Warning Letter Study

Quality is an essential element of clinical trials and quality data is recognized and appreciated by both sponsors and regulators. Clinical trials are largely conducted to collect the data required for academia, industry, and regulators to make decisions about the safety and efficacy of certain preventive medicines and the medicines used to treat various diseases and illnesses.

Trials are conducted in accordance with the ethical principles laid down in the Declaration of Helsinki, primarily protecting rights, safety and well-being of the trial subjects. The stakeholders of clinical trials such as trial sponsors, clinical investigators, institutional review boards (IRBs), and monitors are expected to adhere the protocol and comply with regulatory requirements and standards given in various clinical trial guidelines, such as International Conference on Harmonization—Good Clinical Practice (ICH GCP). In the recent past, clinical trials have crossed the boundaries; evident by the increased number of trials conducted outside the traditional Western Europe and North American region. These mammoth numbers have increased concerns among regulators and the public, leading to debate on how well these trials are being conducted from ethical and scientific standards?¹ Standards of trials are primarily measured through routine audits or regulatory inspections. Regulatory bodies across the globe are trying their best to inspect trials. However, globalization of clinical research coupled with limited inspection resources have left everyone high and dry; and hence, these authorities have no option but to limit inspections and restrict the sample of sites and studies to be inspected. Learning from the errors observed in past inspections can be a tool to improve quality of current trials.

(PHOTODISC/THINKSTOCK)

In the United States under bioresearch monitoring programs, FDA inspectors are conducting inspections since 1977; whereas European Medicines Agency started conducting GCP inspections in 2006. In a non-traditional region, like India, the Drugs Controller General of India has indicated a proposed plan for inspections of clinical research centers across the county on short notice.

Inspectors often examine trials with an aim to evaluate compliance of conduct with protocol and regulations/guidelines. Inspectors principally review the data submitted along with application to the regulators and check the data generated during the trial. Therefore, documentation holds a critical link in assessing trial quality. Poor and inadequate documentations fail to assure quality of data and conduct of trials; leading to serious inspection findings.

When the inspections are conducted by FDA inspectors they categorized serious findings as an "objectionable findings," which are reported through warning letters (WL).³ Warning letters are mainly the post–inspectional correspondence between FDA and stakeholders. WLs are specifically issued whenever there are regulatory violations that are repeated and/or involve submission of false information to FDA. Analysis of findings reported in warning letters provide commonly observed mistakes or errors. Hence, this study was designed to collect all WLs posted on the FDA's website for conduct of clinical trials, tabulating the findings, and analyzing them to quantify for their repetitive occurrence. So that the analysis of the repetitive findings can then be used to draft appropriate training modules on various topics for the concerned stakeholders.

Research methodology and collection of data

In this study, WLs were accessed and downloaded from the FDA website³ for trials carried out and inspected during the period from 1996 through 2010. The findings of WLs were entered in a spreadsheet and summarized by the stakeholders of clinical trials, such as clinical investigators (CI); clinical trial sponsors; institutional review board (IRB); clinical trial sponsor acting as a clinical investigators; monitors; and clinical research organizations (CRO). Very interesting fact, worth reporting is that there was only one WL issued to a CRO during the period of the last 15 years; hence, the findings reported in WL for CRO are included in the findings reported for the monitors. The segregated data was categorized using relevant 21 Code of Federal Regulation Parts (21 CFR)⁴ and their respective sub parts and sub sections. Following sections associated with clinical research were considered for categorizing findings reported in WLs:

• 21 CFR Part 50—Protection of Human Subjects

• 21 CFR Part 54—Financial Disclosure by Clinical Investigators

• 21 CFR Part 56—Institutional Review Board

• 21 CFR Part 312—Investigational New Drug Application

• 21 CFR Part 812—Investigational Devise Exemption

• 21 CFR Part 814—Premarket Approval of Medical Devices

The data was summarized to present frequency of WLs by: stakeholders, parts, subparts, sections, and subsections of 21 CFR.

