Year : 2010 | Volume
: 1 | Issue : 2 | Page : 64--66
Getting ready for inspection of investigational site at short notice
Vice President, Clinical Operations, SIRO Clinpharm Pvt Ltd
Vice President, Clinical Operations, SIRO Clinpharm Pvt Ltd
India is becoming an attractive destination for drug development and clinical research. This is evidenced by the three fold increment in clinical trial applications in last four years to the office of Drugs Controller General of India (DCGI). This upward trend is collaborative efforts of all stake holders and the quality of Indian data. Therefore to sustain this trend, it is important that stake holders such as Regulators, Sponsor, CRO, Monitor, Investigators and trial subjects required maintaining high standards of data and conduct of clinical trials. Indian regulations and the role of DCGI in quality check for Indian clinical trials is always a topic of discussion in various forums. A recent move by DCGI for conducting random inspections of investigational sites and companies at short notice, checking their compliance in accordance with the guidelines, and taking action against non-complier is welcomed. This will certainly increase over quality of the clinical trials. Quality of clinical trial conduct is measured on essential documents for their appropriateness and its correctness. It is observed that the stakeholders engaged in multitasking often overlook the requirements or appropriateness of the document due to their focused approach on a specific activity which is on priority. This can lead to serious quality problem and issues. Understanding of the process and documents reviewed by auditor is important to maintain such high quality. The proper planning and time management working on essential documents can minimize the quality issues, and we can be always ready for any type of inspection, announced or unannounced, or «DQ»short notice«DQ».
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Talele R. Getting ready for inspection of investigational site at short notice.Perspect Clin Res 2010;1:64-66
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Talele R. Getting ready for inspection of investigational site at short notice. Perspect Clin Res [serial online] 2010 [cited 2020 Feb 23 ];1:64-66
Available from: http://www.picronline.org/text.asp?2010/1/2/64/71855
Recently a news item on clinical research highlighted about the proposed plan of Inspections by Drugs Controller General of India (DCGI). The DCGI has hinted at conducting random audits of clinical trial sites across the country and stated that his team of drug inspectors, trained under US FDA personnel, will walk into clinical trial centers, at a short notice, to audit the internal processes and the clinical trials data. DCGI has further informed that the research work at site would get suspended if the sites or the research organizations were found non-compliant with the guidelines, or found violating the guidelines. 
Since over a decade, India is becoming a preferred destination for conduct of clinical trials, and is emerging as a major player in drug development. The entire world is following closely, the conduct of trial and the data generated from India. Therefore, such a type of move by Indian regulatory body was very much needed, and was well accepted by the industry. Inspections by regulatory agency not only give confidence to the stakeholders but also protect creditability of Indian clinical research. Today, rather than a positive publicity of good research work happening in India, our research is quite often attacked by few unfortunate incidences reported in media. This has created a negative impact on clinical research industry. Therefore, to strengthen our image in the world of clinical research, we all need to understand and pay attention to the quality work as required by guidelines and regulations.
As per DCGI, the trained inspectors from workshops conducted by US FDA will be visiting sites with short notice. This process has begun and trained Indian inspectors have already officially inspected few of the clinical sites. Inspectors examine the documents as well as the conduct of trial. To a large extent, we have been and are producing good work, but it needs to be at par with the requirements of guidelines and regulations; therefore, we have the responsibility to make ourselves compliant with these guidelines and regulations, and be prepared ourselves for any quality inspection / audits, at our investigational sites, even if it occurs at a very short notice.
It is important to answer few questions before understanding the entire process of inspection / audits
What are Inspections / Audits? And what is the need for inspection / audit of our trials?What do the Inspectors look for?How can we ensure high quality of work and data for such "short notice inspections"?
What are Inspections/Audits?
Literally, "Inspection" means critical examination or official examination and Audit is a formal, often periodic or a thorough examination of the documents. Therefore, audits performed by "Regulatory Agencies" are categorized in the 'Official Examination of trial', and hence are called as 'Inspections', while audits carried out by non-regulatory auditors are categorized as 'Audits'. Both words are synonymous; and even the processes followed are similar, the only difference being the body performing the audit.
As per the GCP guidelines published by CDSCO  , Audit of a trial is defined under section of 'Definition' as "A systematic verification of the study, carried out by persons not directly involved, such as: (a) Study related activities to determine consistency with the Protocol; (b) Study data to ensure that there are no contradictions on Source Documents. (The audit should also compare data on the Source Documents with the interim or final report. It should also aim to find out if practices were employed in the development of data that would impair their validity.) (c) Compliance with the adopted Standard Operating Procedures (SOPs)."
The objective of any audit or inspection is to ensure that the basic principles of GCP such as the protection of the rights, safety and welfare of human subjects participating in clinical development program are met. Audit / Inspection also ensures that the clinical investigations are conducted in compliance with current understanding of regulators and that the data submitted to regulatory authorities under the 'New Drug Application' are consistent and of high quality. The auditors conduct audits of investigational sites, sponsors, monitors, contract research organizations, ethics committees or IRBs; non-clinical laboratories, and bioequivalent analytical laboratories. In this paper, we are focusing on the information for inspection at investigational site / sites where clinical investigations are conducted in order to support clinical development program or for marketing applications.
