Ethical considerations and regulatory requirements in the development of NAS - Essay Example

Blessilda Borbon Academia Research - Freelance Topic: Ethical considerations and regulatory requirements in the development of NAS 09 October2008 Ethics and Regulations Question #1: In order to comply with the recommendations contained in the ICH Note for Guidance on GCP, how should informed consent be obtained for this trial at UK hospital sites What practical considerations apply and what documents would need to be prepared /completed for the consent process What approval would need to be obtained for the proposed consent procedures Your answer should include references (including section numbers) to the relevant sections of the ICH GCP 2.9 Guideline, EC Directive and the Declaration of Helsinki. The universal standard in the use of human subjects in clinical trials is laid down in the ICH Good Clinical Practice (GCP) guideline that is based on the principles presented in the Declaration of Helsinki. It encompasses the ethical and scientific aspects to be considered when planning, performing, documenting and reporting all phases of the clinical trial. The regulations and guidelines in conducting these trials are set forth in order to safeguard the rights, safety and overall well-being of trial subjects. In the process of obtaining human subjects for the clinical trial, it is necessary to procure a written informed consent from the persons involved. The Nuremberg Code of 1947 states that, "voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment." (Mitscherlich et. al., par. 2) In cases where an individual is considered unable to give informed consent, such as in the case of unconscious patients, children, and/or mentally ill patients, another person is generally authorized to give consent on their behalf. This is permissible only if the necessity of having this particular set of subject has been established and that there are no other alternatives otherwise. Also, the subject should be duly informed of his right to terminate his participation in the experiment at any given time, provided that he informs the investigator of his intentions to withdraw from the study and his reason for doing so. The ICH GCP guideline on informed consent maintains that, "The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject's consent. Any revised written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in advance of use. The subject or the subject's legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject's willingness to continue participation in the trial. The communication of this information should be documented." (ICH GCP 4.8.2, page 20) The written approval or favorable opinion of the written consent form and other written information to be given to the subjects should be obtained from the IRB/IEC before starting the clinical trial. (ICH GCP 4.8.1, page 20) Question #2: Can the testing of medicines in healthy volunteers be justified according to the principles of beneficence, non-maleficence, justice, and respect for autonomy Ethics attempts to distinguish actions from right and wrong. In medicine, the ethical challenge often includes deciding between the lesser of two evils or the greater of two goods. Testing of medicines in healthy volunteers should therefore be based on the four ethical foundations: beneficence, non-maleficence, justice, and respect for autonomy. The ethical principle behind beneficence is to do "good". In the clinical trial setting, this principle is observed in the thorough study and research made by qualified investigators and medical professionals prior to the administration of the NAS with the primary intent of producing a product that would benefit the greater public in the long run. At the same time, the principle of non-maleficence, meaning to do no harm, gives boundaries to the investigators from knowingly and willingly acting in a way that is harmful to the patient. The principle of justice coincides with non-maleficence in the way that it speaks of equality and fairness. It is concerned with giving the patients what is due to them. Last is respect for autonomy. This principle is met by empowering the target human subjects in making informed decisions for their own person. The Nuremberg Code supports this idea as presented in the previous answer. Ultimately, after all is said and done, this last principle, when executed properly together with the rest of the ethical principles, justifies testing medicines for the betterment of future generations. Question #3: Explain why pharmacovigilance is important after a medicine has been marketed to further establish its safety. What specific regulatory requirements are in place to ensure this is carried out Pharmacovigilance (PV) is a scientific discipline that deals with adverse drug reactions. Derived from the root word pharmakon (Greek), meaning "drug", and the Latin vigilare, which means "to keep watch", it is primarily concerned with an ongoing study and constant monitoring of unintended drug reactions on the involved consuming public. While clinical trials aim to determine the efficacy and safety of drugs, limitations to its study are not unknown. The most common limitations to clinical trials are the following: Homogenous Sample Populations. The use of homogenous or similar sample population in clinical trials, concentrating on a population with one common factor may it be disease or age group, excludes the effectivity of the study to