International Conference on Harmonisation

ICH – GCP

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is unique in bringing together the regulatory authorities and pharmaceutical industry of Europe, Japan and the US to discuss scientific and technical aspects of drug registration. Since its inception in 1990, ICH has gradually evolved, to respond to the increasingly global face of drug development, so that the benefits of international harmonisation for better global health can be realised worldwide. ICH's mission is to achieve greater harmonisation to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.
Ethics in Clinical Research
The evolution of clinical research traverses a long and fascinating journey. From the first recorded trial of legumes in biblical times to the first randomized controlled of trial of streptomycin in 1946, the history of clinical trial covers a wide variety of challenges – scientific, ethical and regulatory. The famous 1747 scurvy trial conducted by James Lind contained most elements of a controlled trial. The UK Medical Research Council’s (MRC) trial of patulin for common cold in 1943 was the first double blind controlled trial. This paved the way for the first randomized control trial of streptomycin in pulmonary tuberculosis carried out in 1946 by MRC of the UK. This landmark trial was a model of meticulousness in design and implementation, with systematic enrolment criteria and data collection compared with the ad hoc nature of other contemporary research.
Over the years, as the discipline of controlled trials grew in sophistication and influence, the streptomycin trial continues to be referred to as ground breaking. The ethical advances in human protection include several milestones – Nuremberg Code, Declaration of Helsinki, Belmont Report, and 1996, International Conference on Harmonization Good Clinical Practice guidance. In parallel to ethical guidelines, clinical trials started to become embodied in regulation as government authorities began recognizing a need for controlling medical therapies in the early 20th century. As the scientific advances continue to occur, there will be new ethical and regulatory challenges requiring dynamic updates in ethical and legal framework of clinical trials.
After basic approach of clinical trial was described in 18th century, the efforts were made to refine the design and statistical aspects. These were followed by changes in regulatory and ethics milieu.
Evaluation of ethics and regulatory frame work in Clinical Research
The ethical framework for human subject protection has its origin in the ancient Hippocratic Oath, which specified a prime duty of a physician - to avoid harming the patient. However, this oath was not much respected in human experimentation and most advances in protection for human subjects have been a response to human abuses e.g. World War II experiments. The first International Guidance on the ethics of medical research involving subjects - the Nuremberg Code was formulated in 1947. Although informed consent for participation in research was described in 1900, the Nuremberg Code highlighted the essentiality of voluntariness of this consent. In 1948, Universal Declaration of Human Rights (adopted by the General Assembly of the United Nations) expressed concern about rights of human beings being subjected to involuntary maltreatment. The brush with thalidomide tragedy helped the U.S. pass the 1962 Kefauver-Harris amendments, which strengthened federal oversight of drug testing and included a requirement for informed consent.
In 1964 at Helsinki, the World Medical Association articulated general principles and specific guidelines on use of human subjects in medical research, known as the Helsinki Declaration. The Helsinki Declaration has been undergoing changes every few years, the last one being in 2008. However, the use of placebo and post-trial access continue to be debatable issues. In 1966, the International Covenant on Civil and Political Rights specifically stated, ‘No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment. In particular, no one shall be subjected without his consent to medical or scientific treatment.’ Dr. Henry Beecher’s 1966 study of abuses and the discovery of human exploitation of Tuskegee study in the 1970s reinforced the call for tighter regulation of government funded human research. The US National Research Act of 1974 and Belmont Report of 1979 were major efforts in shaping ethics of human experimentation.
In 1996, International Conference on Harmonization published Good Clinical Practice, which has become the universal standard for ethical conduct of clinical trials. In parallel to ethical guidelines, clinical trials started to become embodied in regulation as government authorities began recognizing a need for controlling medical therapies in the early 20th century. The FDA was founded in 1862 as a scientific institution and became a law enforcement organization after the US Congress passed the Food and Drugs Act in 1906. After that, legislation progressively demanded greater accountability for marketing food and drugs and the need for testing drugs in clinical trials increased. The regulatory and ethical milieu will continue to evolve as new scientific disciplines and technologies become part of drug development.
History behind GCP:
Among the basic ethical principles that are generally accepted in our cultural tradition, three are particularly relevant to the ethics of research involving human subjects. These are the principles of respect for persons, beneficence and justice.
One requirement is to acknowledge the autonomy of individuals, their right to self-determination. This interpretation of the principle underlies the concept of informed consent. Its application demands that human subjects participate in the research voluntarily and with adequate information about the potential benefits and risks to make an informed decision regarding their participation.
Although some individuals may require protection even to the point of excluding them from activities that may harm them, overprotection may be dehumanizing and represent a lack of respect. Thus, a balance must be struck between protecting the welfare of individuals and not repudiating their autonomy.
The principle of beneficence states that ‘‘we . . . have a moral duty to weigh and balance possible benefits against possible harms in order to maximize benefits and minimize risks of harm’’.
The principle of justice represents the concept of fairness. It requires that the benefits and burdens of any activity, such as participation in clinical trials, be distributed equitably across the population. In short, it states that equals should be treated equally.
Federal Food and Drugs Act 1906 That the Act entitled "An Act for preventing the manufacture, sale, or transportation of adulterated or misbranded or poisonous or deleterious foods, drugs, medicines, liquors and for regulating traffic therein and for other purposes," approved June 30, 1906.
Sulfanilamide disaster in 1937: Sulfanilamide, a drug used to treat streptococcal infections, had been shown to have dramatic curative effects and had been used safely for some time in tablet and powder form. In June 1937, however, a sales man reported a demand in the southern states for the drug in liquid form. The company's chief chemist and pharmacist, Harold Cole Watkins, experimented and found that sulfanilamide would dissolve in diethylene glycol. The company control lab tested the mixture for flavor, appearance, and fragrance and found it satisfactory. Immediately, the company compounded a quantity of the elixir and sent shipments 633 of them, all over the country.
