Conducting clinical trials is an expensive and a time consuming process not forgetting the risk it possess to the human trial subjects. In regulating pharmaceutical requirements, ethical behaviour cannot be overlooked. Several guidelines have been put in place to ensure that good practises are followed during clinical trials and manufacture of investigational medicinal products. Among the guidelines are the International Conference Harmonization (ICH) GCP, European Union Directive 2001/20/EC, European Union Directive 2005/28/EC, Food and Drug Administration (FDA) GCP and the European Union Good Manufacturing Practices guidelines. The guidelines generally have the same outlines but differ very little in the principles. The essay is going to outline each guideline and look at some of the differences between them.
Good Clinical Practice
According to the European Medicines Agency (2002), a good Clinical Practice are guidelines that set the standards for design, conduct, performance, monitoring, auditing , recording, analysing and reporting of clinical trials providing that the data collected and the results are credible and accurate while maintaining integrity and confidentiality of trial subjects. Many countries have specified guidelines they adhere to when conducting clinical trials to ensure integrity of human subjects. Most guidelines ensure that an informed consent is obtained from the participating trial subjects and that the person conducting the trials is qualified and well conversant with the guidelines and all procedures to ensure that the scientific interests do not surpass human rights and well being. It is within the provisions that the investigator should have alternative methods of treatment if the investigational medicinal product brings adverse effects that had not been predicted or if the subject decides to quit the trial before he is completely cured. Participants should be compensated if a clinical trial leads to health destruction to an individual who was otherwise healthy, (European Commission Enterprise Directorate-general, July 2002).
Good Clinical practices according to the Directive 2005/28/EC states that the rights, well being and safety of trial subjects should be held paramount to other societal interests of the researcher, (Commission Directive 2005/28/EC, April 2005). This is to mean that if the subjects will not be safe, then the clinical trials should stop. It is required for those conducting the research to be qualified by education in their specialty in the role they play during the trials and proper guidelines should be set up and defined to ensure that this takes place. If the drug is being administered through injection, it is important that only those who know how to use syringes will conduct the exercise. Ethical principles are supposed to be used during the entire clinical process to ensure that the safety of the trial subjects is maintained. The quality of the clinical trials aspects procedures should also be followed. Proposals for clinical trials are supposed to be accompanied by non-clinical and clinical information on concerning the investigational medicinal product. This information is supposed to be adequate. Declaration of Helsinki on Ethical Principles for Medicinal Research Involving Human Subjects should be followed for good clinical practices. Article four of this directive refers to article 2 point h in directive 2001/20/EC which provides a definition on who can be included or omitted from participating in clinical trials, monitoring of the trials and public policy. Guidance on commencing and conducting clinical trail is supposed to be followed by the investigator and sponsor. Article five puts emphasis on the recording of all data collected during the clinical trial. The recording, handling and storage should be done in a manner that it can be reported accurately, properly interpreted and verified while maintaining the confidentiality of trial subjects. To ensure that unnecessary clinical trails do not take place, it is important for the member state to come up with clear guidelines stipulating when a clinical trail can be accepted, (European Medicines Agency,
The directive states that for conduct of clinical trials on humans, the subjects are protected by the application of biology and the protection of human rights. So as to safeguard the rights of the subject, the toxicity of the investigational product should be evaluated by an ethics committee before a clinical trial commences in the member state, (Directive 2001/20/EC of the European Parliament and of the Council, 4 April 2001). Member countries are supposed to give protection to individuals who are not capable of giving consent by laying down rules. Such individuals are not supposed to be included in a clinical trial if similar results can be gotten with persons who can give legal consent. The only reason that would permit inclusion of such individuals in clinical trials would be because there are possibilities that the product under trial would be of benefit to the patient and outweighs potential risks. In case of children, there is need for their inclusion so that treatment used by children can be improved though children are a vulnerable population, who are different in adults in terms of psychology, development and physiology and thus it is important that research conducted should also be age related. For this reason any medicinal product like children vaccines needs proper testing by scientific means before they are given to the wider public by ensuring proper study is done on products beneficial to children. Therefore, clinical trials should proceed in such a way to protect them through laid down procedures by EU member country.
For other persons like those with mental problems and those with dementia, who cannot give legal consent, inclusions in clinical trials should be restricted. The product under investigations should only be given to these individuals only when indicators point that the potential benefits outweigh possible risks. However, legal permission should be in form of writing from the legal representative of the patient in conjunction with the doctor. The legal representative may be a legal person, authority or a body that is recognized by the national law. So as to ensure that health is protected, repetitive tests must not be conducted in a third country or the member country. This puts importance in harmonizing laws in accordance to International Conference Harmonization. The trial patients should make an informed consent to inspection of personal information by the authorities on condition that the information will be kept confidential. Member states are also required to make guidelines to monitor adverse effects of the products so that immediate action is taken to cease the trial. The member states are also required by the directive to set laws so that the trials are not delayed so that the well being of the participating subjects is protected, (European Medicines Agency, April 2008).
