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Descriptive Analysis of Good Clinical Practice Inspection Findings from U.S. Food and Drug Administration and European Medicines Agency

A Correction to this article was published on 06 June 2022

A Correction to this article was published on 30 May 2022

This article has been updated

Abstract

Background

The United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have collaborated in good clinical practice (GCP) inspections since September 2009. The two agencies operate under different regulatory frameworks for GCP oversight. No systematic assessments of GCP inspection findings have been reported.

Methods

We identified common inspections of clinical investigators, sponsors, and contract research organizations conducted by both agencies in support of marketing applications that had the same trial data submitted between 2009 and 2015. We grouped inspection findings into deficiency areas. We reviewed and compared these findings and calculated concordance rate for each deficiency area.

Results

Twenty-six clinical investigator sites and 23 sponsors/contract research organizations were inspected by both agencies in support of 31 marketing applications during this period. For FDA, the most common GCP findings were deficiencies related to Protocol Compliance for clinical investigator inspections and Trial Management issues for sponsor/contract research organization inspections. For EMA, deficiencies related to Documentation (including Trial Master File) were the most common findings for both clinical investigator and sponsor/contract research organization inspections. There was high concordance, of approximately 90%, for deficiencies related to Protocol Compliance for clinical investigator inspections and Trial Management for sponsor/contract research organization inspections between the two agencies. There was a concordance rate of about 70% for Documentation deficiencies for both clinical investigator and sponsor/contract research organization GCP inspections.

Conclusion

GCP inspection findings from 49 common clinical investigator and sponsor/contract research organization inspections were comparable, providing support for continued FDA-EMA GCP collaboration.

Introduction

Good clinical practice (GCP) inspections are conducted by regulatory agencies to assess data integrity and to safeguard the rights, safety, and well-being of study participants as well as to ensure trials are conducted in compliance with GCP and applicable laws and regulations [1,2,3,4,5,6]. challenges associated with the globalization of clinical trials, FDA and EMA began a GCP collaboration in 2009 to conduct collaborative GCP inspections; conduct periodic information exchanges on GCP-related activities; and share information on interpretation of GCP. This collaboration allowed for a better understanding of each other’s inspection procedures [13]. Over time, this collaboration has expanded to include the regular exchange of inspection related information and the sharing of best inspection practices [14].

FDA and EMA operate under different regulatory frameworks for GCP inspections. For FDA’s Center for Drug Evaluation and Research, the assessment of GCP compliance and data integrity for marketing applications is performed by the Office of Scientific Investigations in collaboration with the Office of New Drugs and the Office of Regulatory Affairs. The GCP inspections are conducted by the FDA investigators under the agency wide bioresearch monitoring program using the 21 Code of Federal Regulations for clinical investigators and sponsors/contract research organizations. The basis for FDA inspection findings is 21 Code of Federal Regulations [1, 15]. These GCP inspections utilize a data-focused approach and verify individual subject level data and clinical trial conduct at investigator sites as well as assess sponsor/contract research organizations oversight responsibilities [1, 16]. For FDA, ICH E6 is guidance. In the European Union, in the context of the centralized procedure, GCP inspections are requested by the Committee for Medicinal Products for Human Use (CHMP), coordinated by EMA, and conducted by inspectors from the individual European Union member states following European Union laws, applicable national/local laws, and the International Council for Harmonization (ICH) guideline on good clinical practice (ICH E6) [2, 6]. The basis for the majority of EMA inspection findings is the ICH E6 guideline. EMA’s inspections cover GCP systems and processes in addition to data verification [6, 16].

In this paper, we report on a comparison of GCP findings from common sites inspected by both EMA and FDA covering the same trial data that was received in support of pre-approval applications. We also discuss the results and their implications.

Methods

Data Sources and Identification

The following data sources were used for this project: FDA and EMA internal databases, FDA’s establishment inspection reports and clinical inspection summaries, and EMA’s individual inspection reports and integrated inspection reports. The steps below were followed in order to identify GCP inspection findings:

  1. 1.

    Shared applications, defined as the same applications with the same study data submitted to both agencies for marketing authorization between January 1, 2009 and December 31, 2015, were identified.

