased rate of occurrence of serious suspected adverse reactions from previously listed in protocol or investigator's brochure (IB).

The sponsor QA audit visit is performed to:

1. Show sponsor's quality oversight 2. Identify potential issues and improvement opportunities 3. Identify any potential regulatory risks that may jeopardize product approval.

Sponsor Reports (Safety Related) From 21 CFR 812.150 (b):

1. Sponsor is required to prepare and submit the following complete, accurate, and timely reports: -Unanticipated Adverse Device Effects. A sponsor is required to report any unanticipated adverse device effects to FDA and to all reviewing IRB's and participating investigators within 10 working days after the sponsor first receives notice of the effect. -Withdrawal of IRB Approval. A sponsor shall notify FDA and all reviewing IRB's and participating investigators of any withdrawal of IRB approval of an investigation or a part of an investigation by a reviewing IRB within 5 working days after receipt of the withdrawal of approval. -Withdrawal of FDA Approval. A sponsor shall notify all reviewing IRB's and participating investigators of any withdrawal of FDA approval of the investigation, and shall do so within 5 working days after receipt of notice of the withdrawal of approval. -Recall and device disposition. A sponsor shall notify FDA and all reviewing IRB's of any request that an investigator return, repair, or otherwise dispose of any units of a device. Such notice shall occur within 30 working days after the request is made and shall state why the request was made. -Significant risk device determinations. If an IRB determines that a device is a significant risk device, and the sponsor had proposed that the IRB consider the device not to be a significant risk device, the sponsor shall submit to FDA a report of the IRB's determination within five working days after the sponsor first learns of the IRB's determination.

Drug safety reports (Sponsor):

1. Sponsor is required to review all relevant safety information for the investigational drug that is available [21 CFR 312.32 (b)] 2. Sponsor must report any potential serious risks associated with the investigational product to FDA and all participating investigators as soon as possible, but not more than 15 calendar days after the sponsor determined that the events meet the criteria below. This reporting is called IND Safety Report.

Financial disclosure information (Sponsor):

1. Sufficient accurate financial information to allow the sponsor to submit complete and accurate certification or disclosure statements required under 2. The sponsor shall 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 1 year following the completion of the study.

Monitors need to verify the investigational product(s):

1. That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial. 2. That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s). 4. That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s). 5. That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately. 6. That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.

To check the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other, the monitor specifically should verify that:

1. The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents. 2. Any dose and/or therapy modifications are well documented for each of the trial subjects. 3. Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs. 4. Absence of subject visit, tests, and examinations are clearly reported as such on the CRFs.

During Source Data Verification- the monitor specifically should verify that:

1. The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents. 2. Any dose and/or therapy modifications are well documented for each of the trial subjects. 3. Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs. 4. Absence of subject visit, tests, and examinations are clearly reported as such on the CRFs. 5. All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.

Requirements for electronic records controls for closed systems (21 CFR 11.10):

1. Validation to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records 2. Ability to generate accurate and complete copies of records in both human readable and electronic form suitable for inspection, review, and copying by the agency 3. Protection of records to enable their accurate and ready retrieval throughout the records retention period 4. Limiting system access to authorized individuals 5. Use of secure, computer-generated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete electronic records 6. Record changes shall not obscure previously recorded information 7. Audit trail documentation shall be retained for a period at least as long as that required for the subject electronic records and shall be available for agency review and copying 8. Use of operational system checks to enforce permitted sequencing of steps and events, as appropriate 9. Use of authority checks to ensure that only authorized individuals can use the system, electronically sign a record, access the operation or computer system input or output device, alter a record, or perform the operation at hand 10. Use of device (e.g., terminal) checks to determine, as appropriate, the validity of the source of data input or operational instruction 11. Determination that persons who develop, maintain, or use electronic record/electronic signature systems have the education, training, and experience to perform their assigned tasks 12. The establishment of, and adherence to, written policies that hold individuals accountable and responsible for actions initiated under their electronic signatures, in order to deter record and signature falsification 13. Use of appropriate controls over systems documentation

The sponsor is responsible for implementing and maintaining Quality Assurance and Quality Control systems with:

1. written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). [ICH GCP guideline section 5.1.1] 2. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. [ ICH GCP guideline section 5.1.3]

Sponsor is required to provide the investigator's brochure (IB) to the investigator, following the requirement listed under:

21 CFR 312.55 (a)

Record Retention (Sponsor) requirement:

21 CFR 312.57 (c)requires that sponsor conducting investigational drug trials keeps study records for 2 years after: -A marketing application is approved OR -If an application is not approved for the drug, until two years after shipment and delivery of the drug for investigational use is discontinued and FDA has been so notified

What happens after an IND is submitted?

