The "Sulfanilamide Elixir Incident" - resulting in 358 people suffering from kidney failure, and 107 people dying.
In 1938, the U.S. Congress passed the Federal Food, Drug, and Cosmetic Act: mandated by the FDA. It requires that drugs be tested for toxicity before they go on the market; drug manufacturers must report safety information to the FDA for approval.
United States:
1962: The FDA amended its Federal Food, Drug, and Cosmetic Act to require that all clinical studies be reviewed by the FDA prior to initiation.
1969: Requires that only new drugs that provide results from randomized controlled clinical studies may be approved by the FDA.
The FDA has issued a series of regulations or guidelines on clinical trials.
United Kingdom:
1963: The Committee on Safety of Medicines was established, and the Committee on Safety of Medicine in 1968.
Since 1963, the UK government has required official approval of new drugs before they can be studied in clinical trials and placed on the market.
Japan:
1967: The Ministry of Health and Welfare of Japan adopted measures such as strict approval of new medicines, re-evaluation of medicines, and the obligation of pharmaceutical companies to report side effects to the state.
The second period: 1970s-1990s, the period of standardization and legalization of the formation of management
Tuskegee trial: 1932 U.S. study of black Alabama syphilis patients with no treatment for up to 40 years, even after the discovery of penicillin, an effective treatment for syphilis in the late 1940s, has not yet been administered to the subjects.
In the early 1960s at the Jewish Hospital for Chronic Diseases in the United States, some researchers injected cancer cells subcutaneously into old, frail, terminally ill patients to see if the cancer could spread that way.
Children with mental retardation were inoculated with the hepatitis virus to see how the disease progressed and what could be done to protect humans from it.
The above experiments, which were gross violations of clinical ethics, were the basis for the Declaration of Helsinki.
The Declaration of Helsinki, known as the Declaration of Helsinki of the World Medical Association, sets out the ethical principles for medical research involving human subjects, and is a document that includes ethical principles and limitations for biomedical research involving human subjects, and is the second international document on human experimentation, and is much more comprehensive, specific, and complete than the Nuremberg Code.
The Declaration of Helsinki forms the basis of the core content of today's GCP, which is that the interests of the subject/patient must be paramount.
◆ Specifics:
1. Emphasizes the sacred duty of the physician and quotes from the Geneva Declaration, "The health of the patient is my first concern"
2. Clarifies that ethical norms apply even if the research intervention is part of a clinical treatment
3. written informed consent.
4. When subjects are unable to give voluntary consent themselves, the consent of a legal representative is required.
5. Subjects have the right to withdraw at any time.
◆ Revisions:
1. 18th (Helsinki, Finland, June 1964); 29th (Tokyo, Japan, October 1975); 35th (Venice, Italy, October 1983); 41st (Hong Kong, China, September 1989); 48th (Sisomoset, South Africa, October 1996); and 48th (Sisomoset, South Africa, October 1996) October 1996); 52nd (Edinburgh, Scotland, October 2000); 53rd (Washington, D.C., U.S.A., 2002); 55th (Tokyo, Japan, 2004); 59th (Seoul, Korea, October 2008); and 64th (Fortaleza, Brazil, October 2013);
2. The newly revised Declaration of Helsinki in 2013 restructured the Declaration, added, deleted and modified some articles in terms of content, and modified some wordings in terms of details.
3. The revision of the new version of the Declaration of Helsinki improves the structure of the Declaration, refines its content, strengthens the protection of subjects, raises the requirements for researchers, and clarifies the obligations of countries, research institutions, and sponsors.
4. Implications for China: constantly revise the relevant regulations involving human clinical trials to effectively protect the rights and interests of human subjects; put forward the state's obligation to protect human subjects, and explore the establishment of a national compensation system for clinical trials; clarify the responsibilities and positioning of ethics committees, and explore the establishment of a relatively independent ethical review body.