  2. 2.

    Common inspections, defined as inspections conducted by both agencies at the same sites (clinical investigators, sponsors, or contract research organizations) for the same protocols for the shared applications, were then identified.

  3. 3.

    For these common inspections, FDA identified GCP findings by reviewing their establishment inspection reports and clinical inspection summaries. For EMA, GCP inspection findings were extracted from their internal inspection database, with quality audit checks using the individual inspection reports and integrated inspection reports.

All the GCP findings in the common inspections for the shared applications were collected for this study and grouped as described below.

Grouping of GCP Findings

After FDA and EMA identified GCP findings for each of these common inspections, we grouped these findings by deficiency area using EMA’s list of GCP finding categories (Table 1) [17]. For the purposes of this paper, modifications were made to merge and better reflect the way the two agencies described inspection findings in their inspection reports. Briefly, the modifications consisted of:

  1. 1.

    Renaming several deficiency areas to make them more intuitive to all stakeholders by introducing the terms Protocol Compliance, Documentation, and Study Drug related findings as deficiency areas.

  2. 2.

    Combining Informed Consent, Independent Ethics Committee/Institutional Review Board, and Subject Protection into Human Subject Protection for the purpose of including all findings related to rights, safety and well-being of study participants under a single deficiency area.

  3. 3.

    Placing the findings unique to each regulatory agency (such as Form FDA 1572 [18] and financial disclosure [19] under 21 Code of Federal Regulations for FDA) under deficiency area of Regulatory Issues.

Table 1 Good clinical practice inspection findings by deficiency areas excluded from data analysis

Findings Excluded from Analysis

Prior to our analysis, a number of findings related to known operational and regulatory differences between the two agencies were excluded. For both clinical investigator and sponsor/contract research organization inspections, the findings related to the following deficiency areas (subareas) were excluded from analysis (Table 1):

  1. 1.

    Regulatory issues: this is specific to each agency such as Form FDA 1572, the Statement of Investigator Form [18] and financial disclosure requirements [19].

  2. 2.

    Laboratory/technical facilities: this is generally covered under separate programs for FDA; for example, assay validation, and sample storage.

  3. 3.

    Computer system: FDA was not covering computer system validation in sponsor/contract research organizations inspections during the study period of 2009–2015 [20, 21].

  4. 4.

    Study drug (Manufacturing/Packaging/Labeling): FDA’s GCP inspections do not cover the subareas of manufacturing and product packaging, which are generally covered under Good Manufacturing Practice inspections [6, 22]. Also, the regulatory requirements for labeling are different between the two agencies [6, 18, 23].

  5. 5.

    Trial management (Study Protocol Design, Statistical Analysis and Clinical Study Report): FDA’s review process is different with regards to these subareas. FDA’s multidisciplinary review teams (including biostatisticians) are responsible for evaluating these subareas.

  6. 6.

    Human subject protection (Liability Insurance, Subject Compensation for Trial Related Injuries and The Design of the Trial that Could Compromise Subject Protection): These subareas were excluded as FDA inspections do not cover them.

In addition, the following findings were excluded because clinical investigator and sponsor/contract research organization inspections are inspected under different FDA compliance programs (Table 2) [24, 25].

  1. 1.

    For the clinical investigator inspection analysis, the findings under Trial Management were excluded because, according to FDA’s regulations, trial management is the responsibility of sponsor or entities to whom the sponsor has transferred regulatory obligations such as a contract research organization [25, 26].

  2. 2.

    For the sponsor/contract research organization inspection analysis, the findings under Human Subject Protection were excluded because the findings related to Human Subject Protection are cited under the clinical investigator who was responsible for the study [27].

Table 2 Good clinical practice inspection findings by deficiency areas included in data analysis

Concordance Analysis

After the analysis datasets were created, we reviewed and compared the GCP findings as well as calculated concordance rate for each deficiency area. We defined concordance as both agencies having identified one or more findings in the same deficiency area for a particular site. We calculated concordance rate by site and deficiency areas using the formula below:

$$\frac{Number\,of\,sites\,with\,concordance\,(had\,findings\,by\,both\,agencies)}{{Number\,of\,sites\,\,that\,had\,one\,or\,more\,findings}} \times 100\%$$

Non-concordance was defined as only one agency having findings in a certain deficiency area for a particular site. Due to the number of findings at the non-concordant sites, representative examples are provided in the Results.

