The problem of the lack of 229 original data

CFDA issued Notice No. 229, announcing that it would not approve the registration of 11 drugs in 8 companies. The bulletin details the problems in the clinical trial data of these 11 drug registrations. The most prominent issue is the lack of original data.

While reviewing these inspection findings, the author is also pondering which files belong to the original data.

Compliance with ICH E6 basic principles

The definitions of Source Data and Source Document are given in ICH E6 1.51 and 1.52.

Raw Data Raw data refers to all information about clinical findings, clinical observations, or other activities recorded in the original clinical study records (or copies of certified original records) that can be used to reconstruct and evaluate clinical studies. The original data is also the information recorded in the original file (original record or a copy of the certificate).

The original documents for the clinical study of the original document include the original document, data and records. Examples include hospital records, clinical clinic records, laboratory reports and related records, memos, patient diaries or assessment forms, drug dispensing records in pharmacies, relevant records generated by automated equipment, certified copies or transcripts , microplates, negatives, microfilm or magnetic media videos, X-rays, patient files, and records maintained by pharmacies, laboratories, and medical technology departments associated with this clinical study.

The lack of original data listed in the CFDA Notice No. 229 mainly includes the following aspects:

Clinical test subject identification code table, blood collection timetable, vital signs monitoring table, plasma transport and treatment record table, disintegration time, sample analysis process record, sample out storage record, and other original records are missing; analysis process records, sample entry and exit The library records are missing, there is no original analysis record; there is no record of the original medical record; there is no record of the chest X-ray examination and electrocardiogram examination in the imaging department and the electrocardiogram room; the data of the test drug and biological sample management are incomplete; the analysis of the test data is doubtful; the analysis and test The data is incomplete; the blood collection time is inconsistent with the actual operation; the preparation process of the stock solution is unclear, and the actual concentration cannot be confirmed; the longest time at the room temperature after the sample treatment is more than 24 hours; some samples are reanalyzed without accompanying quality control, but the data Used etc.

Compared with the definition of the original document by ICH E6, it can be seen that the various findings in the CFDA audit on the incomplete original data conform to the basic principles of ICH E6.

Researcher's responsibility

At the same time, ICH E6 also stipulates the researchers' responsibility for the original documents.

Section 4.9 of ICH E6 deals with the Investigator's responsibilities for recording and reporting.

According to 4.9.4 of ICH E6, the investigator or research institution must, in accordance with relevant regulatory requirements, keep the "essential documents" of clinical studies listed in Part 8 of ICH E6. Researchers or research institutions must take appropriate measures to prevent accidental or premature damage to these documents.

Therefore, researchers must be responsible for the "necessary documents" of clinical research. The original document related to clinical research is an integral part of the "necessary document." The original documents are listed in Section 8.3.13 of ICH E6 on "required documents".

These necessary documents are listed in the eighth part of ICH E6, and part 8.3.13 of the eighth part of ICH E6 is the Source Document. In other words, the original data is also part of the necessary documents and is the responsibility of the researcher.

According to ICH E6 8.3.13, the original documented the existence of the patient, confirming the authenticity and completeness of the collected clinical research data, including the original documents related to clinical research, medical treatment, and the subject's medical history.

Therefore, in the course of clinical research, researchers are responsible for the authenticity and completeness of the original documents.

The sponsor's responsibility

ICH E6 also specifies the sponsor's responsibility for the original document.

The 5.1 "Quality Assurance and Quality Control" section of ICH E6 mentions:

“The sponsor is responsible for implementing and maintaining quality assurance and quality control in accordance with the written SOP to ensure the implementation of the clinical study. The production, recording and reporting of the data are in accordance with the requirements of the program, GCP and relevant laws and regulations.” (5.1.1)

“The sponsor has the responsibility to obtain the consent of the parties concerned and can directly check the points, raw data, original documents, and reports of each clinical study, so that the sponsors can carry out inspections and inspections, as well as inspections by drug administration authorities at home and abroad.” (5.1.2)

"Quality control should be performed at all stages of data processing to ensure that all data is reliable and the data processing process is correct." (5.1.3)

Therefore, the sponsor is responsible for ensuring the quality of the data through quality control. Missing original data or original documents should be discovered and reported in a timely manner.

The relationship between the sponsor and CRO

At the same time, ICH E6 also mentioned the relationship between the sponsor and the CRO.

The section 5.2.1 of ICH E6 states: "Although the sponsor may delegate all or part of the study's responsibilities to CRO, it is ultimately responsible for the quality and true integrity of the clinical research data."

Therefore, pharmaceutical companies need to be very cautious when choosing a CRO. Even if it is a CRO issue, pharmaceutical companies cannot exempt their responsibilities.

Another point that should be noted by the sponsor is that clinical work and clinical research work are not the same. The professionalism of doctors' clinical work lies in providing patients with the best diagnosis and treatment, and the clinical research work is specialized in making clinical research comply with the requirements of GCP, company SOP, and laws and regulations related to clinical research. Therefore, as a professional CRO company, it should continue to help researchers become familiar with the requirements of clinical research, but can not rely too much on the researcher's expertise in clinical research.