The development history of GCP

The first period: from the early 20th century to the 1960s, drugs were basically uncontrolled, and the management system of drug clinical trials was gradually formed.

"Sulfonamide incident"-358 people suffered from renal failure, 107 people died.

From 65438 to 0938, the United States Congress passed the Federal Food, Drug and Cosmetic Act, which was enforced by the Food and Drug Administration. It is stipulated that toxicity tests must be carried out before drugs are put on the market; Drug manufacturers must report safety information to FDA for approval.

United States:

1962: The FDA of the United States revised its federal food, drug and cosmetic act, requiring that all clinical studies must be reviewed by the FDA before starting.

1969: It is required that only new drugs that provide randomized controlled clinical research results can be approved by FDA.

The FDA has successively issued a series of regulations or guidelines on clinical trials.

Britain:

1963: drug safety Committee was established, 1968 medical safety Committee was established.

Since 1963, the British government has stipulated that new drugs must be officially approved before they enter clinical research and put into the market.

Japan:

1967: The Japanese Ministry of Health and Welfare has taken measures such as strict examination and approval of new drugs, re-evaluation of drugs, and the obligation of pharmaceutical companies to report the side effects of drugs to the state.

The second period: 1970s-1990s, when standardized and legal management was formed.

Taskey Gee trial: 1932, the United States conducted a 40-year follow-up study on black syphilis patients in Alabama. Even after penicillin was found to be effective in the treatment of syphilis in the late 1940s, the subjects did not receive treatment.

In the early 1960s, some researchers injected cancer cells subcutaneously into elderly and frail patients to see if cancer could spread in this way.

Inoculate children with mental retardation with hepatitis virus, observe the progress of the disease, and find out how to protect human beings from diseases.

The above-mentioned experiments that seriously violate clinical ethics are the basis for the promulgation of Helsinki Declaration.

The Helsinki Declaration, the full name of the Helsinki Declaration of the World Medical Association, stipulates the ethical principles of medical research involving human subjects, is the ethical principles and restrictive conditions of biomedical research including human subjects, and is also the second international document on human trials, which is more comprehensive, specific and perfect than the Nuremberg Code.

Helsinki Declaration forms the basis of the core content of GCP today, that is, the interests of subjects/patients must be put first.

◆ Specific contents:

1, emphasizing the sacred duty of doctors, and quoting the Geneva Declaration that "the health of patients is my first consideration".

2. Explain that even if research intervention is a part of clinical treatment, ethical norms are applicable.

3. Clear written informed consent.

4. When the subjects are unable to make their own voluntary consent, they need the consent of the legal representative.

5. Subjects have the right to quit at any time.

◆ Version:

Published in 1 and 18 (Helsinki, Finland,1June 964); 29th (Tokyo, Japan, 1975 10); The 35th session (Venice, Italy,198365438+1October) was revised; Revision No.41(Hongkong, China,1September, 989); The 48th session (Siso Moset, South Africa, 1996 10) was revised; The 52nd session (Edinburgh, Scotland, 65438+2000 10) was revised; The 53rd revision (Washington, USA, 2002); The 55th revision (Tokyo, Japan, 2004); The fifty-ninth session (Seoul, Korea, 65438+2008 10) was revised; The 64th revision (Fortaleza, Brazil, 20 13,10);

2.20 13 The newly revised Helsinki Declaration has adjusted the structure of the declaration, added, deleted and revised some articles in content, and revised some words in details.

3. The revision of the new Helsinki Declaration has improved the framework and content of the Declaration, strengthened the protection of subjects, raised the requirements for researchers, and defined the obligations of the state, research institutions and organizers.

4. Enlightenment to China: Constantly revise the relevant laws and regulations concerning human clinical trials to effectively protect the rights and interests of subjects; Put forward the obligation of the state to protect subjects and explore the establishment of a national compensation system for clinical trials; Clarify the responsibilities and positioning of the ethics Committee and explore the establishment of a relatively independent ethical review subject.

Other moral statements:

1, Sydney Declaration (Death Judgment) (1968, Sydney, Australia)

2. Tokyo Declaration (Detainees and Prisoners) (1975, Tokyo, Japan)

3. Declaration of Hawaii (Psychiatry) (1977, Hawaii, USA)

4. International Ethical Principles of Dentistry (1972, Mexico)

Declaration on ethics of new technology;

1. UNESCO Universal Declaration of Human Rights on the Human Genome (1997)

2. Statement of International Human Genome Organization on Ethical Principles of Gene Research (Heidelberg, 1996)

3. Statement of the International Human Genome Organization on Cloning (Brisbane, 1977)

4. Ethical Guidelines of the International Organization for Medical Science and the World Health Organization on International Biomedical Research Involving Human Beings (Geneva, 2002)

The United States first put forward the concept of GCP (1977), and promulgated a series of related laws and regulations, such as the responsibilities of applicants and inspectors (1977), the responsibilities of researchers (1978), and the regulations on the protection of subjects (198/kloc-).