Results

GCP Inspection Findings

A total of 49 common GCP inspections were conducted by EMA and FDA in support of 31 shared marketing applications from 2009 through 2015. Twenty-six of the common GCP inspections were for inspections of clinical investigators and 23 were for sponsors/contract research organizations. For the 26 clinical investigator inspections, a total of 170 and 320 findings were included in the final dataset for FDA and EMA, respectively (Fig. 1a). For the 23 sponsor/contract research organization inspections, a total of 165 and 300 findings were included in the final dataset for FDA and EMA, respectively (Fig. 1b). An analysis of the difference in the number of inspection findings between the two agencies is beyond the scope of this study.

Fig. 1
figure 1

a Collection of Good Clinical Practice Findings for Concordance Analysis for 26 Clinical Investigator Inspections. IP Investigational Product, IMP Investigational Medicinal Product. There were no findings in the subareas of Subject Protection: Personal Data Protection,Insurance/Indemnity/Compensation to Subjects, and Payment to trial Subjects by either FDA or EMA # Subcategory of Study Drug (only IP/IMP manufacturing and labeling related findings were excluded); all other IP/IMP related findings are captured under Study Drug. *Excluded Sponsor’s responsibility of Trial Management findings cited in clinicals investigator inspection reports $EMA did not have findings in Computer System, or Regulatory Issues. b Collection of Good Clinical Practice Findings for Concordance Analysis for 23 Sponsor/Contract Research Organization Inspections. # Only IP/IMP manufacturing and labeling related findings were excluded (Subcategory of Study Drug); all other IP/IMP related findings are captured under Study Drug. *Findings related to Human Subject Protection were cited under clinical investigator inspections. †Protocol Design Related Issues including CRF, eDiary or Questionnaire designs (Subcategory of Trial Management); all other trial management related findings are captured under Trial Management by Sponsors and Contract Research Organizations. $ FDA did not have findings in Computer System, Statistical Analysis Plan, and Clinical Study Report. Figure 1 shows how the final data sets for concordance analysis are derived for 26 Clinical Investigator Inspections (Fig. 1a) and 23 sponsor/contract research organization inspections (Fig. 1b) by excluding known regulatory differences between the two agencies described in “Methods

For the clinical investigator inspections, for FDA, the most inspection findings were in the deficiency areas of Protocol Compliance (43%) and Documentation (28%); while for EMA, the most common findings were in the deficiency areas of Documentation (46%) and Protocol Compliance (34%) (Fig. 2a).

Fig. 2
figure 2

Source documentation. *PC related findings not listed under other sub-areas. **including Organization and Personnel, Facilities and Equipment, SOPs, and Contracts/Agreement. $ Others: Documentation related findings not listed under other sub-areas. $$ including lack of informed consent in the site, informed consent process, and informed consent form. # IRB/IEC reporting: including lack of IEC/IRB favorable opinion in the site, Opinion/Amendments/Notifications to the IEC/IRB, and Composition, functions and operation. ## Others: Safeguard of the Safety and well-being of Subject & Supplying/storage/retrieving/destruction

a Percentages of good clinical practice findings by deficiency area in 26 clinical investigator inspections for FDA and EMA. b Percentages of good clinical practice findings by deficiency area in 23 sponsor/contract research organization inspections for FDA and EMA. DA Drug accountability, DAC Drug administration and compliance, EA Efficacy assessment; PD Process documentation, PSR Protocol specified reporting, QT Qualification/training, SD

For sponsor/contract research organization inspections, for FDA, the most inspection findings were in the deficiency areas of Trial Management (45%) and Documentation (33%); while for EMA, the most common findings were in the deficiency areas of Documentation (45%) and Trial Management (40%) (Fig. 2b).

