Clinical trials notification

In Australia, approval of clinical trials involves both the regulatory authority and an ethics committee. Under the Clinical Trial Exemption (CTX) scheme, a clinical trial proposal must first be evaluated by the TGA, and then approved by an ethics committee on-site. Under the Clinical Trial Notification (CTN) scheme, a trial is evaluated and approved by the local ethics committee, and then notified to the TGA. 

There are two schemes under which clinical trials involving therapeutic goods maybe conducted in Australia - the Clinical Trial Notification (CTN) Scheme and the Clinical Trial Exemption (CTX) Scheme. These schemes are used for clinical trials involving any product not entered on the ARTG, or use of a registered or listed product in a clinical trial beyond the conditions of its marketing approval. 

Unapproved (unregistered) products may be supplied in clinical tricds under special provisions in the Therapeutic Goods Act, 1989 which exempt these products from the need for prior registration. There are two mechanisms by which clinical trials may be initiated in Australia a Clinical Trial Exemption (CTX) where the goods require approval prior to their use in a trial, and a Clinical Trial Notification (CTN) where only a notification is required to the TGA. 

Total Before the Clinical Trial Notification At the Completion of Phase 11 Before Individual Application Consultation... 

Guidelines on nonclinical safety studies for the conduct of clinical trials (Notification No. 1019 of the PAB, 1998). 

The standardized guidelines have been compiled to cover test methods in animal studies and in vitro studies on absorption, distribution, metabolism cind excretion in the Notification No. 496 of the PAB in 1998. The guidelines can be applicable for the drugs to be submitted after October 1999. The following principles should be considered in order to select the most appropriate methods bcised on the characteristics of test substance. It is required that the exposure data related to toxicological studies be obtained before the first human study and other pharmacokinetic data before the completion of Phcise I study in principle in accordance with the guidelines on nonclinical safety studies for conducting clinical trials (Notification No. 1019 of the PAB, 1998). 

The legal prerequisites for the conduct of clinical trial and the clinical trial notification process should be followed when conducting clinical trial. 

In the US, an IND (Investigational New Drug) application has to be filed with the FDA. For other countries, a notification has to be submitted to the respective regulatory authorities. For example, Clinical Trial Exemption (CTX) applications are required for the UK, Clinical Trial Notification (CTN) and CTX for Australia, and a Clinical Trial Certificate (CTC) for Singapore and the European Agency for the Evaluation of Medicinal Products (EMEA). A more extensive discussion concerning regulatory authorities and the processes and procedures of applications is presented in Chapters 7 and 8. The relevant authority will review the application. A positive response from the authority is required before the trial can commence. 

The LA had 35 days to respond to the notification to proceed with a clinical trial but could in exceptional circumstances require a further 28 days to consider the notification, if the CTX was refused, the applicant could apply for a CTC, in which case complete data had to be filed, if the CTC application was refused the statutory appeal procedures came into play if the applicant company wished to avail itself of this provision. These appeal procedures were identical with those applying to marketing applications. The CTX scheme proved highly successful in encouraging inward investment into research in the United Kingdom, in a sample of 42 companies, an increase in research investment of 10% or more was attributed to the scheme by 23 of them. its implementation was criticised by consumer groups and its effect was carefully monitored every 6 months to ensure that no added risk to patients had been introduced. 

The Directive contains detailed articles on the conduct of a clinical trial, exchange of information between Member States, EMEA, and the EC, the reasons and procedures for suspension of the trial by a Member State, and notification of adverse events, including serious adverse reactions. 

The government had required that the sponsors should have their own in-house study review board to review the ethical aspects of clinical trial protocols. Such a requirement was based on the former Japanese GCP, which stipulates that the company should organise an internal formal body or mechanism that reviews and authorises its planned studies before submitting to either study centres or the MHW for clinical trial plan notification. 

An outline of the data from non-clinical studies must be submitted to the PMDA with the protocol for the proposed clinical study before commencing the clinical trial. A notification is required for each protocol. The list of items required for Clinical Trial Plan Notification is shown in Table 23.4. Furthermore, supplementary data must be added on entry to subsequent clinical phases, that is, general clinical trials and comparative trials. Such data are reviewed by the PMDA, and for this purpose the sponsor must wait for 30 days after submitting the initial notification before executing a contract with the medical institute. For a subsequent notification, the review period is reduced to 14 days. The notification also... 

