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Clinical trialWhat is (Clinical trial)?MedicineOrMedical equipmentManufacture and sale[Note 1]AboutPharmaceuticals and medical devices lawMade to get the above approvalClinical trialIs that..Originally,"TreatmentClinical trial of medical treatmentExaminationIs an abbreviation for.
In the past, the purpose was to obtain approval, so it was led by a company, but due to the revision of the law, it is not always necessary to get involved in the development process of a company, and it can be carried out by a doctor.Using animals非 臨床 試 験(Preclinical study) is conducted when the safety and efficacy of drug candidate substances or medical devices are examined and it is expected that they can be safe and effective drugs or medical devices.
The drug is approved by passing a three-stage study from Phase I study (Phase I) to Phase III study (Phase III).America'sFederal Food, Drug and Cosmetic ActThen, twiceClinical trials with appropriate controlsThe drug is approved if it is shown to be effective by..On the other hand, if you manage the numbers, the developers of statistical methodsRonald FisherSometimes the result of being accidental is validTherefore, there is an opinion that this system is incomplete.
Clinical trial flow
Clinical trials are often conducted in three stages, from phase I to phase III...However, with regard to anti-cancer agents (especially cytotoxic anti-cancer agents), Phase I clinical trials are usually conducted in cancer patients due to the significant potential disadvantages known and expected. Regarding phase clinical trials, the tumor shrinkage effect (response rate) by the international standard RECIST is examined, strong side effects, and bioethical problems.Due to the size of the drug, randomized controlled trials are often more difficult to perform than general drugs, and the designs and methods are often different.
Phase I study (Phase I)
For healthy adults who voluntarily volunteered, the dose of the test drug was gradually increased from a small amount, and the pharmacokinetics of the test drug (absorption,distribution,metabolism,excretion) And safety (harmful events,Side effects) Is an exploratory test whose main purpose is to examine.Animal experimentationIn response to the result ofHuman capitalIt is the first step to apply to and is an important process in considering safety.However, if surgery or long-term follow-up is required, or if side effects are expected in advance, such as administration of anticancer drugs, patients who have been surgically treated (superficially). May be tested as adjuvant chemotherapy in healthy individuals).In the case of anticancer drug testing, it is also an important purpose to consider the limits of dosage and administration used in the next phase.
Phase II study (Phase II)
Phase II trials are based on Phase I results and are relatively mild in a small number of casespatientThis is a study to examine the efficacy, safety, pharmacokinetics, etc. ofMost of the patients have the main purpose of examining the dosage and administration used in the next phase of the study, but the dose should be gradually increased while confirming efficacy and safety, or 3 or more groups including the placebo group. Set the dose groupDose-responsiveVarious test designs are adopted depending on the purpose of the test.Since it often has both exploratory and verification purposes, it may be divided into exploratory early phase II and verifiable late phase II.In addition, there are test designs that are continuous with Phase I as Phase I / II and test designs that are transitioned to Phase III as Phase II / III.In addition, regarding highly toxic anticancer drugs, in this phase IItumorThe effectiveness may be verified using indicators that can be evaluated in a short period of time, such as the reduction effect, and an application for approval may be submitted.
Phase III study (Phase III)
Actually that after launchCompoundPhase III will be conducted on a larger scale for patients who will use the drug, with the main purpose of verifying efficacy and examining safety.Since the main purpose is to prove the efficacy examined so far, trial designs such as randomization and blinding are often adopted.Since the scale may be several hundred or more, it is often done jointly by multiple facilities.In the case of anticancer drugs, it is often carried out after manufacture and sale.
The person conducting the clinical trial is obliged to explain to the participants in the clinical trial the purpose and content of the trial to be conducted prior to the clinical trial.In addition, if the participant is a patient, the advantages and disadvantages of the treatment method, other existing treatment methods, etc. must be explained in detail, and an agreement must be reached regarding the worst possible consequences.Participation in the clinical trial must be decided only by the free will of the participants who have a sufficient understanding.In addition, participants must be free to withdraw from the trial at any time and must ensure that withdrawal from the trial will not suffer any disadvantages such as future treatment or financial sanctions (indirect). No coercion is allowed).
Organizations / occupations involved in clinical trials
Medical institution side
There are various types of investigators, investigators, sponsors, etc., and in order to perform these tasks, each clinical trial must be performed in advance.Clinical trial screening committeeMust be approved.