Other ethical declarations:
1. Sydney Declaration (Determination of Death) (Sydney, Australia, 1968)
2. Tokyo Declaration (Detainees and Prisoners) (Tokyo, Japan, 1975)
3. Hawaii Declaration (Mental Illness) (Hawaii, U.S.A., 1977)
4. International Principles (Mexico, 1972)
Declarations on the Ethics of New Technologies:
1. Universal Declaration on the Human Rights of the Human Genome of the United Nations Educational, Scientific and Cultural Organization (1997)
2. International Human Genetic Organization Declaration of Principles on the Ethics of Genetic Research (Heidelberg, 1996)
3. International Human Genetic Organization Statement on Cloning (Brisbane, 1977)
4. International Code of Ethics for Biomedical Research Involving Human Beings of the International Organization for Medical Sciences and the World Health Organization (Geneva, 2002)
The concept of GCP was first introduced in the U.S. Code of Federal Regulations (1977), which promulgated the duties of the sponsor and monitor (1977), the duties of the investigator (1978), and the duties of the subject (1978).
Korea (1987), Scandinavia (1989), Japan (1989), Canada (1989), Australia (1991) and many other countries have developed and must be published their own clinical trial management norms.
The third period: from the 1990s to the present, it is the period of the gradual formation of the international standard for the management of drug clinical trials.
In 1995, the WHO Guidelines for the Management of Clinical Trials of Medicinal Products were promulgated
In 1991, the International Coordination Committee for the Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) held its first general meeting in Brussels, Belgium, and every two years thereafter, to discuss the development of an internationally harmonized standard for the management of clinical trials of medicinal products.
1996: ICH finalized the guidelines for Good Clinical Practice (GCP).
June 1996-March 1997: The European Union, Japan, and the United States accepted or issued decrees requiring that all clinical trials in support of new drug applications should be conducted in accordance with ICH-GCP, and Australia, Switzerland, Canada, and the World Health Organization, as the regions or organizations involved in the development of ICH-GCP, also endorsed this.
The parallel development of GCP and clinical pharmacology in China
1980: Beijing Medical College established the first Institute of Clinical Pharmacology in China; a number of institutes of clinical pharmacology were established in Shanghai, Guangzhou, Hangzhou, Hefei, Wuhan and Chengdu.
Representatives: Sang Guowei, Zhou Hongwei, Zhong Nanshan, academician of the Chinese Academy of Engineering.
1983: the Ministry of Health approved the establishment of the first batch of medical units under the Ministry of Clinical Pharmacology base (14, later two or three batches of *** counted 42 more than 100 base specialties; reconfirmed in 1998 *** 81 378 clinical drug specialties)
1985: the Ministry of Health set up a Drug Evaluation Committee, composed of 51 experts in medicine, the Chinese Society of Pharmacology Clinical Pharmacology Committee. Pharmacology Society of Clinical Pharmacology Committee 7 members were hired.
In 1992, members were sent to participate in the meeting to finalize the WHO-GCP guidelines.
In 1993, foreign experts were invited to China to introduce the foreign GCP situation.
In 1994, a GCP seminar was held and the drafting of China's GCP was conceived.
In 1995, a GCP drafting group was established (Li Jiatai, Zhu Junren, Sang Guowei, Wang Fu, and You Kai), and China's "Code of Practice for the Administration of Pharmaceutical Clinical Trials (Submission for Review)" was drafted.
The first version of the GCP (Trial Version): March 2, 1998, was promulgated by the Ministry of Health.
1999: State Drugs Administration (SDA) was established. The former Clinical Pharmacology Base of the Ministry of Health was renamed as National Drug Clinical Research Base after acceptance by SDA.
The second version of the GCP: September 1, 1999, the State Drugs Administration officially shall be implemented.
The third version of GCP: September 1, 2003, the State Food and Drug Administration officially promulgated the implementation.