Pressure increased for the TGA to free up the regulatory system for prescription medicines, in particular, the 1990 report by the Australian National Coimcil on AIDS Working Party on the Availability of HIV /AIDS Treatments recommended that a notification scheme be introduced for clinical trials of unapproved products that had already been approved by respected agencies overseas. 

Eees apply to almost all evaluation activities undertaken by TGA - not only to the review of general marketing applications but also to minor marketing-related matters, clinical trial applications and notifications, and GMP evaluations and inspections in Australia or overseas, but not to ADR assessments. 

In 2003 there were 2378 CTN scheme notifications. It should be noted, however, that this does not indicate the number of different clinical trial protocols, which was approximately 560 in 2003-4. This contrasts with two CTX 50 working day applications in the same period and zero 30 working day applications. 

If concerns are found, a deficiency letter will be sent, and if the deficiencies are serious enough to delay clinical trials the agency will impose a clinical hold on the product that can be lifted after the deficiencies are corrected. Clinical holds are classified as complete or partial, depending on whether the issues relate to the product or its manufacture or are specifically related to protocol concerns. Application sponsors should respond to clinical hold notifications promptly. Additionally, FDA is required to respond to completed responses within 30 days of receipt. Examples of reasons for clinical holds are... 

Failure to comply with cGMP requirements is just one of the areas during clinical trials that may result in compliance issues. Improperly assigned expiration dates, inadequate procedures related to the extension of expiration dates, and abreakdown in any of the steps from manufacture of a clinical trial material to its use in a clinical trial could result in compliance issues. Starting with the manufacture of clinical trial material, there must be well-designed and documented procedures that effectively involve all appropriate persons and departments to assure that only material within specifications is used in clinical trials. There must be procedures that ensure the timely availability of clinical supplies, timely and appropriate extension of expiration dates, timely investigation of out-of-specification (OOS) results and rapid notification of appropriate persons, timely recall of all OOS and expired materials, and timely resupply with fresh materials. Depending on the severity of the compliance issue, the clinical trial could be considered compromised. 

Detailed guidance for the request of authorization of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial. October 2005. http //ec.europa. eu/enterprise/pharmaceuticals/eudralex/vol-10/ll ca 14-2005.pdf... 

Ministry of Health and Welfare. Non-chnical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (revision), 2000. Notification No. 1831. 

Before a new pharmaceutical product can be tested in clinical trials, the test product, its labelling and the intended trials must be approved. This is usually done by the same authority that is responsible for the market approval of the final product. The formal procedures to obtain permission for clinical trials vary. Some countries require only a notification to the authority, which may then object within a certified period, other countries require a formal application in order to obtain approval, e.g. by issuing a Clinical Trial Certificate (CTC), before the trials can commence. 

Notifications or applications for clinical trials are supported by summaries or full reports on the preclinical pharmacology and safety assessment. The kind of safety data (e.g. the type and duration of toxicity tests), which are expected at this time, should correspond to the intended route and duration of application. Data on process details and on the quality of the product are not always required. But it must be kept in mind that clinical trials can only render useful results for the later product registration, if the quality characteristics of the tested product and its method of production are the essentially same as for the final product. If available, clinical data from trials in other countries must also be provided. Protocols for the intended clinical trials are an essential part of the application. 

In the EEC, applications or notifications for clinical trials have to be lodged with the individual national authorities. A common procedure or even mutual recognition of clinical trial certificates does not exist. A list of the different national requirements is provided in "The Rules Governing Medicinal Products in the European Communities" Volume III, Annex 1. A discussion paper (III/ 3044/91) released in 1991 by the EEC Division for Pharmaceuticals (DG III) addresses various issues on the harmonization of approval of clinical trials and may eventually lead to common, non-binding recommendations. 

Clinical Trial Protocol Notification. The sponsor is obligated to submit the clinical trial protocol notification of the test drug. The following drugs are required to submit the notification of the clinical trial (The article 66-6 of the Enforcement Regulations of PAL. Notification No. 421 of the PAB in 1997) ... 

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