Clinical Trials Exemption

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. 

In the United Kingdom, clinical trial applications are submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA). There are several schemes for clinical trial application the major two are the Clinical Trial Certificate (CTC) and Clinical Trial Exemption (CTX) schemes. 

Medicines Control Agency. Medicines Act 1968. Guidance Notes on Applications for Clinical Trial Exemptions Clinical Trial Certificates. Revised December 1995. London HMSO, 1995. 

In view of the regulatory delay that was caused by the need to apply for a CTC, a Statutory Order (SI 1974/498) was made during 1974, to provide an exemption from the need to hold a CTC in such cases, subject to certain conditions. This order applied to trials conducted by doctors and dentists on their own responsibility (DDX). The basis of the clinical trial exemption (CTX) scheme, introduced in 1981, to include studies initiated by the pharmaceutical industry, was that together with a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and human volunteer studies, a clinical trial in patients may proceed without the need for the additional details normally required for a CTC or Product Licence application. This exemption scheme was based on the requirements that ... 

Prior to the introduction of EU Clinical Trials Directive, there were four ways of seeking approval for the commencement of clinical trials in the United Kingdom. These were by means of a Clinical Trial Certificate (CTC), a Clinical Trial Exemption (CTX), a Doctor s and Dentist s Exemption (DDX) or as a Clinical Trial on a Marketed Product (CTMP). Each required provision of a detailed protocol of the proposed trial. 

A Clinical Trial Exemption (CTX) Scheme was introduced in Australia in 1987, with the intention of encouraging clinical trial activity. However, in addition to the aforementioned TGA restrictions, which required all clinical trials of an active substance underway in Australia to be completed before the review of a general marketing application relating to that substance, the specified data package included requirements unique to Australia, and the 60 working day review period compared with a 35 calendar day review imder the UK CTX Scheme. 

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. 

The mechanism of regulatory control is dependent upon whether the clinical trial is conducted under the auspices of a company, or independently, for example, by a medical or dented practitioner and whether it is to be conducted within or outside the terms (e.g., indication, dosage) of an MA. Most commonly the clinical trial will be sponsored by a company, and be designed to investigate a new aspect of efficacy or Scifety in the absence of or outside the terms of an MA in this case the company sponsor must, by application to the MCA, obtain a Clinical Trial Exemption (CTX), or rarely by choice, a Cliniced Trial Certificate (CTC). However,... 

Table 5. Information required to accompany a clinical trial exemption (CT)Q application. Source Derived from The Medicines (Exemption from Licences) (Clinical Trials) Order 1995 SI No 2808. 

The legal basis for the CTX scheme is given in SI 1995 No. 2808 The Medicines (Exemption from Licences) (Clinical Trials) Order, and SI 1995 No. 2809 The Medicines Exemption from Licences and Certificates) (Clinical Trials) Order. The MCA provides guidance notes on applications for clinical trial exemptions and clinical trial certificates. Special forms (MLA 164, 165,166, and 168), obtainable from the MCA, are provided for use by applicants in preparing a CTX application, notification of chcinge, and renewal. 

As stated in 321.21, A sponsor shall submit an IND if the sponsor intends to conduct a clinical investigation with a new drug. .. [and] shall not begin a clinical investigation until. .. an IND. .. is in effect. (Similar procedures are in place in other major countries. In the United Kingdom, for example, a clinical trials certificate (CTC) must be filed or a clinical trial exemption (CTX) obtained before clinical trials may proceed.) Clinical trials are divided into three phases, as described in 21 CFR 312.21. Phase I trials are initial introductions into healthy volunteers primarily for the purposes of establishing... 

The IND differs in a number of ways from its European counterparts. First, it is much longer a typical IND is of at least 1000 pages, and for dmgs with foreign human experience, often many multiples of this number. The UK Clinical Trials Certificate, used very rarely for this reason, and not the Clinical Trials Exemption ( CTX ), would be the nearer comparison. Second, an IND is required for all human exposure to INDs, and this includes normal volunteer studies. Third, all being well, there is only a 30-day wait between filing and commencement of the clinical study no news from FDA after this time period has elapsed is presumptive evidence that the study may proceed (most FDA divisions will, in fact, issue affirmative letters that this is the case, within 30 days). Fourth, once an IND has become active, there is no subsequent 30-day wait when further clinical protocols are submitted. 

Speirs CJ, Saunders RM, Griffin JP. 1984. The United Kingdom Clinical Trial Exemption Scheme - its effects on investment in research . Pharm. Int. 5 254-256. 

At the time of writing, the conduct of studies in non-patient volunteers in the UK is not regulated by the Medicines Act (1968). Similarly, studies in non-patient volunteers in the Netherlands, Belgium and some other European countries do not require regulatory approval. This situation is about to change, as the EU Directive issued in 2001 will require to be implemented in all European countries by 2004. All healthy volunteer studies will then require regulatory approval in addition to that of an ethics committee. The Directive, with which all member states must comply, makes no distinction between healthy volunteer studies and clinical trials in patients who may benefit from treatment. However, the precise details of documentation required for authorisation of healthy volunteer studies may vary from country to country it is possible that the application in the UK will be somewhat less detailed than the current Clinical Trials Exemption. 

Speirs and Griffin described the effect of the clinical trial exemption scheme in attracting clinical studies on new chemical entities (NCE) in the first year of operation of the scheme. In 1980 there were 87 applications for... 

There is no general "experimental use" exemption or defense against a charge of infringement (196). There is, however, a so-called clinical trial exemption that is of special interest to the drug discovery and development industry. This clinical trial exemption generally provides that it is not infringement to make, use, or sell a patented invention... 

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. 

Australia— Studies should reveal potentially useful and harmful properties of the drug in a quantitative manner, which will permit an assessment of the therapeutic risk. .. Investigations of the general pharmacological profile should be carried out (Guidelines under the Clinical Trial Exemption Scheme, pp. 12, 15)... 

---