- Investigator / Clinical Trial Coordinator
- The investigator is responsible for conducting the clinical trialDoctororDentistThat thing.There is one for each clinical trial and each medical institution.In other words, if hospital A conducts three types of clinical trials, there will be three investigators in hospital A, and if clinical trial B is conducted jointly by three medical institutions, There will be three investigators in the trial B.The investigator is a doctor or dentist who divides the duties related to the clinical trial under the guidance of the investigator, and there may be any number of doctors in one clinical trial.
- Clinical Trial Coordinator (CRC: Clinical Research Coordinator)
- A person who cooperates in clinical trial work under the guidance of the investigator or the investigator.Normal,nurse,pharmacist,Clinical technologistMedical personnel such as will be clinical trial collaborators.Informed consentThe role played by clinical trial collaborators in clinical trials, such as acquisition assistance, clinical trial schedule management, clinical trial patient support, and case report preparation assistance, is extremely large, and it is virtually impossible to conduct clinical trials without clinical trial collaborators. It is no exaggeration to say.
- Clinical Trial Secretariat
- GCPAn organization that is in charge of various affairs related to clinical trial implementation based on.Nominated by the head of the medical institution.
- Clinical Trial Facility Support Organization (SMO: Site Management Organization)
- An organization that contracts with a medical institution, which is a clinical trial facility, and supports complicated clinical trial work at the medical institution.
Pharmaceutical company (trial client) side
- Contract research organization (CRO)
- An institution that acts on behalf of pharmaceutical companies in developing new drugs, especially in conducting clinical trials.
- Monitor (CRA: Clinical Research Associate)
- A person in charge appointed by the sponsor to confirm that the clinical trial is conducted scientifically and ethically in compliance with the clinical trial protocol and various laws and regulations.It is permitted to view medical records related to clinical trials such as medical records, the human rights, safety and welfare of subjects are protected, and clinical trial data reported by the investigator or investigator is accurate and complete. Obliged to confirm that.In addition, almost all information exchange between medical institutions and sponsors is carried out via monitors.
In clinical trials, substances that are not actually effective (in order to examine the effect of the test drug)Placebo, placebo), And comparisons are made with drugs that have already been confirmed to be effective and are on the market, but if the subject knows whether the test drug or the control drug is being administered, the effect of the drug will change. (This phenomenon is called the placebo effect).In order to prevent this, a study that does not inform the subject of which one is being administered is called a single-blind study.
In addition, knowing which one is being administered by the administering physician may manifest itself in attitudes and may lead to prejudice in assessing efficacy and safety.To prevent these, neither the subject nor the doctor who administers the drug should be informed whether the drug is being administered as a test drug or a control drug.Double blindThis is a (double blind) test.
When conducting a double-blind study, the study drug and control drug will be prepared for one person (prior to allocation) at a third-party organization (assignment manager) independent of the sponsor after manufacturing (before delivery to the medical institution). Each one) is placed in a package with exactly the same appearance, and each one is given a unique number.This work is called drug allocation.The correspondence table between the drug number and the actual contents is prepared by the person in charge of allocation at the time of allocation, and is stored after being tightly sealed.After that, the test drug and the control drug that became indistinguishable by this work are delivered to the medical institution and randomly prescribed to the study participants.After the clinical trial is completed, the sponsor obtains the allocation table for the first time in a state where all the data is collected and the database cannot be changed (data is fixed), the allocation information is opened (key open), and the result is analyzed. Will be.
Recently, there has been a movement to avoid the word "blind", especially in Europe, and in such cases, it is sometimes called the "double mask method".
Federal Food, Drug and Cosmetic ActEstablished the concept of drug efficacy since 1962, twiceClinical trials with appropriate controlsThe drug was approved if it was shown to be effective...That is, evidence is needed to prove that the benefits of medicines outweigh the risks..
The U.S. Food and Drug Administration (FDA) approves the drug if two trials show efficacy, but this is sweet and statistical method developerRonald FisherThought that the chance was low when the results were reproduced in 20 out of 19 times, but according to FDA standards, even if it failed to show effectiveness 100 times out of 98 times, it showed effectiveness twice. And the result that Fisher thinks by chance is valid..Since the efficacy could not be shown, the number of clinical trials was completed, and the trials with negative results were submitted and not published.Information disclosure lawCombine all data submitted to these regulatory agencies based onMeta-analysisMay give negative results..In other words, the more participants in the study, the more effective the dubious panacea can be..
AntidepressantAlthough there is an indication for depression, the difference cannot be detected by the general impression evaluation scale-improvement (CGI-I) for detecting the impression of change perceived by the doctor, and there is only a statistically significant difference. Instead, it is pointed out that whether the difference is clinically significant should be considered when approving the drug..