The following stake holders were considered for the purpose of this analysis:

Clinical Investigator.² A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator (PI).

Sponsor.² An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.

Sponsor/investigator.² An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject.

Contract research organization.⁶ CROs assume, as an independent contractor with the sponsor, one or more of the obligations of a sponsor (e.g., design of a protocol, selection or monitoring of investigations, evaluation of reports, and preparation of materials to be submitted to the Food and Drug Administration).

Institutional review board (IRB).² An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial for, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

Results

Total number of warning letters by year. Number of WLs in each of the years reported on the FDA's website selected for analysis is presented in Table 1. A total of 466 WLs issued to various stakeholders during the years—1996 through 2010 were reported.

Table 1. The number of WLs issued during a period of 15 years shows an increasing trend.

Warning letters issued to various stake holders. Number of WLs issued against specific regulations of 21 CFR to various stake holders are tabulated in Table 2.

Table 2. Clinical investigators received the highest percentage of 466 warning letters issued.

Number of findings categorized by parts of 21 Code of federal regulations. Data collected from findings reported in WLs were tabulated as per the relevant 21 CFR Parts⁴ 50; 54; 56; 312; 812; and 814. All WLs downloaded over a period between 1996 and 2010 contained 2,422 objectionable findings. These findings were classified under various sub parts of the 21 CFR.

Discussion

The idea for this research was conceived in 2007 and tables were designed in 2010. USFDA also came out with similar tables⁷ in March 2011. The data matched with one of the tables released by USFDA on their website in March 2011. The repetitive findings noted in warning letters in past 15 years indicative of continuing same errors again and again by the stakeholders. This is a point of concern. The analysis of findings reported in WLs shows that there is a gap in understanding of protocol or the regulations by the stakeholders; these stakeholders deviate from requirements causing errors in conduct of clinical trials.

Table 3. Out of 2,422 finding reported in WLs, 42.0 % were for 21 CFR Part 812.

The ninth slide in the presentation entitled Bioresearch Monitoring and Inspection⁷ (BiMO) depicts the number of inspections carried out by FDA inspectors during 2002 to 2009 of various stakeholders like sponsors, clinical investigators, IRB/RDRS, bioequivalence, and good laboratory practices. It reveals that the number of inspections of CIs throughout the period between 2002 and 2009 is higher than the number of inspections for the IRB and sponsors. The analysis of WLs was indirectly supported by the observations presented in the BiMO slides; the analysis also suggests that like the number of inspections, the numbers of WLs issued to CIs are relatively more than those issued to other stakeholders. Similarly the number of inspections of IRBs presented in BiMO slides and the corresponding numbers of WLs found in the study are followed after CIs. It was discovered that 58.80% WLs (274/466) were addressed to CI during 1996 through 2010. These high numbers of WLs can be correlated to the higher number of inspections conducted for a specific stakeholder compared to the others. The CIs either participating in therapeutic drug trials or device trials are bound by responsibilities listed in 21 CFR 312 Subpart D; and 21 CFR 812 Subpart E and G. These subparts respectively deal with investigators responsibilities, including the process of consenting; adhering to the protocol and investigational plan; and protecting safety and well being of the trial patients.

Analysis of WLs with regard to 21 CFR against the number of inspections reported in the slides of BiMo, showed similarity in the findings. The analysis reported in slides of BiMO for the inspections carried out in the year of 2009 indicate a total of 40.07% findings for non-compliance with the protocol; followed by 27.46% findings for investigators' record keeping and record retention. In identical manner, analysis of the findings reported in WLs showed 38.71% findings (256/651) reported for clinical investigators participating in therapeutic drug trials, whereas 21.32% (217/1018) findings are reported for clinical investigators participating in device trials for failing in relevant responsibilities for ensuring an investigation was conducted according to the signed investigator statement, and the investigational plan as described in 21 CFR 312.60 for therapeutic trials, and 21 CFR 812.100 device trials. Similar, to the number of inspections conducted in slides of BiMO compared with this analysis, the number of findings also showed an identical pattern; 29.49% findings (192/651) for CI conducting therapeutic trial as per 21 CFR 312.62; and 23.48% findings (239/1018) reported for CI conducting device trials as per 21 CFR 812.140 for device trials failing in investigators' record keeping and record retention regulations.