Korea (1987), Northern Europe (1989), Japan (1989), Canada (1989), Australia (199 1) and many other countries.

The third period: from the 1990s to the present, an internationally unified management standard for drug clinical trials has been gradually formed.

1995: issue who guidelines for drug clinical trials.

199 1 year: "ICH" held its first meeting in Brussels, Belgium, and then held 1 time every two years, and * * * discussed the establishment of GCP international unified standards.

1996: ICH completed the good clinical practice guideline (GCP).

1June, 1996-June, 0997,1March, 1997, the European Union, Japan and the United States accepted or promulgated decrees requiring that all clinical trials used to support new drug applications must be conducted in accordance with the requirements of ICH-GCP, and Australia, Switzerland, Canada and the World Health Organization, as regions or organizations participating in the formulation of ICH-GCP, also recognized this.

GCP and clinical pharmacology are developing hand in hand in China.

1980: Beijing medical college established the first clinical pharmacology institute in China; A number of clinical pharmacology institutes have been established in Shanghai, Guangzhou, Hangzhou, Hefei, Wuhan and Chengdu.

Representatives: Academician Sang Guowei, Zhou and Zhong Nanshan of China Academy of Engineering.

1983: The Ministry of Health approved the establishment of the first batch of subordinate clinical pharmacology bases in medical units (14, followed by the second and third batches of 42 bases 100; 1998 reconfirmation ***8 1 378 clinical medicine specialty)

1985: The Ministry of Health set up a drug evaluation committee in Beijing, consisting of 5/kloc-0 medical experts, and hired 7 members of the Clinical Pharmacology Committee of the Chinese Pharmacology Society.

1992 sent personnel to attend the final meeting of WHO -GCP guidelines.

1993 invite foreign experts to China to introduce foreign GCP.

GCP seminar was held on 1994, drafted by GCP of China.

1995 set up a drafting group (Li Jiatai, Zhu, Sang Guowei, Wang Fu, You Kai) and drafted China's "Management Standards for Drug Clinical Trials (Draft for Review)".

GCP First Edition (Trial): 1998, promulgated by the Ministry of Health on March 2nd.

1999: State Administration of Pharmaceutical Products was established. The former clinical pharmacology base of the Ministry of Health was renamed as the National Drug Clinical Research Base after being accepted by National Medical Products Administration.

The second edition of GCP: 1 September 19991was officially implemented in the State Administration of Pharmaceutical Products.

The third edition of GCP: On September 1 day, 2003, the State Food and Drug Administration of the United States officially promulgated and implemented it.

CFDA has revised and reissued the following regulations and guiding principles:

(1) Measures for Accreditation of Drug Clinical Trial Institutions (Trial), 2004.

(2) Measures for the Administration of Drug Registration, 2007

(3) Guiding Principles for Ethical Review of Drug Clinical Trials, 20 10.

(4) Guiding Principles for the Management of Phase I Clinical Trials of Drugs (Trial), 20 1 1 year.

(5) Management Guide for Biological Sample Analysis Laboratory in Drug Clinical Trials (Trial), 20 1 1 year.

(6) Guiding Principles for Quality Management of Vaccine Clinical Trials (Trial), 20 13.

(7) Drug Administration Law of People's Republic of China (PRC) (Revised), April 20 15.

Technical Guidelines for Drug Clinical Trials (36)

(1) August 23rd, 2007: Biostatistics Technical Guide for Clinical Trials of Chemical Drugs and Biological Products.

(2) August 23rd, 2007: Technical Guide for the Structure and Content of Clinical Trial Reports of Chemical Drugs.

(3) August 23rd, 2007: Principles for writing clinical trial reports of traditional Chinese medicines and natural medicines.

(4) September 04, 2008: Guiding principles for grading standards of adverse reactions in clinical trials of preventive vaccines.

(5) September 4, 2008: Biostatistics Technical Guide for Clinical Trials of Chemical Drugs and Biological Products.

(6) September 4, 2008: Technical Guidelines for Vaccine Clinical Trials

(7) 20111208: Management Guidelines for Biological Sample Analysis Laboratories in Drug Clinical Trials (Trial)

(8)20 12 12 08: guiding principles for the management of phase I clinical trials of drugs (for trial implementation)

(9)20 12 May 15: Guiding Principles for Clinical Trials of Drugs and Biological Products for Diabetes.