Concealment of fraud and side effects is also a problem. In 2013, in the treatment of hypertensionDiovan caseBecame a problem.It may be discovered later that the drug is administered by selecting patients who are likely to be effective rather than randomly..
Clinical research registration system
Since conventional clinical trials were often clarified together with the implementation guidelines at the time of result reporting without disclosing details during the implementation, "only those with favorable results are published. It has been pointed out that there is a possibility that "what is not done will not come out" (publication bias).Therefore, it has been pointed out that there is an ethical problem that information that seems to be inconvenient for the tester is not studied until the final stage, or even if it is studied, it is not reported.
In addition, since the participating facilities were limited to the medical institutions that participated in the plan in advance, it was difficult to carry out public relations activities to widely call for participation in clinical trials.
Against this background, the International Committee of Medical Journal Editors (ICMJE) Proposed "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication" in September 2004, regarding clinical trials submitted to medical journals. We called on each journal to require the registration and publication of the protocol (procedure) in advance.In response to this, multiple clinical trial registration institutions have been established in North America, Europe, and Japan, and the University Hospital Medical Information Network has been established in Japan since 9.UMIN) And Japan Pharmaceutical Information Center (JAPIC) Has started, and in 2006, the Japan Medical Association is making similar efforts.
The information required for registration does not differ greatly between registered institutions, but each has its own characteristics, such as the scope of research to be registered and the type of language used for information disclosure.
- Pharmaceuticals and Medical Devices Act (August 35, 8, Act No. 10)
- Pharmaceutical and Medical Device Law Enforcement Ordinance (January 36, 1, Cabinet Order No. 26)
- Pharmaceuticals and Medical Devices Law Enforcement Regulations (February 36, 2, Ministry of Health and Welfare Ordinance No. 1)
GCP Ministerial Ordinance
- Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals (March 9, 3, Ministry of Health and Welfare Ordinance No. 27)
- Ministerial Ordinance to partially revise the Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals (Ministry of Health, Labor and Welfare Ordinance No. 15, June 6, 12)
- Ministerial Ordinance to partially revise the Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals (Ministry of Health, Labor and Welfare Ordinance No. 16, June 12, 21)
- Ministerial Ordinance to partially revise the Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals (Ministry of Health, Labor and Welfare Ordinance No. 18, June 3, 31)
- Ministerial Ordinance to partially revise the Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals (Ministry of Health, Labor and Welfare Ordinance No. 20, June 2, 29)
- Enforcement of the Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals (March 9, 3, Pharmaceutical Issue No. 27)
- Enforcement of the Ministerial Ordinance to partially revise the Ministerial Ordinance on the Standards for Conducting Clinical Trials of Pharmaceuticals (June 15, 6, Pharmaceutical Issue No. 12)
- Enforcement of the Ministerial Ordinance to partially revise the Ministerial Ordinance on the Standards for Conducting Clinical Trials of Pharmaceuticals (December 16, 12, Pharmaceutical Foods No. 21)
- Enforcement of the Ministerial Ordinance (related to improving the quality and function of the clinical trial review committee) to partially revise the Ministerial Ordinance on the Standards for Conducting Clinical Trials of Pharmaceuticals (April 18, 4, Yaksik No. 1)
- Enforcement of the Ministerial Ordinance to partially revise the Ministerial Ordinance on the Standards for Conducting Clinical Trials of Pharmaceuticals (December 20, 2, Pharmaceutical Foods No. 29)
Notification of section chief
- Regarding points to note regarding the enforcement of the "Ministerial Ordinance for Partial Revision of the Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals" (related to the improvement of quality and function of the clinical trial review committee) (April 18, 4, Yaksik Review) No. 1)
- Regarding the operation of standards for conducting clinical trials of pharmaceutical products (September 18, 9, Pharmaceutical and Food Safety Examination No. 21)
- Precautions regarding the enforcement of the Ministerial Ordinance to partially revise the Ministerial Ordinance on the Standards for Conducting Clinical Trials of Pharmaceuticals (March 20, 3, Yaksik Examination No. 26)