specific populations such as pregnant women, children, and other people taking whose health is already compromised with ongoing diseases. Sample size. Small sample size decreases the opportunity to discover uncommon side effects. Duration. Clinical trials that are of short duration prevent the realization of long term effects. Drug Interaction. The unpredictability of the real world having real people with individual health status and drug reaction exacerbated by drug interaction is a limitation that clinical trials may not be able to overcome. Thus, giving rise to the need for pharmacovigilance in safeguarding the welfare of the people. The regulation of medicinal drugs, products, and other therapeutic goods and devices, vary by jurisdiction. In UK and all of Europe, the pharmacovigilance effort is headed by the European Medicines Agency (EMEA) whose main function is to regulate and develop a system called "EudraVigilance" which holds the records of both human and veterinary reactions to drug use. Pharmaceutical companies submit an application for marketing authorization for products that are qualified for approval to the EMEA. The actual evaluation is carried out by the Committee for Medicinal Products for Human Use (CMPH) who determines the quality, safety and effectivity of the product. If the product is amply proven effective after evaluation, the CMPH gives its positive opinion to the European Commission to be turned into marketing authorization applicable for all of the member states in the European Union (EU). Specific regulatory requirements are laid down in Directive 2001/83/EC of November 6, 2001, on the community code regarding medicinal products for human consumption. The latest amendment of this directive was done by the European Parliament and Council on March 31, 2004, under Directive 2004/27/EC. On a national level, the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK government works alongside the Commission on Human Medicine (CHM) and other expert advising bodies in the approval and regulation of therapeutic products. Functions of the MHRA involve surveillance of medicinal drugs and other medicinal products after it has been open to the market including but not limited to constant monitoring of adverse drug reactions, oversee the compliance of manufacturers and pharmaceutical companies to regulatory requirements, inspect sales made on the internet and possible drug counterfeiting and, promotion of safe use of drugs and devices. Background: You are working in the UK subsidiary of a Japanese company. A new active substance (NAS) for the treatment of asthma is ready for clinical development. It is to be administered orally. The first administration to man will be done in the UK. Subsequent development will be carried out in Europe and Japan with a view to a centralized application in the UK. Question #1: List the requirements that need to be met prior to the first Phase I study. The Statutory Instrument 2004 No. 1031 on The Medicines for Human Use (Clinical Trials) Regulations became a law based on the EU Clinical Trials Directive (2001/20/EC). The legislation aims to safeguard the safety and well-being of research participants in course of clinical trials. According to Part 3 of the EU Directive regarding Authorization for Clinical Trials and Ethics Committee Opinion, the following regulations should be met prior to Phase 1 of clinical trials: (a) Application for authorization to conduct a clinical trial duly submitted and approved by an ethics committee, (b) completion of protocol, and/or (c) submission of the other particulars or documents supplementing the application for approval by the ethics committee. Chapter 8 of the ICH Harmonised Tripartite Guideline, the Guideline for Good Clinical Practice (E6 R1) -Step 5, lists the following documents to be completed before commencement of trial as follows: (1) Investigators brochure. This contains significant information regarding the test product. (2) Signed protocol and amendments, if any, and sample case report form. This is a documentation of the agreement between the sponsor and investigator plus the CRF. (3) Information given to trial subject. This would consist of the informed consent form, other written information, translations, if any, and, advertisement used for subject recruitment to determine proper execution of the same. (4) Financial Aspects of the Trial. To recognize financial obligations and agreements between the sponsor, investigator and, institution. (5) Insurance Statement. To ensure availability of compensation for injuries incurred by the subjects as a result of the trial. (6) Signed agreement between involved parties. (7) Dated, documented approval/favourable opinion of Institutional Review Board (IRB)/Independent Ethics Committee (IEC). To document evidence of review and identify date of documents and version number. (8) IRB/IEC Composition. To determine that the said committee amounts to the requirements of GCP. (9) Regulatory authority authorization/approval/notification of protocol. For evidentiary purposes of approval. (10) Curriculum vitae and/or other relevant documents evidencing qualifications of investigators and sub-investigators. To establish qualifications and ability to conduct the experiment. (11) Normal value(s) range(s) for medical/laboratory/technical procedure(s) and/or test(s) included in the protocol. For documentation purposes. (12) Medical/laboratory/technical procedures/tests. To determine capability