(10) 201May 15: Technical Guidelines for Clinical Trials of Antitumor Drugs

(11) 2012may15: technical guidelines for the design of non-inferiority clinical trials of antibacterial drugs.

(12) 2012may15: guiding principles for clinical trials of antibacterial drugs for simple and complex skin and soft tissue infections.

(13) 2012may15: guiding principles for estimating the maximum recommended initial dose of drugs in the first clinical trial of healthy adult volunteers.

(14) 201May 2005 15: Technical Guide for Clinical Trials of Antitumor Drugs.

(15) 201312.30: Technical Guidelines for Clinical Trials of Depression Drugs (Draft for Comment)

(16) 2015 065438+3010: Guidelines for International Multicenter Drug Clinical Trials (Trial)

(Omit ...)

20 15 GCP revised and solicited opinions.

GCP was revised again on 20 17 (refer to ICH-GCP content and form).

The fourth edition of GCP: July 1 day, 2020, jointly issued and implemented by the State Administration of Pharmaceutical Products (NMPA) and the National Health and Wellness Commission (NHC).

Reflections on the revision of the 2020 edition;

1. Follow the Opinions of the State Council, China on Deepening the Reform of Review and Approval System and Encouraging the Innovation of Medicines and Medical Devices (Guo Ban Fa Zi (2017) No.42).

Second, according to the newly revised Drug Administration Law, referring to international practice, highlighting the problem orientation and clarifying the responsibilities of all parties in drug clinical trials, which meets the basic requirements of ICH technical guidelines.

Revision of the 2020 edition:

On the basis of the 2003 edition of GCP, the 2020 edition has increased from more than 9,000 words to more than 24,000 words, and has been adjusted from the original chapter 70 of 13 to 9 chapters and 83 sections. The Helsinki Declaration of the World Medical Congress is required to be included in the General Principles as a general rule, and the full text is no longer attached; Clinical trial preservation documents should be published separately as guiding principles.

The 2020 GCP specification mainly defines the following seven aspects:

1. Refine and clarify the responsibilities of the participants:

(1) Ethics Committee (composition and operation, ethics review, documents);

(2) the applicant (the ultimate responsible person of clinical data quality and the supervisor of outsourcing work);

(3) contract outsourcing agencies (QA, QC);

(4) researchers (clinical trial authorization and supervision division of responsibilities);

(5) Clinical trial institutions (internal management departments and corresponding clinical trial management);

2, strengthen the protection of subjects:

(1) Pay special attention to the vulnerable subjects and examine whether the subjects are improperly affected;

(2) Accepting and handling the relevant requirements of the subjects;

(3) When making a plan, the applicant shall specify the key links and data for protecting the subjects, make a monitoring plan, and emphasize the protection of the rights and interests of the subjects;

(4) Researchers should pay attention to other diseases and concomitant medication; After receiving the safety information provided by the sponsor, the researcher decides whether the treatment of the subject needs to be adjusted;

3, establish a quality management system:

(1) The applicant shall establish a clinical trial quality management system, carry out risk-based quality management, and strengthen QA and QC;

(2) The applicant shall establish an independent data monitoring committee to carry out monitoring on the basis of risk assessment;

(3) The researchers should supervise all the researchers to carry out the trial plan, implement the quality management of clinical trials, and ensure the authenticity and reliability of the source data;

4. Optimize the safety information report:

(1) Standards, paths and requirements for safety information reporting by researchers and sponsors during clinical trials';

(2) The researcher reports all serious adverse events (SAE) to the applicant;

(3) The Ethics Committee requires researchers to report all suspicious and unexpected serious adverse reactions (Susar);

(4) The sponsor analyzes and evaluates the collected safety information of a single case, and promptly reports suspicious and unexpected serious adverse reactions (Susar) to all stakeholders participating in the clinical trial;

5, standardize the application of new technologies:

(1) Electronic data management should be verified by a reliable system to ensure the integrity, accuracy and reliability of clinical trial data;

(2) When the information system of clinical trial institutions meets the conditions for establishing clinical trial electronic medical records, researchers should give priority to it;

(3) The corresponding computer system should have complete authority management and audit trail;

6, refer to the international clinical supervision experience:

(1) the principle of avoiding conflicts of interest;

(2) Clinical drugs for bioequivalence test shall be sampled and preserved;

(3) The specific time and personnel of the informed consent of the subjects shall be recorded in the timing record;

(4) In case of serious violation of clinical trial plans and specifications, the applicant may investigate the responsibilities of relevant personnel and report to the pharmaceutical supervisory and administrative department;

7, reflect the requirements of health authorities for medical management.

