Clinical Trials Certification

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. 

The Medicines Act 1968 included the definitions of a clinical trial and of a medicinal product. Clinical studies involving healthy volrmteers did not meet this definition of a clinical trial and, as a result, did not come under the remit of regulatory controls. Such studies were subject to self-regulation by the pharmaceutical industry. Consequently, only the clinical trials in patients had to be covered by a clinical trial certificate (CTO. 

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. 

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. 

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. 

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,... 

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. 

A Clinical Trial Certificate application is not usually considered as the best choice of strategy unless a CTX heis been refused, or perhaps when a company requires a... 

Under the Medicines Act, the licensing system for MAs, Manufacturer s, and Wholesale Dealer s Licences, and for Clinical Trial Certificates, allows the opportunity for an applicant or licence holder to appeal against an unfavourable recommendation or decision, right up to the High Court if necessary, although that has rarely happened. Nevertheless, appeals to the appropriate advisory committee such as the Committee on Safety of Medicines, and to the Medicines Commission, are commonplace in the process leading to grant of an MA. Appeals may also arise in connection with the suspension, revocation, or compulsory variation of MAs or certificates. Manufacturer s Licences and Wholesale Dealer s Licences are rarely subject of the need for such appeal action. 

Fees are levied in respect of applications for MAs, Manufacturer s Licences, Wholescile Dealer s Licences, Clinical Trial Certificates, and variations thereto inspections of manufacturing sites annual maintenance fees and issue of export certificates. No fees are levied in respect of applications for exemption from a Clinical Trial Certificate, so-called CTX applications, or for MA renewcils. The fees are based upon the statute SI 1995 No. 1116 The Medicines (Products for Human Use-Fees) Regulations as eimended, and for 1999/2000 are summcu-ised in Table 7. 

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. 

Sections 31-39 of the Medicines Act, which set out the general provisions governing the conduct of clinical trials in the UK, are unaffected by the 1994 Regulations. The Act pro sddes that a clinical trial must be authorised before taking place, either by the terms of the marketing authorisation of the product involved, or by a clinical trial certificate ( CTC ) (sections 31(3) and 35(1)). Exemptions, allowing use in clinical trials in other circumstances, are contained in the Medicines (Exemption from Licences) (Special Cases and Miscellaneous Pro visions) Order 1972 (exemption for trials initiated by doctors and dentists - DDX scheme), the Medicines (Exemption from Licences) (Clinical Trials) Order 1995" and the Medicines (Exemption from Licences and Certificates) (Clinical Trials) Order 1995" (exemption for company initiated trials - CTX scheme). Both of these exemptions are subject to certain conditions, such as notification to the MCA. 

The basis of the CTX scheme is that, following an evaluation of a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and, when appropriate, human volunteer studies, a clinical trial may be permitted. This obviates the provision of the additional details normally required for a Clinical Trial Certificate or Product Licence application. 

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. 

CRO Contract research organization CTC Clinical trials certificate CTM Clinical trials material CV Coefficient of variation CVS Cardiovascular system... 

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