US food and drug administration Indian site inspections: An experience.

Since 2005, USFDA has begun inspections of Indian clinical trial investigator sites. This paper reports experience of an FDA inspection performed at two Indian centers. The inspection started with an in-depth discussion with the investigator and his team about the conduct of the clinical trial at the site and was followed by a tour of the important locations - registration, outpatient department, specialty clinic, medical record section, and special procedure department. The inspector reviewed the critical processes - protocol compliance, ethics committee approval, informed consent process, case record form and source documents completion, investigational product accountability, serious adverse events documentation and reporting. The inspector reviewed all documents from the investigator site file and conducted audit of all subjects enrolled at both the sites. As the Indian sites are not exposed to regulatory inspections, it is vital for the sponsor to conduct preinspection audit, provide training and support to face the FDA inspection.

INTRODUCTION

US Food and Drug Administration (FDA) have begun inspections of Indian clinical trials since 2005. Till date, 23 sites have been inspected. There have been articles focusing on FDA inspections[12] and USFDA guidance on inspections.[34] These articles provide a general approach and framework of FDA inspections. However, there is hardly any published information capturing the actual experience of the inspection process at Indian sites. Hence, there is little awareness among Indian sites about how to face an inspection. We describe here our experience of site inspections, discuss the challenges, and describe strategies to prepare the Indian sites for regulatory inspections.

INSPECTION OBJECTIVES

The inspector explained the objectives of the FDA inspection,[4] which are as follows:

To protect the rights, safety, and welfare of subjects involved in FDA-regulated clinical trials.

To verify the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications.

To assess compliance with FDA's regulations governing the conduct of clinical trials.

As FDA has limited jurisdiction over foreign investigators, the primary focus is to validate the data from the study through an onsite inspection and confirm credibility of data.

INSPECTION OUTCOME

After the inspection is over, the inspector prepares an establishment inspection report (EIR).The EIR classifications are as follows:[4]

NAI - No Action Indicated. No objectionable conditions or practices were found during an inspection (or the objectionable conditions found do not justify further regulatory action).

VAI - Voluntary Action Indicated. Objectionable conditions or practices were found, but the agency is not prepared to take or recommend any administrative or regulatory action.

OAI - Official Action Indicated. Regulatory and/or administrative actions will be recommended.

INSPECTION PROCESS

The site was informed 4 weeks in advance regarding the inspection through the sponsor. No direct communication from the FDA inspectors was sent to the sites. The inspection required the presence of clinical research associate (CRA) at the site to provide active assistance in locating documents and in establishing clear communication with the investigator and his team. However, the inspector did not expect CRA to pick up or accompany him. It is also advisable for the CRA not to travel with the inspector to avoid any discussions on the study conduct. The inspector also required a room to conduct the review of documents and also access to a photocopy machine to make copies of important documents. The duration of inspection was 4--5 working days. The inspection began with a meeting with the investigator and his team.

OPENING INTERVIEW WITH THE SITE TEAM

For FDA inspectors, the opening interview with the investigator and his team is essential to gain an understanding of how the trial was conducted. If the trial documentation does not reflect the process as described by the site staff, FDA inspectors may see that as a possible signal of a problem. The FDA inspectors gain their initial impressions of a site's conduct of a study through these early interactions with the investigator and site team, and focus on problem areas during the inspection process.

The inspector introduced himself, presented credentials to the investigator and began by asking the names, qualifications, and roles and responsibilities of each site staff, who participated in the study. He checked whether this information was as per FDA 1572 submitted by the sponsor. The inspector asked the investigator about his recruitment strategy and the overall recruitment status of the study at his site. The inspector asked the investigator to provide him with a list of all the trials that the PI has worked on along with the name of the sponsors.

The inspector conducted a detailed interview the investigator and requested detailed and specific answers for the following aspects of the study:

Study start date

Who was responsible for performing important aspects of the study?

Verification of inclusion and exclusion criteria

Obtaining informed consent

Assessing efficacy end points

Collecting and reporting adverse event

Whether the ethics committee (EC) approved the protocol, informed consent form (ICF), and any amendments to the protocol prior to implementation?

Whether the investigator and study team comply with the sponsor's protocol?

Whether protocol deviations were documented and reported to EC and sponsor?

How was the consent process conducted?

Which aspects of the study conduct were delegated?