- Regarding the operation of the "Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals" (October 20, 10, Pharmaceutical and Food Safety Examination No. 1)
Notifications, etc. referred to in Operational GCP (Good Clinical Practice No. 0921001)
- Contents of Criteria for Conducting Clinical Trials of Pharmaceuticals (GCP) (Report of Central Pharmaceutical Affairs Council on March 9, 3)
- Handling of safety information obtained during clinical trials (March 7, 3, Pharmaceutical Trial No. 20)
- Data items and message specifications for transmitting individual case safety reports (March 13, 3, Pharmaceutical Safety No. 30, Pharmaceutical Trial No. 39)
- Report on clinical trial side effects, etc. to the Pharmaceuticals and Medical Devices Agency (March 16, 3, Pharmaceuticals and Medical Devices Agency No. 30)
- Partial revision of "Report of clinical trial side effects, etc. to Pharmaceuticals and Medical Devices Agency" (December 17, 12, Pharmaceuticals and Medical Devices Agency No. 15)
- Post-marketing adverse drug reactions and clinical trial adverse drug reactions (March 18, 3, Pharmaceutical and Food Safety Examination No. 31, Pharmaceutical and Food Safety No. 0331022)
- Points to note when reporting adverse drug reactions, etc. (April 18, 4, Pharmaceutical and Food Safety Examination No. 26)
- Guidelines for the structure and content of the clinical trial summary report (May 8, 5, Pharmaceutical Trial No. 1)
- Regarding the partial enforcement of the Pharmaceutical Affairs Law and the Law for Partial Revision of the Blood Collection and Blood Donation Business Control Law (May 15, 5, Pharmaceutical Issue No. 15)
- Regarding the revision of "Report of clinical trial side effects, etc. by persons who conducted clinical trials by themselves after the establishment of Pharmaceuticals and Medical Devices Agency" (October 17, 10, Yaksik Examination No. 25)
- Points to note when reporting adverse drug reactions, etc. (April 18, 4, Pharmaceutical and Food Safety Examination No. 26)
- Regarding the structure of essential documents for the operation of standards for conducting clinical trials of pharmaceutical products (October 16, 10, administrative communication)
- Ministerial Ordinance on Standards for Conducting Clinical Trials of Medical Devices (March 17, 3, Ministry of Health, Labor and Welfare Ordinance No. 23)
- Report on clinical trial defects related to machinery and equipment to the Pharmaceuticals and Medical Devices Agency (March 19, 3, Pharmaceuticals and Medical Devices Agency No. 30)
- Notification of clinical trial plans, etc. related to machinery and equipment (July 19, 7, Yakushoku No. 9)
- Regarding points to note when reporting clinical trial defects related to machinery and equipment to the Pharmaceuticals and Medical Devices Agency (March 19, 3, Yaksik Machine No. 30)
- Handling of notifications such as clinical trial plans related to machinery and equipment (July 19, 7, Yaksik Machine No. 9)
- ^ “Manufacturing and sales” defined by Article 2 of the Pharmaceuticals and Medical Devices Act includes consignment manufacturing, importing, leasing, and awarding.
- ^ "Clinical trial, January 2009, 1 Revised Edition, Glossary of Pharmacy, Pharmaceutical Society of Japan
- ^ http://medg.jp/mt/2010/03/vol-87.html
- ^ a b c Laurie Burke "OFF-Label Drug Use: FDA's View" "Evidence of Off-Label Use of Drug" (Translation) Kiichiro Tsutani, Chieko Kurihara, Digital Press, 1999, 153-175 page.ISBN 4-925066-01-3.
- ^ a b c David Healy"Pharmagedon" Translated by Osamu Tajima, Translated by Kyoko Nakazato, Misuzu Shobo, 2015, pp. 112-122.ISBN 978-4-622-07907-1. Pharmageddon, 2012.
- ^ Japan Pharmaceutical Manufacturers Association What is a clinical trial?> 2. Clinical trial rules "GCP"
- ^ Ikuo Sekine Naoki Ishizuka Tomohide Tamura "Design and Ethics of Cancer Clinical Trials-Phase II Study" Chiba Medicine 84: 309-314, 2008
- ^ Irving Kirsch (January 2010, 1). “Antidepressants: The Emperor's New Drugs?”. The Huffington Post 2012/3/1Browse.
- ^ Moncrieff, Joanna; Kirsch, Irving (2015). “Empirically derived criteria cast doubt on the clinical significance of antidepressant-placebo differences”. Contemporary Clinical Trials 43: 60–62. two:10.1016 / j.cct.2015.05.005. PMID 25979317.
- ^ "St. Mari to stop six new clinical studies”. Yomiuri Shimbun (March 2017, 2). 2017/2/19Browse.
- Clinical research ethics
- Clinical trial screening committee
- Ethics Committee
- Informed consent
- Good clinical criteria (GCP: Good Clinical Practice)
- QMS Ministerial Ordinance
- Research on humans
- Drag lag
- International Medical Association Council
- Pandemic of New Coronavirus Infection (2019-) ――Clinical trials are being conducted in various fields for the development of new therapeutic agents and the diversion of existing drugs.