(1) The composition and filing management of the ethics committee shall meet the requirements of the health authorities;

(2) Researchers should report suspicious and unexpected serious adverse reactions to drug regulatory authorities and health departments;

Thoughts on national supervision and evaluation of drug clinical trials

1. Establish the strictest standards: the standards should be comprehensive, scientific and practical, and the standards should be revised in time.

2. Implement the strictest supervision: strictly accept examination, on-site verification, sampling inspection and drug re-registration.

3. Implement the most severe punishment: implement the main responsibility of enterprises in all aspects of drug research and development, production, circulation and use, severely punish illegal acts found in inspections, and do a good job in making law enforcement results public.

4. Implement the most serious accountability: we must strictly supervise accountability for delay, inaction and chaos in supervision.

Regulations and guiding principles issued on 20 15

1, Guidelines for International Multicenter Drug Clinical Trials (Trial), 20 15 1.

2. Technical Guidelines for Clinical Trials of Drugs in Pediatric Population (published), 2065438+August 2005.

3. Biostatistics Guiding Principles for Drug Clinical Trials (for comments), 2065438+August 2005.

4. Technical guiding principles for vaccine clinical similarity research and evaluation (for comments), 2065438+September 2005.

5. Four technical guiding principles (published), such as General Principles for Clinical Research of New Chinese Medicine, 20 15 1 1 month.

6. Technical Guide for Bioequivalence of Generic Drugs with Pharmacokinetic Parameters as the End Point Evaluation Index (for comments), 20151month.

7. General consideration of drug clinical trials (soliciting opinions), 20 15 12.

Regulations and guidelines issued on 20 16

1, Quality Management Standard for Clinical Trials of Medical Devices, March 20 16.

2. the State Council's opinion on consistency evaluation of generic drug quality and efficacy, 2065438+March 2006.

3. Opinions of the State Council on the Pilot System of Drug Listing Permit Holder, 2065438+June 2006.

4.CFDA's implementation opinions on comprehensively strengthening the legal construction of food and drug supervision system, 2065 438+06. 8.

5.CFDA Drug Clinical Trial Quality Management Standard (Revised Draft) (20 16- 12-02)

6.CFDA's opinion on "Guiding Principles for On-the-spot Verification of Quality and Efficacy Consistency Evaluation of Generic Drugs" (2016-12-21)

Regulations and guiding principles issued by 20 17

1.CFDA Announcement on Policies to Encourage Innovation and Reform in Clinical Trial Management (Draft for Comment) (20 17 No.53) (2017-05-11)

2.CFDA Announcement on Relevant Matters Concerning the Consistency Evaluation of the Quality and Efficacy of Generic Drugs (Draft for Comment) (20 17-06-09)

3.CFDA "Administrative Measures for Conditions and Filing of Clinical Trial Institutions of Medical Devices (Draft for Comment)" (20 17-08-04)

4. Measures for the Administration of Drug Registration in 4.CFDA (Revised Draft) (20 17- 10-23)

5. Regulations on the Administration of 5.CFDA Drug Clinical Trial Institutions (Draft for Comment) (20 17- 10-27)

20 18 Laws and regulations issued so far

1, NMPA "Inspection Points and Decision Principles in Clinical Trials of Medical Devices" 2018-1-19.

2. Opinions of the General Office of the State Council on Establishing a Professional Team for Drug Inspection (Guo Ban Fa (2019) No.36) 20 19-07-09.

3. People's Republic of China (PRC) Vaccine Management Law 20 19-06-29 was implemented by 2019-12-0/.

4. People's Republic of China (PRC) Drug Administration Law 20 19-08-26 was implemented by 2019-12-0/.

5. The Measures for the Administration of Drug Registration (2020-0 1-22) was promulgated and implemented in July, 2020-0/kloc-0.

China CFDA joined ICH member organizations.

At 9:30 a.m. on June 20 18, Montreal time, the first meeting of ICH 20 1 7 voted behind closed doors on the application of CFDA, and finally announced that it agreed to join CFDA. It fully reflects the support and confidence of the international community in the reform of the drug review and approval system of China municipal government.

2. Joining ICH means that China's drug regulatory authorities, pharmaceutical industry and R&D institutions:

(1) will greatly improve the national evaluation level of innovative drugs;

(2) The highest international technical standards and guidelines will be gradually transformed and implemented;

(3) will actively participate in the formulation of international new drug review and approval rules;

(4) Promote international innovative drugs to enter the China market as soon as possible to meet the clinical drug demand;

(5) Enhance the innovation ability and international competitiveness of domestic pharmaceutical industry.

GCP specification requires that all parties in clinical trials should clarify their responsibilities and establish a quality system.

GCP*** has the same goal: to protect subjects; Ensure that the data is true and reliable.