ICH good clinical practice guidelines provide unified standards that as applied by the European Union, Japan and United States meant to harness the acceptance of the clinical data within these jurisdictions by regulatory authorities. According to the guidelines of International Conference on Harmonization, the principles for good clinical practices should be that the clinical trials should be done in reference to Declaration of Helsinki in accordance with GCP and the regulatory requirements. Before commencing a clinical trial, it is important that potential risks and inconveniences do not outweigh the benefits of the trial subject. Rights, safety and well being of the trial subjects are the most important above the interests of science and society. Clinical trials proposals should be accompanied by adequate nonclinical and clinical information on the medicinal product under investigation. Clinical trials should be well described and should be applicable in scientific terms following a detailed protocol. The trial is supposed to follow a protocol approve by institutional review board (IRB) or independent ethics committee (IEC). Medical care and medical decisions concerning trial subjects should be done by a professional. Individuals conducting the investigations should be qualified in education, training and experience coinciding with their specific roles. The subjects should give free and informed consent on participating for the trial before being involved. Clinical information should be recorded, handled and stored for accurate reporting, interpretation and verification. The confidentiality of the subjects should be maintained thus it is important to keep any record that may expose them confidential. The products under investigations should ne manufactured, handled and stored following the good manufacturing practice (GMP). Quality of the trial should be assured through proper implementation of system checks throughout the trial, (Ich.org, June 1996).
The IRB is supposed to protect the rights of all trial subjects with special attention being paid to vulnerable subjects. In possession of IRB is supposed to be documents o trial protocols and any amendments, informed consent forms with additional proposals from the investigator and the subject recruitment procedure. The IRB should review the consent forms to ensure that no mode of coercion was used and that proper guidelines were followed in obtaining the legal consent from the individual, parents or the legal representative. Payments and compensations to the subjects should also be indicated and also the mode of payment. IRB is also supposed to review the clinical trial proposal and document views on it in together with approval, disapproval and prior modification before approval. The IRTB is supposed to ensure that the investigator is qualified for to conduct the trial based on information given on curriculum vitae. Ongoing trials are supposed to be reviewed by IRB to determine the degree of human subject risks since clinical trials take time to complete and it is important that all phases are investigated to ensure that proper guidelines are being applied by the investigator and whether the trial should continue or be stopped due to the danger it presents to human test subjects. It is within the jurisdiction of IRB to ask for additional personal information on the participating human subjects without jeopardizing confidential information, (Ich.org. June 1996).
Foods and Drugs Administration GCP
All human subjects are supposed to make an informed consent about their involvement in clinical trials either from the individual directly or from a legal representative. This means that no means of coercion should be considered by the investigator. It is also important that the person is given the information in a language that can be understood which should state clearly the rights of involvement. Consent is considered feasible unless the investigator and an independent physician certify that the subject is under a threatening condition and thus it was better to use the investigational medicinal product to try and improve the condition. However, informed consent cannot be obtained when the subject is unable to communicate and thus the necessity to use a legal representative, (FDA, August 2009). The President has the power to waive prior consent for investigation of a new drug to a member of the military through writing that the involvement in such a procedure for a military man is not to the interest of national security. Informed consent should be documented using an IRB form that is approved by IRB and signed by the subject or legal representative.
The FDA good clinical practice puts down the description of an informed consent as explaining to the potential subject about the purpose of the study, duration of participation, procedures to be followed in additional to description of experimental procedures. The person is also supposed to be informed of the potential risks and benefits that may arise due to the research. It is important that the investigator informs the patient of possible treatment procedures if the experiment fails, (FDA, January 2011). The investigator should assure the subject of the confidentiality of any personal information and the possibility of the FDA authorities investigating the records. Information on whom to contact if the subject is injured and also information and that participation is voluntary and that the subject has the right to discontinue with the trials without any loss of benefit.
It is the duty of IRB to investigate clinical trials involving children as subjects and they should also approve those proposals that meet all the requirements. The clinical investigations should have benefits to the child patient that outweigh the potential risks which should be verified by IRB. Parents or legal guardians are supposed to give an informed consent on the participation of the children in clinical trials.
FDA and ICH GCP
The main difference is on the area of jurisdiction where FDA is concerned with clinical trials inside the US and Puerto Rico while the ICH is an international harmonization that bridges the gap between US, European Union and Japan. Both guidelines require the patients to give an informed consent after being informed on clinical trial procedures and methods. Both requirements however do not require the participation of physicians. In ICH clinical studies, a personal care doctor is supposed to receive notice that the patient is participating in a trial. FDA does not require notification to any physician. ICH also requires that the participants should authorize the consent forms while the FDA only says the participants should receive copies of the forms. On study medications, the ICH requires the investigator to document use of medications by the patient where medications can only be distributed over a specified time while FDA documentation is also required but drug manufacturers are not prohibited from distributing medications to the participants before official commencement of the trial.