How did the investigator supervise the study conduct?

How did the investigator ensure that his study team was trained about the protocol and the study conduct?

Who performed specific investigations – lab, imaging? Where? How?

Was an investigator meeting (IM) conducted? Did sponsor provide any training for special procedures/investigations? How was the training conducted and documented?

How the study data were collected and where the study data were recorded?

How was IP accountability – shipping, storage, disposition, and destruction – handled?

Did the investigator disclose information regarding his financial interests?

How did the monitor communicate with the investigator?

What was the recruitment process? How did the recruitment flow occur, e.g., from registration, outpatient department, specialty clinic, special procedure department?

How were the endpoints investigated/assessed/documented/confirmed?

How were the SAEs recorded and reported?

How were the documents archived?

TOUR OF THE FACILITY

The inspector visited all the areas as per the flow of recruited patients. The inspector checked the evidence of patient registration in all the areas – registration, outpatient department, medical record section, specialty clinic, and special procedure department. The site team was asked to re-enact the flow of the patient visit.

Later the inspector reviewed investigational product (IP) storage area and checked whether

IP storage was secure with access limited to authorized persons,

IP storage was under controlled conditions as specified in the protocol,

temperature records were available.

Next the inspector focused on the equipment used for the trial and verified the following details:

Equipment details – user manual, probes, manufacturer, calibration, maintenance staff in hospital.

Software used/updates.

Equipment certificate/calibration records for special equipment, e.g., ultrasonography (USG).

Storage and retrievability of images after long term storage.

REVIEW OF INVESTIGATOR SITE FILE

The review of site file began with

FDA1572

Identification of investigator and all team members responsible for critical study tasks checked against study site personnel log

Identification of protocol, facilities, ethics committee (EC), lab/special procedure facility

Review against FDA 1572 submitted by sponsor to FDA.

This was followed by review of all key documents:

Protocol and protocol amendments

Ethics Committee (EC) approval

Informed consent (IC) process

Case record form (CRF)

Source documents (SD)

Investigational product (IP) accountability

Serious adverse events (SAE)

Site logs

Training documentation

Monitoring documentation.

The inspector collected photocopies of all the above documents.

The inspector copied the contents of the CRF CD onto his laptop and captured all the subject-wise data in his diary.

The focus of inspection was on process, personnel, and paper (documentation), which would provide evidence of compliance, to GCP, regulatory requirements, and the protocol [Figure 1, Tables 1 and 2].

Figure 1

FDA inspection focus

Table 1

FDA inspection: Review of site personnel documentation

Table 2

FDA inspection: Review of critical processes

The inspector reviewed the following:

Processes – How and when was the process carried out? Why did deviation occur?

Personnel – Who was authorized/trained/responsible for the process?

Paper – Where. When and how the process was documented?

The inspector made extensive use of site logs – screen failure, subject identification, enrolment -- and study site personnel log and training certificates to confirm most critical study-related personnel and processes.

PROTOCOL

The inspector verified

whether protocols on site the same as submitted to the FDA

reviewed if all protocol amendments implemented

whether the regulatory/EC approval were obtained for all protocol amendments prior to implementation.

The inspector checked whether the investigator adhered to the protocol with respect to:

patient selection - inclusion and exclusion criteria,

number of patients enrolled,

randomization of patients,

required procedures and evaluations (e.g., blinding procedures),

administration of the IP - dosage, route of administration, and frequency of dosage.

The inspector verified whether the investigator followed the protocol/version approved by the EC and reviewed protocol amendments and deviations.

PROTOCOL AMENDMENTS AND DEVIATIONS

The inspector checked whether changes to the protocol were

documented by an amendment, dated, and maintained with the protocol;

reported to the sponsor if initiated by the investigator;

approved by the EC and regulatory agency prior to implementation.

The inspector looked for evidence of deviations from protocol and reviewed

the reasons for deviation

whether the investigator failed to conduct examinations or investigations as required by the protocol

whether the patients failed to complete scheduled visits as required by the protocol,

documentation and reporting of protocol deviations to EC and sponsor

list in the final study report matched the protocol deviation log for the site.

ETHICS COMMITTEE APPROVAL

The inspector reviewed whether the EC composition and approval process were in compliance with applicable regulations.