The CFDA has revised and newly promulgated the following regulations and guidelines:
(1) Measures for the Accreditation of Drug Clinical Trial Organizations (for Trial Implementation), 2004
(2) Measures for the Administration of Drug Registration, 2007
(3) Guiding Principles for Ethical Review of Clinical Trials of Drugs, 2010
(4) Guidelines for Management of Phase I Clinical Trials of Drugs. (4) Guiding Principles for the Management of Phase I Clinical Trials of Drugs (for Trial Implementation), 2011
(5) Guidelines for the Management of Laboratories Analyzing Biological Samples in Clinical Trials of Drugs (for Trial Implementation), 2011
(6) Guiding Principles for the Management of Quality in Clinical Trials of Vaccines (for Trial Implementation), 2013
(7) Law of the People's Republic of China on the Administration of Pharmaceutical Products (Revised), April, 2015 April
Technical Guidelines for Clinical Trials of Drugs (36)
(1) August 23, 2007: Technical Guidelines on Biostatistics for Clinical Trials of Chemical Drugs and Biological Products
(2) August 23, 2007: Technical Guidelines on the Structure and Content of Clinical Trial Reports of Chemical Drugs
(3) August 23, 2007: Principles for Writing Clinical Trial Reports on Traditional Chinese Medicines and Natural Medicines
(4) September 04, 2008: Guiding Principles on Adverse Reaction Grading Criteria for Clinical Trials of Vaccines for Prophylaxis
(5) September 04, 2008: Technical Guidelines on Biostatistics for Clinical Trials of Chemical Drugs and Biological Products
(6) September 04, 2008: Technical Guidelines for Clinical Trials of Vaccines
(7) December 08, 2011: Guidelines for the Management of Laboratories Analyzing Biological Samples in Clinical Trials of Drugs (Trial)
(8) December 08, 2012: Guidelines for the Management of Clinical Trials of Drugs in Phase I (Trial)
(9) May 15, 2012 (10) May 15, 2012: Technical Guidelines for Clinical Trials of Antineoplastic Drugs
(11) May 15, 2012: Technical Guidelines for the Design of Clinical Trials of Antibacterial Drugs for Non-inferiority
(12) May 15, 2012: Technical Guidelines for the Design of Clinical Trials of Antibacterial Drugs for Simple and Complicated Skin and Soft Tissue Infections: Guidelines for Clinical Trials of Antimicrobial Drugs
(13) May 15, 2012: Guidelines for Estimating the Maximum Recommended Starting Dose of Drugs for the First Clinical Trial in Healthy Adult Volunteers
(14) May 15, 2012: Guidelines for Endpoints of Clinical Trials of Antitumor Drugs
(15) December 30, 2013: technical guidelines for clinical trials of drugs for the treatment of depression (draft for comment)
(16) January 30, 2015: guidelines for international multicenter clinical trials of drugs (for trial)
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The 2015 GCP was revised and consulted on.
2017 GCP reopened for revision (with reference to the content and form of ICH-GCP)
Fourth edition of GCP: July 1, 2020, jointly issued and implemented by the State Drug Administration (NMPA) and the National Health Commission (NHC, directly under the authority of the State).
The 2020 version of the revised ideas:
First, follow the implementation of the Office of the State Council of the Central Office of the "on deepening the reform of the review and approval system to encourage innovation in pharmaceuticals and medical devices" (Office of the word (2017) No. 42)
Second, according to the newly amended "Drug Administration Law", with reference to the international practice, highlighting the problem-oriented, detailed and clear responsibilities of all parties to the clinical trials of drugs. requirements, and consistent with the basic requirements of the ICH Technical Guidelines.
The revised content of the 2020 version:
The 2020 version of the GCP on the basis of the 2003 version of the GCP from the original more than 9,000 words to more than 24,000 words, from the original 13 chapters and 70 articles adjusted to 9 chapters and 83 articles; the "Declaration of Helsinki of the World Medical Assembly" as a general principle of the requirements of the "General Provisions", no longer attached to the text The World Medical Congress Declaration of Helsinki as a general principle of requirements in the "General Provisions", no longer attached to the full text; clinical trial preservation of documents as a guiding principle issued separately.