FDA and EU GCP
The FDA and EU GCP guidelines also differ in areas of jurisdiction with EU GCP governing jurisdiction of its member states and FDA dealing with clinical trials in the US and Puerto Rico. Generally, they both seek to protect human safety during clinical trials and they have similar principles.
Good Manufacturing Practice
Good manufacturing practices cover the manufacture and testing of the pharmaceutical products. GMPs are guidelines that delineate aspects in production and testing in relation to product quality. Manufacturers are supposed to embrace new technologies of manufacture that ensure the quality of the investigational medicinal product is maintained while cutting down manufacturing costs. The authorities should also incorporate state-of-art methods to ensure that quality control is maintained at all processes of manufacture (FDA 2009 pg 1). The manufacturers are also supposed to be conversant with the regulatory guidelines in the country they want to export the investigational medicinal products ensuring they met all set protocols for human safety.
Directive 91/356/EEC on Good Manufacturing Processes
The European Commission Directive 91/356/EEC is a guideline was laid out for good manufacturing products for investigational medicinal products manufactured for human use in relation to personnel, premises, equipment, production, documentation, quality control and labelling, work contracted out, inspections, complaints and product recalls. Quality assurance system refers to guidelines laid down for personnel, premises and equipment. The manufacturer is supposed to have a pharmaceutical
quality assurance system which is effective and is supposed to involve the management and personnel of the concerned departments. In each site of manufacture, the manufacturer is supposed to hire competitive personnel with the required skills so that quality assurance is ensured. It is the responsibility of the manufacturer to train personnel on theoretical and application of quality assurance together with good manufacturing practice and what is required for manufacture of investigational products. Hygiene procedures concerning health, clothing and practice of personnel should be implemented. In relation to the equipment, hygiene standards should also be met so that the equipment does not become a source of contamination for the medicinal product leading to adverse effects. In addition, the equipment and premises which will be used during manufacture should acquire proper validation because they are critical to product quality, (Europa Summaries of EU Legislation, May 2007)
According to the directive, the production should follow the good manufacturing practice and the pre-established instructions. Any deviation on process or product defects should be recorded and investigated to ensure that product quality. To avoid cross-contamination, it is important that the organizational or technical measures are taken. Investigational medicinal products should be properly handled during and after blinding operation. It is essential that new processes of manufacturing medicinal products and any method that has been changed to be validated followed by revalidation on critical phases during the process of manufacturing.
Documentation system should be set up by the manufacturer that includes all manufacturing processes. In the documents, history of the manufacture of each batch should be included together with any changes that are introduced during investigational medicinal product development. In case the manufacturer wants changes from written documentation to electronic or other data processing methodologies, it is important that the manufacturer provide proof that product recording will take place for all information gathered during the manufacture.
Quality control systems should be set up by the manufacturer and placed under control of an independent person with the right qualifications. This person should have access to the laboratories that deal with quality control so that beginning products, intermediate products and the final product can be tested. The final control of the product that is finished production conditions should ne taken into account, results of the in-process controls, manufacturing documents examination and whether the product has maintained its conformity. It is also important to maintain the final product samples for two years in addition to packaging components after clinical trial completion. Raw materials samples used during the manufacture should also be maintained for two years. Labelling investigational medicinal products should be done in such a way that the subject is protected and it is not easy to trace them. It is also meant to enhance proper use of the product and also to allow for easy identification of the product in relation to how it is used during trial.
Regarding contracted work there should be a written contract between the contract giver and the acceptor about the manufacturing operation. This contract is supposed to lay down responsibilities of each party. The acceptor of the contract must follow and respect guidelines and principles of a good manufacturer practice. While following the guidelines, the contract acceptor must submit to inspections done by independent competent authorities.
Concerning complaints, product recall and emergency unbinding, member states of European Union should set up inspections that ensures that manufacturers are following the guidelines and principles for a good manufacturing practice, taking into account Community procedures concerning inspection and information exchange. It is the responsibility of the manufacturer to ensure that the manufacturing operations coincide with the good manufacturing practices with proper authorization for all manufactures including those products for exportation. For investigational medicinal products imported from countries that re not member countries of EU, the importer should check and ensure that the manufacturing process was equivalent to that of European Community. It is also the responsibility of the importer to ensure that the manufacturers are authorized in their countries. For investigational products, the manufacturer must ensure that information provided by the sponsor and accepted by the authorities is correct regarding the process of manufacture. Manufacturers are also supposed to evaluate complaints about product defects and inform proper authorities of any product defect that could culminate to product recalls in the trial sites. Sponsors of investigational medicinal products should implement unblinding of blinding products which could lead to recall. Identity of blinded product is also necessary.
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