The inspector confirmed whether EC approval was obtained prior to initiation of study-specific procedures on subjects: (a) the protocol and any amendments and (b) informed consent documents.

The inspector went through EC approval letter and checked whether EC stipulate any conditions for the informed consent process. If so, did the clinical investigator follow those instructions/stipulations?

The inspector reviewed nature and frequency of communications with the EC and verified whether investigator promptly submitted (a) reports of deaths and SAEs and (b) unanticipated problems involving risk to human subjects. Later he collected a copy of each version of the consent document approved by the EC.

INFORMED CONSENT PROCESS

The inspector reviewed the consent process and checked

Who from the site team was responsible for explaining the study and consent document to the prospective study participants?

Which language was used? Was it understandable for the patient? Are back translations available?

How was the informed consent process conducted?

Did the site personnel obtain the consent prior to performance of any protocol-related tests and administration of investigational product (IP)?

Whether each subject or the legally acceptable representative (LAR) was given a copy of the consent document?

Whether the version of informed consent document approved by EC prior to initiation of the study?

How the consent process is described in the source notes?

How was reconsenting done and documented?

Were subjects consented on the latest version of the ICF? Next the inspector reviewed 100% of consent forms and verified the following:

Did the patient, LAR or the impartial witness sign the ICF prior to entry into the study?

What was the relationship of LAR to the patient?

How did the investigator confirm that the person who signed on behalf of the patient was LAR?

Whether patients signed the version of ICF that was current at their time of entry into the study?

CASE REPORT FORMS

The inspector reviewed the process of CRF completion focusing on the following:

Who obtained and recorded the information?

How was the CRF information recorded from source?

Corrections to the CRF –

who made them

reason(s) for the changes, and

did the investigator oversee aware of these changes.

The inspector took eCRF pages – selection and efficacy endpoints for comparison with source data and the data submitted by the sponsor to the FDA.

SOURCE DOCUMENTS

Initially, the inspector examined the organization, condition, completeness, and legibility of the source data and source documents and checked whether the source documents conform to standard ALCOA (attributable, legible, contemporaneous, original, accurate). The inspector visited the medical record section to check original source notes for a few randomly selected patients.

Later the inspection focused on the following:

Documentation which can confirm that all subjects were alive and available for the duration of their stated participation in the study

Documentation and data on the condition of the patient at the time of screening and enrollment

Documentation of the patient's exposure to the IP

Documentation and data on the condition of the subject during the trial, including results of lab investigations, special procedures, intercurrent illness, etc.

Responsible key personnel involved in collecting and analyzing data at the site

Documentation for screen failures and drop outs

The inspector also determined whether the hospital records contain

all original source documents from medical record section/other departments source data entries signed and dated by authorized personnel as per study site personnel delegation log

source documentation of consent process, subject's medical condition, selection criteria, end-points, SAE, IP administration, concomitant medication

source data from lab/other department, e.g., ultrasound images

CRF AND SOURCE DATA VERIFICATION

The inspector collected the CD containing all CRFs. The inspection process followed was

checking source data for CRF entries

checking CRFs versus data submitted by the sponsor.

The inspector conducted 100% source data verification (SDV) for all patients. The SDV covered the following aspects:

Whether the patients were selected as per the eligibility criteria described in the protocol?

Whether the protocol-specified lab tests – biochemistry, lab, ECGs, X-rays, etc. and other investigations, e.g., USG, CT/MRI were carried out as per the protocol and documented by laboratory records?

Whether the adverse events/SAEs were documented and appropriately reported?

Whether all concomitant therapies and/or intercurrent illnesses were documented and reported?

The inspector also checked whether the investigator documented the patients who dropped out, with reasons for discontinuing the trial, and reported them to the sponsor.

The inspector collected samples of some important source data related to key investigations and endpoints and CD containing CRFs.

SERIOUS ADVERSE EVENT

The inspector checked the site records of serious adverse event (SAEs) against the data submitted by the sponsor to the FDA. He checked the following:

How the investigator assessed the severity of the adverse event and causal relationship between the AE and the IP?

Did the investigator report the SAE to the sponsor and EC as per regulations?

Compared the date of SAE occurrence in the source notes, CRF, and SAE form to date of reporting to the sponsor and EC.

Documentation of SAEs in the source notes.

IP ACCOUNTABILITY

The inspector reviewed IP accountability in detail.

