Drug Development 1.2 Procedures for Clinical Trials

1 35 CHAPTER 3 Drug Development 1. PROCESS FROM Development TO APPROVAL New drugs are defined as drugs with active ingredients, dosage, administration route, or indications, which are clearly different from those of drugs, which have already been approved for manufacture and marketing or those listed in the JP. Applications for approval to manufacture and market new drugs must be submitted to the Ministry of Health, Labour and Welfare with results of nonclinical and Clinical studies required to show the quality, efficacy, and safety of a new drug attached to the approval application form (Article 14-3 of the Law).

2 Development of New Drugs It is important to prepare data for the review process during the course of drug Development . Results to show quality, efficacy, and safety of new drugs must be obtained in nonclinical and Clinical studies. The nonclinical studies include physicochemical studies and animal studies on pharmacology, pharmacokinetics, and toxicity. The Clinical studies usually consist of Phase I, II and III studies (or human pharmacology, therapeutic exploratory, therapeutic confirmatory, and therapeutic use categories).

3 On starting each phase of Clinical studies, it is necessary to adequately confirm the safety of the drug product from the results of nonclinical studies or of previous Clinical studies. The Drugs and Medical Devices Law specifies that the data submitted to obtain approvals must be obtained and compiled according to the standards specified in its Article 14, Paragraph 3. Related ordinances include the Ordinance on Standards for Conduct of Clinical Trials (GCP) (MHW Ordinance No. 28 dated March 27, 1997, partially revised by MHW Ordinance No.)

4 127 dated October 20, 2000, MHLW Ordinance No. 106 dated June 12, 2003, MHLW Ordinance No. 172 dated December 21, 2004, MHLW Ordinance No. 72 dated March 31, 2006, MHLW Ordinance No. 24 dated February 29, 2008, MHLW Ordinance No. 163 dated November 28, 2008, MHLW Ordinance No. 68 dated March 31, 2009, and MHLW Ordinance No. 161 dated December 28, 2012; the Ordinance on Standards for Conduct of Nonclinical Studies on the Safety of Drugs (GLP) (MHW Ordinance No.)

5 21, March 26, 1997, partially revised by MHW Ordinance No. 127 dated October 20, 2000 and MHLW Ordinance No. 114 dated June 13, 2008) and Standards for the Reliability of Application Data (Article 43 in the Enforcement Regulations) which were enforced from April 1, 1997. Therefore, the acceptance of the data is conditioned on adherence to the standards. It is important that studies to obtain data for approval reviews should be performed by standard methods whenever possible in order to assure proper evaluations of drugs.

6 Reviews on compliance with these standards are performed by the Pharmaceuticals and Medical Devices Agency (PMDA, KIKO) at the request of the MHLW. A flowchart from Development to approval of new drugs is shown in Fig. 8 (Flowchart of New Drug Development and Approval). Procedures for Clinical Trials For Clinical studies ( Trials ) to be conducted for collection of data to be submitted in marketing approval application of a new drug, etc., the Law and the GCP specified sponsor s responsibility for submitting a notification of the Clinical trial plan in advance and matters that a sponsor must comply with in requesting a medical institution to conduct a Clinical trial.

7 Scope of GCP includes not only Clinical Trials in patients but also Phase I studies in healthy volunteers, bioequivalence studies in human, studies for additional indication of an approved drug and post-marketing Clinical Trials after marketing. Furthermore, its partial amendment 2003 specifies investigator-initiated Clinical Trials as well. According to the new GCP, when a Clinical study is requested, a contract for Clinical Trials can be concluded only when 30 days have passed from the initial notification of the study protocol is received by the PMDA (KIKO) (at least 2 weeks for subsequent notifications, as a rule).

8 The sponsor must report to the authorities any severe adverse reactions or infections that occur during the study, and the authorities may undertake on-site inspections concerning GCP compliance in the sponsor's facilities and the medical institution performing the study when problems arise during the study. For drugs required in emergencies to prevent diseases that have a major effect on the life or health of the patient or to prevent other damage to the health, Clinical study protocols may be submitted within 30 days after the start of the study (MHLW Ordinance No.)

9 89 dated May 15, 2003). At the time of the Clinical trial protocol notification, a system by which the PMDA reviews the contents of the initial notification at the request of the MHLW is now specified by law, and a " Clinical trial consultation system" in which the PMDA gives guidance and advice concerning study protocols has also been established (refer to Section : Interview Advice Meetings). It is necessary to submit Clinical trial (protocol) notifications in the following instances.

10 (1) Drugs with new active ingredients (2) Drugs with new administration routes (excluding bioequivalence studies) (3) New combination drugs, drugs with new indications or new dosage and administration (excluding bioequivalence studies) (4) Drugs containing the same active ingredients with the drugs with new active ingredients, for which the reexamination period has not been completed yet (excluding bioequivalence studies) (5) Drugs considered to be biological products [excluding (1) to (4)] (excluding bioequivalence studies) (6) Drugs manufactured using gene recombinant technology [excluding (1) to (5)] (excluding bioequivalence studies) The types of Clinical trial protocol notifications and documents to be submitted are shown below.