Analysis indicates 22.87% (554/2422) of total findings related to IRB under various subsections of 21 CFR Part 56. Within this group 30.69% (170/554) reported for non compliance of 21 CFR 56.108—IRB functions and operations; this was followed by 27.62% (15⅗54) findings for non-compliance of regulation 21 CFR 56.115—IRB Records.

Common and repetitive findings for IRB were: failing to have adequate written procedures governing the functions and operations of the IRB and failing to maintain adequate records of members, procedure, IRB activities, minutes of meeting, etc.

In addition 7.97% (193/2422) findings for non-compliance of 21 CFR Part 50—Protection of Human Subject were found. Of these, 34.20% (66.193) findings reported in WLs were because of inadequate informed consent as defined by 21 CFR 50.20. This was followed by 32.64% (63/193) non-compliance issues in documentation of informed consent, as required by 21 CFR 50.27.

Conclusion

The findings reported in WLs indicates serious concerns over repetitive errors in the trials inspected by US FDA inspectors in the last 15 years. The analysis is primarily for US stakeholders, because almost all warning letters are issued to the stakeholders from United States, except one which was issued to an Investigator from Moscow, Russia. This analysis can help to identify the gaps in understanding of Protocol and regulations by the stakeholders; using the analytical data one can develop adequate training modules for all stakeholders on topics such as:

• Overall investigators responsibilities, as defined by regulations and guidelines

• Obtaining and documenting subject consent

• Comprehensive and correct understanding of protocol

• Investigational record keeping and record retention

• IRB functions and operations, as per regulations and guidelines

IRB records and maintenance of records

Detailed research is required in this field at a granular level to pinpoint the areas for improvement. However, in the present era of globalized clinical trials, the analysis of these findings could be the starting point to improve the overall quality of trials, assuring people at large about protection of safety, well being, and rights of the trial subjects, which is the basic principle of ICH GCP.

Rajendra Talele* is Senior Vice President, Global Operations, Lambda Therapeutic Research Ltd, Mumbai, India, e-mail: rajendratalele@lambda-cro.com. Suresh K. Bowalekar, PhD, C Stat, C. Sci), is Managing Director, PharmaNet Clinical Services Pvt Ltd, Mumbai, India.

*To whom all correspondence should be addressed.

References

1. European Medicines Agency, "EMEA Strategy Paper: Acceptance of Clinical Trials Conducted in Third Countries, for Evaluation in Marketing Authorization Applications," (2008), http://bit.ly/OezvkT.

2. International Conference On Harmonization, "ICH Harmonized Tripartite Guideline: Guidelines for Good Clinical Practice, E6 (R1), http://bit.ly/rndBWm.

3. United States Food and Drug Administration, "Inspections, Compliance, Enforcement, and Criminal Investigations: Warning Letters from 1996 to 2010," http://1.usa.gov/FWc9M.

4. United States Food and Drug Administration, "CFR - Code of Federal Regulations Title 21," http://1.usa.gov/nX4Bot.

5. EMA-FDA GCP Initiative, "Terms of Engagement and Procedures for Participating Authorities," http://1.usa.gov/cVhQzZ.

6. United States Food and Drug Administration, "CFR - Code of Federal Regulations Title 21: Food And Drugs Chapter I," http://1.usa.gov/NI9xFB.

7. T. Purohit–Seth, "Bioresearch Monitoring and Inspections," United States Food and Drug Administration, http://1.usa.gov/PEqiTK.