He verified (a) who was authorized to dispense the IP? (b) did any unauthorized person get the IP?

The inspector compared the quantity of IP shipped, received, used, and returned to the sponsor.

He did this by checking the IP records of

receipt -- dates, quantity, and the condition upon receipt

dispensing -- dates, patient number, and quantity

return - dates and quantity

unused supplies.

The inspector verified the following:

Was IP labeled as per regulatory requirement?

How and where the IP was stored?

Was the IP stored under appropriate conditions as specified in the protocol?

Are temperature records available and in compliance with storage conditions specified by the sponsor?

Was IP storage secure? Who had access to IP?

MONITORING DOCUMENTATION

The inspector reviewed the monitoring activities at the site. He looked at follow-up letters and cross checked the visit dates with the site visit log. He also checked how the investigator followed up on the deficiencies described by the monitor. He also looked at other relevant information, e.g., telephone calls, facsimile, e-mail correspondence.

CLOSEOUT DISCUSSION

The close out meeting covered important study aspects such as

informed consent documentation.

protocol compliance

CRF and SDV

IP accountability

SAE record and report

documentation.

The inspector mentioned that there are always small discrepancies. However, the inspector looked at the bigger picture – to ensure that data integrity is maintained and subject safety is protected.

The inspector did not find any objectionable conditions or practices during the inspection. Hence, the EIR was NAI. The inspector concluded that the investigators had adhered to the applicable regulatory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects.

CHALLENGES FOR INSPECTIONS AT INDIAN SITES

For Indian sites, which are still on the learning curve of clinical trial conduct, FDA inspection is a huge challenge.

Indian investigators are not used to any audits or inspections of their medical practice or clinical research from any agency. Hence, they underestimate the importance of FDA inspection. This may lead to a casual attitude to inspection. They are unwilling to devote 4--5 days time required for the inspection. Also, there could be administrative hurdles from the institutional head, who is unaware of the seriousness of the regulatory inspections.

Another issue is time gap between site close-out and inspection, which could be 6 months or longer. The investigator and his key team could be busy with other projects and would have forgotten critical aspects of clinical project conduct. The site staff and other department personnel, who handled special investigations, e.g., imaging, may have left the institute. The clinical team which may have supported the study may have moved on to other departments and other places after their residencies have been completed.

There could also problems in tracing original medical records of the patients and manufacturers documents for key instruments. The instruments used for the study may not be functioning at the time when the inspection occurs or may have been replaced with new instruments.

These challenges require a lot of planning from the sponsor team. The site should be made aware of the likelihood of inspection when the trial is ongoing. There should be a thorough audit of the site before the close out. All documents listed in Tables 1 and 2, e.g., trial master files, photocopies of all source documents, CD of CRFs, radiological/other images, etc. should be organized in an orderly manner and kept securely at the site.

The FDA inspection is too important to be left to CRA and QA personnel. As soon as the inspection is announced, a senior person, e.g., director – clinical operation should talk/meet the investigator to stress on the seriousness of the inspection process and should continue the communication till the inspection is over. On the announcement of the inspection, the CRA for the concerned site should reach the site and re-open the site, as it was during the active study time. This means retrieval of all the files, documents, logs, CRFs, SD, patient records, etc. This should be followed by a thorough preinspection audit of the site along with training to face the inspection. The audit should be as per the expected FDA inspection process,[34] using a check list covering items listed in Tables 1 and 2. The audit and training should be conducted by a senior QA person, who has experienced FDA inspections or by an ex-FDA inspector. At the end of the audit, the investigator and his team should be appraised about the deficiencies in the conduct of trial and the site documentation, and advised about how to respond to FDA inspector's inquiries and findings, by training them in dos and don’ts for the interview and the inspection process [Table 3]. It is recommended that this should be again followed by a CRA visit to the site to settle all discrepancies and reappraise the investigator of the trial conduct. Similarly, the sponsor's clinical operations team – all CRAs and their team leaders should be trained in how to support the inspection process at the site and how to respond to inspector's requirements for documents and queries on the trial conduct process.

Table 3

FDA inspection: Dos and don’ts for the investigator team

CONCLUSIONS

USFDA inspections at Indian sites are a recent regulatory focus. Most Indian sites are naive about the inspection process and require in-depth preinspection audit and training to be able to successfully face inspections.