Concordance for Clinical Investigator Inspections

The concordance rates between the two agencies by site and deficiency area were calculated for each of the inspected sites (Fig. 3). Out of the 26 common clinical investigators inspected, 25 clinical investigator inspections had findings under the deficiency areas of Protocol Compliance and Documentation. Both agencies identified deficiencies related to Protocol Compliance at 22 of the 25 clinical investigator sites, a concordance rate of 88%. For the three non-concordant sites (one had findings by FDA and two had findings by EMA), 13 findings were identified, examples of which included FDA’s finding that a concomitant medication for one subject was not reported to the sponsor and EMA’s finding that an enrolled subject did not meet study eligibility criteria.

Fig. 3
figure 3

a Concordance rate (%) by deficiency areas for 26 clinical investigator inspections. b Concordance rate (%) by deficiency areas for 23 sponsor/contract research organization inspections. The concordance rate is calculated by the number of sites with concordance (had findings by both agencies) divided by the number of sites which had one or more findings in the same deficiency area times 100%

For Documentation deficiency area, both agencies identified findings at 17 of the 25 clinical investigator sites, making for concordance rate of 68%. All eight non-concordant sites had Documentation findings by EMA. The differing findings were mainly due to the following reasons: (1) FDA generally does not include sponsor responsibility related findings in its clinical investigator inspection reports [24] and (2) some findings reported by EMA were related to ICH-E6(R1) GCP requirements, [6] for which the FDA does not have parallel requirements under 21 Code of Federal Regulations. (1) (Table 3) Examples include delayed placement of qualification or training documentation in trial master file, and lack of adequate version control for essential documents [6].

For Human Subject Protection, 19 of the 26 sites had findings, with both agencies identifying findings at 11 of the 19 sites (concordance rate of 58%). Five of 8 non-concordant sites had findings by FDA and three had findings by EMA. One example of FDA’s findings was related to inadequate informed consent processes for two subjects [27]. An example of EMA’s findings at the three remaining non-concordant sites was sending a protocol amendment late to the Independent Ethics Committee [6].

Twenty-three [23] sites had Study Drug findings, with both agencies identifying findings at 10 of the 23 sites (concordance rate of 43%). Nine of 13 non-concordant sites had findings by EMA. An example of EMA findings included inadequate documentation of study drug shipment and late acknowledgement of receipt of study drug [6]. An example of FDA’s findings at the remaining 4 non-concordant sites included inadequate documentation of the amount of the study drug taken by one subject (see Table 3).

Table 3 Good clinical practice inspection regulatory references

Concordance for Sponsor/Contract Research Organization Inspections

The concordance rates between the two agencies by deficiency area for the common sponsor/contract research organization are provided in Fig. 3b.

Out of the 23 common sponsor/contract research organizations inspected, 19 had findings related to Trial Management. Both agencies identified deficiencies related to Trial Management at 17 of these 19 (concordance rate of 89%). The two non-concordant sites had Trial Management findings reported by EMA. These differing findings were mostly due to EMA requirements linked to ICH-E6 with regard to timeliness of maintenance of essential documents and a delay in establishing the monitoring plan [6] (Table 3).

For the Documentation deficiency area, all 23 inspections had findings. Both agencies identified findings at 16 of the 23 sites (concordance rate of 70%). The seven non-concordant sites had findings by EMA. Example findings include deficiencies in completeness of documentation in trial master file, and lack of updating standard operating procedures in a timely manner.

For Protocol Compliance, of 17 sites with findings, 11 were identified by both agencies (concordance rate of 65%). Five of 6 non-concordant sites had findings by EMA, and one had findings by FDA. Examples of EMA findings included an inadequate process to collect and review protocol deviations. FDA’s finding at the remaining non-concordant site was that radiographs were taken out of the scheduled visit windows.

Eleven sites had findings related to Study Drug, and both agencies identified findings at 6 of these 11 sites (concordance rate of 55%). Four of 5 non-concordant sites had findings by EMA, and one had findings by FDA. An example of EMA findings included inadequate management and oversight of study drug shipment to clinical investigator sites. FDA’s finding at the remaining non-concordant site was that study drugs were diluted before administration.