The 2020 version of the GCP specification mainly specifies the following seven aspects:
1. Refinement and clarification of the responsibilities of the participants:
(1) Ethics committees (composition and operation, ethical review, documentation);
(2) sponsor (the ultimate responsibility for the quality of the clinical data, and supervision of outsourcing work);
(3) contracts Outsourcing organization (QA, QC);
(4) Investigators (authorization and supervision of clinical trial division of labor);
(5) Clinical trial organization (internal management department of the organization, and the corresponding management of the clinical trial);
2. Enhancement of the protection of the subjects:
(1) Pay special attention to the vulnerable subjects, and examine whether the subjects are subject to undue influence;
(2) Receive and handle subject-related claims;
(3) When the sponsor develops the protocol, it should clarify the key aspects and data to protect the subjects, and formulate a monitoring plan to emphasize the protection of the subjects' rights and interests;
(4) The investigator should pay attention to the subjects' other diseases and coadministered medications; the investigator should decide whether the treatment of the subjects needs to be adjusted or not, after receiving the safety information from the sponsor;
(5) The investigator should pay special attention to the subject's other diseases and coadministered medications. whether subjects' treatment needs to be adjusted;
3. Establishment of a quality management system:
(1) The sponsor should establish a quality management system for clinical trials, conduct risk-based quality management, and strengthen QA and QC;
(2) The sponsor should establish an independent data monitoring committee to carry out risk-assessment-based monitoring;
(3) Investigators should supervise all investigators to execute trial protocols and implement clinical trial quality management to ensure that the source data are true and reliable;
4. Optimize safety information reporting:
(1) Investigators, sponsors during clinical trials in the standards, pathways, and requirements for safety information reporting';
(2) Investigators report all serious adverse events (SAEs) to the sponsor;
(3) Ethics committees require investigators to report all suspected and unanticipated serious adverse reactions (SUSARs);
(4) The sponsor analyzes and evaluates the collected safety information on an individual basis, and rapidly reports suspected and unanticipated serious adverse reactions (SUSARs) to all participating Clinical trials of relevant parties;
5, standardize the application of new technologies:
(1) electronic data management should be reliable system validation, to ensure that the clinical trial data is complete, accurate and reliable;
(2) clinical trial institutions of the information technology system to have the conditions for the establishment of the clinical trial of the electronic medical record, the investigator should be preferred to use;
(3) (3) The corresponding computer system should have complete authority management and audit trail;
6. Referring to the international clinical regulatory experience:
(1) The principle of conflict of interest avoidance;
(2) Bioequivalence test of clinical drugs should be sampled and preserved;
(3) Timing records should be recorded in the subject's informed consent of the specific time and personnel;
(4) The clinical trial organization should have the conditions to set up clinical trials electronic medical records. /p>
(4) If the violation of clinical trial protocols and specifications is a serious problem, the sponsor may hold the relevant personnel responsible and report to the drug regulatory authority;
7. Reflecting the requirements of medical management of the competent authorities in charge of health care
(1) The composition of the ethical committee and the management of the record shall comply with the requirements of the competent authorities in charge of health care;
(2) Investigators should report suspected and unanticipated serious adverse reactions (SUSAR) to the drug regulatory authorities and health and health authorities;
National thinking on the regulation and review of drug clinical trials
1. Establishment of the most rigorous standards: the standards should be comprehensive, scientific, and in line with the actual situation, and the standards should be revised in a timely manner.
2, the implementation of the most stringent supervision: strict acceptance of the review, on-site verification, sampling and testing, drug re-registration work.
3, the implementation of the most stringent penalties: the implementation of drug research and development, production, circulation, use of all aspects of the main responsibility of enterprises, severe penalties for violations found in the inspection, and do a good job of law enforcement results of public work.
4, the implementation of the most serious accountability: for the regulatory work of procrastination, negligence, inaction, chaotic action, to strictly supervise accountability.