30 day hold period - there is a 30 calendar days period for the FDA to review the IND for safety. The sponsor or sponsor-investigator must wait until after this 30 calendar days period before initiating the clinical trials.

Curriculum vitae (Sponsor):

A curriculum vitae or other statement of qualifications of the investigator showing the education, training, and experience that qualifies the investigator as an expert in the clinical investigation of the drug for the use under investigation.

Investigator's brochure (IB):

A document that summarizes the known information about the investigational product.

21 CFR 312.3- Sponsor is defined as:

A person (entity) who takes responsibility for and initiates a clinical investigation. 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. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.

Investigations of marketed drugs (Sponsor):

A sponsor of a clinical study of a drug marketed or approved in the United States that is conducted under an IND is required to submit IND safety reports for suspected adverse reactions that are observed in the clinical study, at domestic or foreign study sites.

21 CFR 312.53 (a) describes specific requirements that sponsors should follow when selecting an investigator / clinical trial site as:

A sponsor shall select only investigators qualified by training and experience as appropriate experts to investigate the drug.

Annual Report - Drug Trials (21 CFR 312.33) Sponsor:

A sponsor shall within 60 days of the anniversary date that the IND went into effect, submit a brief report of the progress of the investigation.

21 CFR 312.3- Sponsor-Investigator is defined as:

An individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual. The requirements applicable to a sponsor-investigator under this part include both those applicable to an investigator and a sponsor.

Quality Assurance (QA) (Sponsor):

As part of Quality Assurance (QA) processes, sponsor companies usually have a separate QA team to oversee the quality of the clinical trial conduct. The QA team typically conducts sponsor QA audit visit to clinical trial sites

When to submit an IND?

Before clinical trials are initiated for a new investigational drug or biologic to be marketed in the United States or for a new indication or different mode of administration of an approved drug or biologic.

Section 5.6.2 of the ICH GCP guideline:

Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator's Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.

21 CFR 312.55 (a):

Before the investigation begins, a sponsor (other than a sponsor-investigator) shall give each participating clinical investigator an investigator brochure containing the information described in 312.23 (a)(5).

FDA Form 3454:

Certification. This is for financial disclosure certification for any clinical investigator who has no disclosable financial interests in or arrangements with any sponsor of the covered clinical study.

FDA 21 CFR 11.30: Closed system

Closed system- When access to the system is controlled by persons who oversee the content.

FDA Form 1571:

Cover page for an investigational new drug application (IND). This is the cover sheet for investigational new drug application (IND) submissions. This form lists the information being provided in the submission.

FDA Form 3455:

Disclosure Statement. This is for each financial disclosure for clinical investigator who, or whose spouse or dependent child, had disclosable financial interests in and/or arrangements with any sponsor of the covered clinical study.

The common goal of the sponsor QA audit:

Ensure that the clinical trials are conducted following the required regulation and that human subject rights and safety area protected.

Study Plan (Sponsor):

In clinical research, a study plan is also known as an investigational plan or a protocol. Section 5.4.1 of the ICH GCP guideline requires that sponsor utilize qualified individuals (e.g. biostatisticians, physicians, etc.) as appropriate to oversee the design of the protocol.

IDE:

Investigational Device Exemption (IDE) application. This is the application to FDA to seek permission to test a new medical device (or in vitro diagnostic) in clinical trial involving human subjects. This applies for clinical studies supporting a premarketing approval application (PMA) and some 510(k) applications.

IND:

Investigational new drug (IND) application. This is the application to FDA to seek permission to test a new drug (or biologic) in clinical trial involving human subjects.

Clinical Protocol- Sponsor responsibility:

It is generally the responsibility of the sponsor to generate and provide a protocol to investigator. This is also indirectly stated in section 5.4.1 and directly stated in section 5.6.2 of the ICH GCP guideline.

MEDWATCH (Form 3500A):

Mandatory reporting. This is for sponsors, manufacturers, distributors, importers, user facilities for mandatory reporting of adverse events found.

Study Coordination (Sponsor):

One of the responsibilities of a study monitor is to maintain communication between the sponsor and the investigator. The reason for this is to oversee the progress of clinical trial conduct at the site.

Clinical trial monitor/ CRA:

Professional who oversees all aspects of clinical trial conduct. A monitor may be an employee of the sponsor, also called In House CRA. The sponsor may also contract the monitoring work to a vendor, such as a contract research organization (CRO) or an independent monitor who is selfemployed.