Discussion

In this paper, we described similarities and differences in findings for common inspections between EMA and the FDA over a 6-year period of GCP collaboration. For deficiencies related to Protocol Compliance for common clinical investigator inspections and Trial Management for common sponsor/contract research organizations inspections, there was high concordance of ~ 90%. There was a concordance rate of ~ 70% for Documentation deficiencies for both clinical investigator and sponsor/contract research organizations inspections. The concordance rate of 70% in Documentation is encouraging given the known differences in the operation and regulatory requirements between the two agencies.  The discordance in Documentation deficiency area for clinical investigators and sponsors/contract research organizations inspections was in large part due to differences primarily related to trial master file and signature requirements on a number of essential documents like contracts and standard operating procedures by EMA (Table 3).

There were various limitations to our study. This was a retrospective analysis of GCP inspection data. It is important to note that the trial records reviewed/audited at any inspected site could vary between the two agencies. In some cases, even if the same trial participant records were reviewed, it was possible that not all records were completely examined by both agencies. The inspections might not have covered exactly the same study records (for example, source records, administrative records) by the two agencies. There were other factors that could have affected the differences in inspection findings, such as the number of inspectors who participated in each inspection, the number of hours spent by each inspector, the training, background, and expertise of GCP inspectors. Due to the limitations described above, the definition of concordance appears meaningful in comparing the deficiencies in GCP inspections between the two agencies.

Conclusion

GCP inspection findings from 49 common clinical investigator and sponsor/contract research organization inspections were comparable. The analysis provides support for our existing practice of sharing information between the two agencies for GCP inspection planning purposes as well as for the exchange of inspection reports. Also, this allows for the broadening of inspection coverage and avoiding duplicate inspections. This in turn permits more efficient utilization of the finite resources available for GCP inspections.

Recently, EMA-FDA GCP collaboration has been expanded to include Pharmaceuticals and Medical Devices Agency (PMDA) Japan as trilateral GCP collaboration [28]. Moving forward, EMA-FDA-PMDA plan to enhance their existing GCP collaboration in terms of continuous process improvement through guidance development and joint training programs, strengthen regulatory convergence, and form global GCP inspection collaboration in support of shared marketing application review. Joint GCP workshops, global regulatory engagement at professional society conferences, scientific exchange programs and ongoing participation in the ICH-E6(R3) GCP renovation effort would be beneficial in achieving these goals [29,30,31,32].

Change history

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Acknowledgements

We thank Amir Tahami, M.B.A., for helping to extract FDA inspection information; Michelle J. Foringer, M.P.H. for helping making Figure 1; Laurie Muldowney, M.D., Jean Mulinde, M.D., and David Burrow, Pharm.D., J.D. in the FDA’s CDER Office of Scientific Investigations for their review of the draft manuscript. The authors also wish to thank Fergus Sweeney, PhD, Head, Clinical Studies and Manufacturing Taskforce and Francesco Pignatti, M.D., Head of Oncology, Hematology, Diagnostics, European Medicines Agency for their review of the draft manuscript. We also thank all GCP inspectors from EU member states and FDA investigators from Office of Regulatory Affairs (Office of Bioresearch Monitoring Operations) for the inspections they conducted on behalf of EMA and FDA, respectively.

Funding

No financial support was received for the research, authorship, and/or publication of this article.

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Correspondence to Jenn W. Sellers M.D., Ph.D..

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The authors declared no conflict of interest. The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the agencies or organizations with which the authors are affiliated. Of note, Dr. Khin contributed to this work while she was an employee of the US Food and Drug Administration. Dr. Khin reported she is currently employed by Neurocrine Biosciences, Inc.

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Sellers, J.W., Mihaescu, C.M., Ayalew, K. et al. Descriptive Analysis of Good Clinical Practice Inspection Findings from U.S. Food and Drug Administration and European Medicines Agency. Ther Innov Regul Sci 56, 753–764 (2022). https://doi.org/10.1007/s43441-022-00417-w

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Keywords

  • Good clinical practice inspection
  • Inspection finding
  • Bioresearch monitoring
  • Clinical investigator
  • Sponsor