Clinical studies/trials European requirements

All formulations for administration to humans must be prepared in compliance with good manufacturing practice (GMP) and the certificates of analysis must be provided. The European Clinical Trials Directive requires that details of the formulations be provided to, and approved by, regulatory authorities and a qualified person at the investigator site(s). In principle, the Directive has been in force throughout the EU since May 2004 though it has been implemented at various times in different member states. The Directive applies to healthy volimteer as weU as patient studies. The requirements for pharmaceutical products for administration to humans are summarised in Box 4.6. 

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. 

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. 

While there are exceptions, the U.S. FDA typically requires two adequate and well-controlled Phase III studies whose results confirm each other in order to gain approval for marketing. One important aspect of worldwide development of a new drug is the FDA requirement for Phase III studies with a placebo arm for comparison while other Health Authorities, typically European, require Phase III studies with the current therapy of choice as the control arm in the trial. This requires the conduct of additional clinical testing to meet all requirements worldwide. 

There are slight differences in the requirements for the European Union, the United States, and Japan. Duration to support Phase III trials in the EU, when they differ from the other data, is given in parentheses. Readers are referred to Guidance for Industry M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, EDA, Rockville, MD, 1997. http //www.fda.gov/cder/guidance/1855fnl.pdf [accessed September 20,2007]. 

The new European Directive (2001/20/EC) has reinforced the need for European agencies, as well as those of the United States and Japan, to conduct inspections of clinical trials. Sponsors, mindful of the implications of failed inspections, are carrying out audits by their QA units to try to ensure that standards at a particular site meet the regulatory requirements of GCP, and of any future regulatory inspection. Frequently, the inspections will occur 2 or more years after the end of the study. 

The FDA has clarified the minimum requirements for an IND submission in three areas chemistry, toxicology reports (draft) and size (2-3 volumes, each 3" thick) in an attempt to relax current practices somewhat, to the level required for a UK CTX. However, full reports are to be provided within a short time after the initial drafts. (Conversely, however, information needed to conduct human studies in the European Union has increased, recently, with the implementation of the Clinical Trial Directive.)... 

Clinical trials and clinical trial authorizations in the European Union are controlled under the Clinical Trial Directive, 2001/20/EC [9], and all member states are bound by its requirements. Under the provisions of the Directive, a clinical trial is an investigation in human subjects that is intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of one or more medicinal products, identify any adverse reactions or study the absorption, distribution, metabolism, and excretion, with the object of ascertaining the safety and/or efficacy of those products. This definition includes pharmacokinetic studies. 

Hydroxocobalamin (vitamin another antidote, is a potential alternative to sodium nitrite treatment. It works by binding with cyanide to form nontoxic cyano-cobalamin (vitamin Bj ). Although effective and relatively safe in experimental models, the concentration available in the United States requires large infusion volumes and has a short shelf life due to light instability, and reports of anaphylactoid reactions have limited its use (8,13,21). Further studies using higher concentrations available in European formulations may eventually lead to its use as an outpatient alterative to sodium nitrite treatment in the United States (7,32). Other alternatives currently used or undergoing clinical trials in Europe include cobalt salts, limited by their toxicity, aldehydes, and aminophenol derivatives. These alternative treatments are not currently available in the United States (7). 

If this EU Directive on the protection of personal data were to be taken literally, most clinical trials would cease, particularly where clinical data were transferred outside the EU. Of the non-EU countries, only Switzerland and Hungary apparently meet the requirements of the Directive at the present time Other countries such as the US, Ganada, Australia and New Zealand apparently fail to meet the requirements of the Directive when handling personal data and therefore, in theory, European data cannot be processed in these countries. Fortunately, the so-called Safe Harbor scheme allows clinical data to be sent to defined organisations in the US that comply with the Directive s principles. It is anticipated that similar agreements will be set up to overcome these legislative hurdles so that global studies driven by European pharmaceutical companies and institutions can be undertaken without problems. 

Preclinical toxicology studies should address the standard systemic and local reactogenicity, histopathology, and toxicity (acute and chronic dosage) in rodent and nonrodent animals. Since the FDA and some European authorities decided to classify mRNA-based therapies as no-gene therapy (for nonreplicative mRNA as depicted in this chapter), the implementation of clinical trials does not require additional specific toxicology testing. 

As elderly people are perceived to be a frail population, European regulation requires presentation of the research protocol to an ethics committee. Directive 2001/20/EC regulates and harmonizes ethical rules governing clinical trials in Europe. The ethics committee is an independent body made up of healthcare professionals and nonmedical members. Its responsibility is to protect the rights, safety and well-being of human subjects involved in a clinical trial, and to control the protocol, the suitability of investigators and the documents used to inform the subjects. Consequently, it is the responsibility of each investigator to ensure compliance of the sensory studies with the ethics laws of his country. 

Specifically for Class HI devices, the assessment of conformity rehes in most cases on the submission of clinical data. Nevertheless, according to European directives, manufacturers just have to demonstrate the safety and performance of devices, while evidence of effectiveness is not required at the stage of certification by a notified body. Also, specific requirements for the clinical evaluation of most devices are not available in the guidance. In fact, in most cases, the submission of robust chnical data is limited, and often the evidence submitted is from laboratory testing, literature reviews, or small clinical trials. Typically, this means nomandomized and feasibility studies involving less than 100 patients for which the primary objective is to demonstrate safety (Fraser etal., 2011). 

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