At the moment, no specific norms are being followed for selection of a site for an audit/inspection. Thus, in absence of specific criteria for such a selection, invariably the selection of site for inspection is done randomly. Often the number of subjects enrolled on a site plays an important role in selection. Thus, a site having maximum number of patients enrolled in a study from country or overall in a study, has high chances of getting selected for an audit. The other factors which influence selections are the study conduct issues or any trial subject safety issues at site, which an auditor can easily find out from the site monitoring visit reports. Therefore, principally all the sites could qualify for audits and hence all sites are required to be kept in a state of "ready for inspection", at any point in time. However, FDA guidelines on 'Inspections for Clinical Investigators'' throw some light on selection of sites  . FDA conducts both announced and unannounced inspections of clinical investigator sites; and the selection of study and sites for inspections can fall under any of the following categories -
- Routine audit to verify data that has been submitted to the agency
- As a result of a complaint to the agency about the conduct of the study at the site
- In response to sponsor concerns or termination of the clinical site
- At the request of an FDA review division and
- Related to certain classes of investigational products that FDA has identified as products of special interest in its current work plan (i.e. targeted inspections based on current public health issues)
As per the US FDA website, as on January-2009, India has witnessed 9 inspections by FDA inspectors which were categorized under 'Routinely to verify data that has been submitted to the agency'.
What Inspectors look for?
Investigational site audit is mainly based on the interviews of investigators and inspection of documentation. Therefore, investigators are required to permit inspectors for access, copy, and verify any records or reports made by the clinical investigator during the conduct of clinical trial. To ensure that there would not be any observations or findings in terms of absence of documents, the documents should always be kept ready for audit. As per the ICH GCP guidelines, Investigators are responsible for maintaining the records. The responsibilities of maintenance of record are defined in the 'responsibilities' section of Investigators under Section 4.9.7 of ICH GCP  and section 3.3.3 of GCP guidelines published by CDSCO. 
The important point is to understand which of the documents will satisfy the questions/ queries of an auditor/ inspector. In other words, which documents do the inspectors generally review? The Guidance document published by US FDA for 'FDA Inspection of Clinical Investigations'  gives idea about it.
According to this guidance document, the FDA inspector during an inspection of a clinical investigative site, will typically verify:
- Who performed various aspects of the protocol? E.g. who verified inclusion and exclusion criteria? Who obtained informed consent, who collected AE data? Etc.
- The degree of 'delegation of authority' - e.g. how the clinical investigator supervised the conduct of investigations during a trial?
- Where the specific aspects of investigations were performed?
- How and where the data were recorded?
- Accountability for the investigational product.
- The monitors' communication with the clinical investigator and
- The monitors' evaluations of process of the investigations.
FDA personnel also audit the study data by comparing the data filed with agency or the sponsor, if available, with records related to the clinical investigation. Such records include - the Case Report Forms (CRFs) and supporting data, signed and dated consent forms, patient medical records including progress notes of the physician, the individual hospital chart(s), and the nurses' notes; the study eligibility criteria documents, safety documents, and subjects' records covering a reasonable period after completion of the product related portion of the investigations to determine if there was proper follow up as outlined in the protocol.
Above listed documents reviewed by FDA inspectors or any auditors are the commonly generated documents in any clinical trial and cover every other information about conduct of a trial.
How can we ensure high quality of work and data for such short notice inspections?
The stakeholders for clinical research working at various capacities such as Investigators, Sponsors or Monitors for a trial are required to perform and focus on activities, emphasizing on documentation. If activities in the trial are planned correctly, there could be less chances of missing any of the documents such as:
- Essential documents as defined in guidelines
- Informed Consent forms and its associated documentation
- Medical history of trial subjects
- Previous medications of trial subjects
- Aes, SAEs and associated documents
- Investigational product related documents such as drug inventory, storage and reconciliation of the medications,
- Laboratory and other investigations reports as required by protocol. Absence of any of reports could be a protocol deviation.
It is often observed that the stakeholders / professionals working on some task or the other are pre-occupied with many responsibilities, such as, Monitors handle multiple sites, and Investigators usually conduct clinical trials beside their scheduled work. Hence, one tends to focus on the activities that are on priority, neglecting some important aspect of trial. For example, during the start up phase of trial, the focus is on collection of documents, and sometimes quality get compromised under timelines pressure; during treatment phase the focus would be either achieving recruitment numbers or with the completion of CRFs for interim database lock, resulting in the poor documentation, completion of source notes, and investigational product inventory. Similarly at the close out phase, the focus again gets shifted to achieve the database lock timelines, when generation of essential documents or reconciliation of the Site File gets neglected. Such approach, which is mainly focusing on 'a specific' activity, leads to serious quality problem and issues. If one can manage and plan the time effectively keeping above listed points in mind, it will minimize quality issues, and thus one will be always ready for any type of inspection, whether it is announced or unannounced, or to face any "short notice inspection" as said by DCGI.
I wish to thank Dr. Suresh Bowalekar, Managing Director, PharmaNet Clinical Services Pvt. Ltd. for all his help and guidance.
|1||"FDA-approved inspectors plan short-notice audit of trials" The Economics Times - 23-May-2009.|
|2||Essential Documents, Appendix V; Good Clinical Practices For Clinical Research In India; Central Drugs Standard Control Organization; Dte.GHS, Ministry of Health and Family Welfare, Government of India, 2005, pp 111-126|
|3||Essential Documents for Conduct of Clinical Trials; International Conference on Harmonisation (ICH) Harmonized Tripartite Guideline: Guidelines for Good Clinical Practice, E6 (R1); Current Step 4 version, 1996; pp 41-52|
|4||"FDA Inspection of Clinical Investigators" Information sheet Guidance for IRBs, Clinical Investigators, and Sponsors; U. S. Department of Health and Human Services Food and Drug Administration; 2006.|