Regulations and guidelines issued in 2015
1, International Multicenter Drug Clinical Trials Guidelines (Trial), January 2015
2, Technical Guidelines for Drug Clinical Trials in the Pediatric Population (released), August 2015
3, Biostatistical Guidelines for Drug Clinical Trials (for comment), 2015 Technical Guidelines for Clinical Similarity Research and Evaluation of Vaccines (for comments), September 2015
5. General Principles for Clinical Research of New Traditional Chinese Medicines and Four Other Technical Guidelines (issued), November 2015
6. Technical Guidelines for Bioequivalence Study of Chemical Generic Medicines in Humans with Pharmacokinetic Parameters as the Endpoint Evaluation Indicators (for comments), November 2015
6. Principles (for comment), November 2015
7, General Considerations for Drug Clinical Trials (for comment), December 2015
Regulations and Guidelines Issued in 2016
1, Code for Quality Management of Clinical Trials of Medical Devices, March 2016
2, State Council's Opinions on the Conduct of Consistency Evaluation of Generic Drugs in Terms of Quality and Efficacy Consistency Evaluation of Generic Drugs, March 2016
3. Opinions of the State Council on the Pilot Program of the Drug Listing License Holder System, June 2016
4. CFDA Implementation Opinions on Comprehensively Strengthening the Rule of Law of the Food and Drug Supervisory System, August 2016
5. CFDA's "Code of Practice for Quality Management of Clinical Trials of Medicines ( Revision) (2016-12-02)
6. CFDA's Opinion on Guiding Principles for Research Site Verification and Other Guidelines for Consistency Evaluation of Quality and Efficacy of Generic Drugs (2016-12-21)
Regulations and Guiding Principles Issued in 2017
1. CFDA's "Relevant Relevant Policies on Encouraging Innovation of Drugs and Medical Devices to Reform Clinical Trial Management Policies (Exposure Draft) Announcement (No. 53 of 2017) (2017-05-11)
2. CFDA's "Announcement on Matters Related to the Consistency Evaluation of the Quality and Efficacy of Generic Drugs (Exposure Draft)" (2017-06-09)
3. CFDA's "Measures for the Administration of Conditions and Filing of Clinical Trial Organizations for Medical Devices ( (Draft for Comment) (2017-08-04)
4, CFDA "Drug Registration Management Measures (Revised)" (2017-10-23)
5, CFDA "Drug Clinical Trial Organization Management Regulations (Draft for Comment)" (2017-10-27)
2018 a so far issued regulations
1, NMPA "Medical Device Clinical Trial Inspection Points and Determination Principles" 2018-11-19
2, "Opinions of the General Office of the State Council on the Establishment of a Professionalized and Specialized Pharmaceutical Inspector Team" (Guo Ban Fa (2019) No. 36) 2019-07-09
3, "The People's Republic of China*** and the State of China's Vaccine Administration Law" 2019-06- 29 Adopted 2019-12-01 Implementation
4, "Chinese People's **** and the State Drug Administration Law" 2019-08-26 Adopted 2019-12-01 Implementation
5, "Drug Registration Management Measures" 2020-01-22 Promulgation 2020-07-01 Implementation
China's CFDA to join the member states of the ICH Organization
1, Montreal time June 1, 2018 9:30 am, the first meeting of the ICH 2017 closed vote on the application of CFDA, and finally declared consent to CFDA membership. It fully reflects the international community's support and confidence in the Chinese government's reform of the drug review and approval system.
2. Joining ICH means that China's drug regulatory authorities, pharmaceutical industry and R&D organizations:
(1) will greatly enhance the national level of review of innovative drugs;
(2) will gradually translate and implement the highest international technical standards and guidelines;
(3) will actively participate in the formulation of international rules for the review and approval of new drugs;
(4) will promote the early entry of international innovative drugs into the market. (4) It will promote the early entry of international innovative drugs into the Chinese market to meet clinical needs;
(5) It will enhance the innovation capability and international competitiveness of the domestic pharmaceutical industry.
GCP standardization requirements: clinical trials of all parties to clarify the responsibilities, the establishment of quality systems.
GCP***similar goals: to protect subjects; to ensure the truthfulness and reliability of data.