of facility to conduct the said tests and maintain dependability of results. (13) Sample of label(s) attached to investigational product container(s). This would determine conformity with regulations on labeling and suitability of instructions given to the subjects. (14) Instructions for handling of investigational product(s) and trial related materials. To ensure proper handling of products if this has not yet been included in the protocol or Investigator's Brochure. (15) Shipping records for investigational product(s) and trial related materials. To determine shipment dates and other relevant information concerned with shipment of product. (16) Certificate(s) of analysis of investigational product(s) shipped. To ensure quality of product after shipment. (17) Decoding procedures for blinded trials. This shall be used in cases of emergency, when the identity of blinded product needs to be revealed without compromising the blind for the remaining duration of the subject's treatment plan. (18) Master randomization list. To identify the method used in the randomization of the trial population. (19) Pre-trial monitoring report. To determine suitability of the trial site. (20) Trial initiation monitoring report. As evidence that the investigators and the investigating staff duly reviewed the procedure prior to starting the trial. Question #2: What data would you except to have prior to therapeutic trials in patients Therapeutic trials are designed to test the effectiveness and safety of the drug under investigation. The usually data that needs to be established prior to starting therapeutic trials can be found in Chapter 8 of the ICH Harmonised Tripartite Guideline, the Guideline for Good Clinical Practice E8 -Step 4; as follows: (1) evaluation of short-term safety and tolerability; (2) pharmacodynamic and pharmacokinetic information, and (3) suitable dosage range and administration schedule. Question #3: Outline, in bullet points, a development plan for this NAS up to and including the marketing authorization application (MAA). A new active substance (NAS) development plan by Dr. Kenneth Sokoll coincides with the discussion on this paper, where he stated the following steps in optimizing drug development strategies from pre-clinical trial up to clinical development. Discovery. Discovery involves basic research, drug identification and early-stage process and analytical method development. Pre-clinical development. This includes laboratory and animal studies where early toxicology and pharmacology studies are conducted in the appropriate animal models. Clinical development. Preparation of clinical protocols including studies relevant to proving safety of drug product. Filing for licensure. Approval/licensure. Post-approval. Improvements to manufacturing processes and the analytical characterizations of the drug substance and drug product (yield, purity, stability) are completed in support of the preparation of an investigational new drug application (IND). With regulatory review of the IND and receipt of approval to proceed into clinical trials. Clinical Development. Pertains to the execution of phase I to IV of the clinical-trial (Sokoll, vol.3, issue 6). If the new compound comes out with acceptable levels of toxicity and safety profile, and has produced desired results in the clinical trial, then it can be submitted for marketing approval to the MHRA. The development for the plan for the NAS would then be concerned with the following: Review of clinical trial and other scientific data Biopharmaceutical and pharmacology review Review of clinical trial design and protocol Review of drug identity, stability and manufacturing procedures Review of official instructions for use or proper labeling, and Review of target market and market assessments Question #4: What are the key issues that you think will need to be addressed in the clinical overview Based on what has been discussed in this paper, key issues in the clinical overview that need to be addressed are as follows: Quality aspects of the NAS Pharmacokinetics Pharmacodynamics Clinical efficacy involving subject response to dose and other main clinical studies Clinical safety involving adverse events and safety in special populations Establishment of pharmacovigilance system, and Availability of risk management plan Works Cited "Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code relating to Medicinal Products for Human Use." Official Journal L - 311: p. 67 - 128. 28 November 2004 ICH Harmonised Tripartite Guideline: General Considerations for Clinical Trials E8. 17 July 1997. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Step 4 ver. 9 October 2008 ICH Topic E 6 (R1): Guideline for Good Clinical Practice. July 2002. European Medicines Agency. Step 5. 8 Oct 2008 Medicines and Medical Devices Regulation: What you need to know. April 2008. The Medicines and Healthcare products Regulatory Agency. 09 October 2008 Mitscherlich A, Mielke F. "The Nuremberg Code (1947)" Doctors of Infamy: the story of the Nazi medical crimes. New York: Schuman, 1949: xxiii-xxv: par 2. 8 Oct 2008 "Pharmacovigilance." Wikipedia: The Free Encyclopedia. 7 October 2008. 8 October 2008 Sokoll, Kenneth. "Optimizing Drug Development Strategies". Pharma&Bio Ingredients 3.6 (2006). 9 October 2008 Statutory Instrument 2004 No. 1031: The Medicines for Human Use (Clinical Trials) Regulations. Office of the Public Sector Information. 6 April 2004. Crown Copyright 2004. 09 October 2008 Read More