Annual Report - Medical Device Trials (21 CFR 812.150) -Sponsor:

Required that a sponsor submit progress reports to all reviewing IRBs at regular intervals, and at least yearly. Sponsor conducting clinical trials on a significant risk device is also required to submit progress report to FDA. A sponsor of a treatment IDE shall submit semi-annual progress reports to all reviewing IRB's and FDA and annual report. In addition, sponsor must notify the FDA within 30 working days of the completion or termination of the investigation of a significant risk device clinical trial. The sponsor is also required to submit a final report to FDA and all reviewing the IRBs and participating investigators within 6 months after completion or termination. In the case of a device that is not a significant risk device; the sponsor shall submit a final report to all reviewing IRBs within 6 months after termination or completion.

21 CFR 312.50 describes general responsibilities of sponsors as:

Responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols contained in the IND, maintaining an effective IND with respect to the investigations, and ensuring that FDA and all participating investigators are promptly informed of significant new adverse effects or risks with respect to the drug.

Investigational Product training requirements:

Section 5.14.3 of the ICH GCP guideline requires that the sponsor provides written procedures / instructions to the investigator on: -The handling and storage of investigational product(s) for the trial -Receiving and dispensing of investigational product(s) -Retrieval of unused product from subjects -Return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).

Study Training requirement (Sponsor):

Section 5.18.3 of the ICH GCP guideline detailed the requirement for sponsor's trial oversight through monitoring: The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators' training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.

GCP training requirements:

Section 5.6.3(a) of the ICH GCP guideline requires that sponsor obtain investigator's agreement to conduct the trial according to GCP guideline, appropriate regulations, and study protocol. This places the responsibility on the sponsor to ensure that the investigator receives appropriate GCP training prior to participation. Most IRBs will require that the investigator submit prove of GCP and / or human subject protection training as a part of IRB application. Thus, the sponsor should obtain this proof of GCP and / or human subject protection training for sponsor's records.

21 CFR 312.53 (d):

Selecting monitors. A sponsor shall select a monitor qualified by training and experience to monitor the progress of the investigation.

For the sponsor, abstracting-verifying information from medical records is called:

Source Data Verification (SDV)

FDA Form 1572:

Statement of Investigator. This is an agreement signed by the investigator to provide information to the sponsor and assure that he/she will comply with FDA regulations related to the conduct of a clinical investigation of an investigational product.

Maintenance of Essential Study Related Documents (Paper / Electronic) For Sponsors

The sponsor is required to have a more stringent standard of an established quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure appropriate processes are in place. SOPs that describe the method and procedures to be used to file and maintain sponsor-specific essential documents should be a part of the sponsor's QA and QC system.

Section 5.1.1 of ICH GCP guideline states the Sponsor requirement for standard operating procedures (SOPs) as:

The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

Monitoring responsibilities of the Sponsor:

The sponsor is the responsible party for the clinical trial under its initiation. Thus, it is the responsibility of the sponsor to monitor the clinical trial to ensure that it is being conducted following regulations.

Unexpected fatal or life-threatening suspected adverse reaction reports (Sponsor):

The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the information.

21 CFR 312.55 (b):

The sponsor shall, as the overall investigation proceeds, keep each participating investigator informed of new observations discovered by or reported to the sponsor on the drug, particularly with respect to adverse effects and safe use. Such information may be distributed to investigators by means of periodically revised investigator brochures, reprints or published studies, reports or letters to clinical investigators, or other appropriate means.

Section 5.4.1 of the ICH GCP guideline:

The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.

Section 5.5.6 of the ICH GCP guideline requires that a Sponsor:

The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial.

Clinical protocol (Sponsor):

This protocol is usually given to the investigator by the sponsor. An acknowledgement signature from the investigator is usually needed.

FDA 21 CFR 11.30: Open system

When access to the system is not controlled by persons who oversee the content- records can be read, modified, or compromised by others. Thus, for open systems, FDA regulations emphasize the need to ensure authenticity, integrity, and confidentiality via the use of appropriate digital signature standards and encryption as: Persons who use open systems to create, modify, maintain, or transmit electronic records shall employ procedures and controls designed to ensure the authenticity, integrity, and, as appropriate, the confidentiality of electronic records from the point of their creation to the point of their receipt. Such procedures and controls shall include those identified in 11.10, as appropriate, and additional measures such as document encryption and use of appropriate digital signature standards to ensure, as necessary under the circumstances, record authenticity, integrity, and confidentiality.