The new formulation had not been tested for toxicity. At the time the food and drugs law, did not require that safety studies be done on new drugs. Selling toxic drugs was, undoubtedly, bad for business and could damage a firm's reputation, but it was not illegal. Because no pharmacological studies had been done on the new sulfanilamide preparation, Watkins failed to note one characteristic of the solution. Diethylene glycol, a chemical normally used as antifreeze, is a deadly poison.
The first shipments were sent out in early September. On October 11, the American Medical Association (AMA) received reports from physicians in Tulsa, Okla, that an unfamiliar sulfanilamide compound was responsible for a number of deaths. The AMA asked for samples of the drug and then wired the Massengill Co, requesting the composition of the compound. The AMA laboratory isolated diethylene glycol as the toxic ingredient and immediately issued a warning, through newspapers and radio, that Elixir Sulfanilamide was toxic and deadly.
Food, Drugs and Cosmetic ACT 1938: More consumer-oriented than its predecessor, the 1938 Food, Drug and Cosmetic Act was a watershed in US food policy. In contrast to the limited health-based standards that the Ministry of Health proposed in Britain during the Depression, the US, largely through the efforts of women’s groups, pioneered policies designed to protect the pocketbooks of consumers, and food standards were enacted to ensure the ‘value expected’ by consumers. The 1938 Act eliminated the ‘distinctive name proviso’ and required instead that the label of a food ‘bear its common or usual name’. The food would be misbranded if it represented itself as a standardised food unless it conformed to that standard. The law provided for three kinds of food standards: 1) standards (definitions) of identity, 2) standards of quality and 3) standards regulating the fill of container. Regulators had the discretionary authority to set standards ‘whenever in the judgment of the Secretary such action will promote honesty and fair dealing in the interests of consumers’
Nuremberg Code 1946 :  Evaluation of Nuremberg code with 10 principles focusing on experiments involving human subjects .These primarily were based on legal concepts because medical codes of ethics existence at the time of Nazi atrocities did not address the consent and other safeguards for human subjects. Brutal ways of conducting clinical trials on soldiers and civilians by Nazi physicians during World War II never offered justification. This incident invoked regulations in clinical trials involving human subjects.
Thalidomide Disaster 1962: In 1962, Thalidomide, a sleeping pill was developed and widely used to overcome sleeping disorders in pregnant women during first trimester. Children born to such mothers, who used thalidomide, often were born without limbs and other severe deformities.
Declaration of Helsinki 1964:
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects.
“The Health of the patients will be the first consideration”... declared in Helsinki, June 1964.
GCP Introduction
Good Clinical Practice is a set of guidelines that must be followed when conducting clinical trials to ensure that the rights and well-being of the trial participants are protected and that the data generated in the trial is valid. Good Clinical Practice is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve human participants.
 The guidelines were developed in order to provide, clinical trials with a unified standard across the European Union, Japan and the United States and were labelled ICH-GCP at the International Conference on Harmonization, 1996.
The UK Medicines for Human Use (Clinical Trials) Amendment Regulations 2006 implement the EU Clinical Trials Directive in the UK. The Regulations are a legal requirement introduced in an attempt to harmonize the administration of clinical trials across the EU. For more information see the UK for Human Use (Clinical Trials) Regulations 2005 leaflet. The adherence to GCP is a requirement encompassed in the Clinical Trial Regulations and the new EU GCP Directive, which is based in ICH-GCP. This Directive requires an amendment to the current legislation which is underway at present.
Concern for the regulation of trials emerged in response to medical tragedies such as the discovery of the effects of thalidomide in pregnancy in the 1960’s which highlighted the world-wide need for central records of trials that are occurring. In addition problems have arisen with obtaining marketing authorizations for drugs across different countries where different versions of GCP are being adhered to. With a common piece of legislation this should be avoided.
Purpose of GCP
There are two main purposes of GCP:-
1) To protect participants involved in trials.
2) To ensure the credibility of the data generated in the trial.
Potential participants should also be made aware of the expected benefits or if they are no intended clinical benefits, this should also be explained.
The main principles of Informed consent
The subject should be informed of the following:
• the purposes of the trial
• the methods of the trial
• the study drug(s) and treatment regimens
• available alternative treatment(s)
• the potential risks and benefits and possible discomforts.
• the subject should understand:
• that informed consent should be given freely
• that consent should not be obtained through inducement or coercion
• that he/she may withdraw from the study at any time
• that withdrawal from the study will not affect his/her future medical care.
PRINCIPLES OF ICH – GCP
ICH-GCP Principles
1. Clinical trials should be conducted in accordance with the ethical principles
2. Before a trial is initiated, foreseeable risks and inconveniences should be weighed
3. The rights, safety, and well-being of the trial subjects are the most important
4. The available nonclinical and clinical information on an investigational product should be adequate
5. Clinical trials should be scientifically sound
6. trial should be conducted in compliance with the protocol
7. The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician
8. Each individual involved in conducting a trial should be qualified by education, training, and experience
9. Freely given informed consent should be obtained from every subject
10. clinical trial information should be recorded, handled, and stored
11. The confidentiality of records that could identify subjects should be protected
12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP).
13. Systems with procedures that assure the quality of every aspect of the trial should be implemented.
Ethics
Clinical trials should be conducted in accordance with the ethical principles stated in the Declaration of Helsinki and that are consistent with GCP and the Medicines and Healthcare products Regulatory Agency (MHRA) standards.
Trials risk vs. trial benefit
Before a trial commences, the foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial participants and society. A trial should be initiated and continued only if the anticipated benefit/s justifies the risks.
Trial participants
The rights, safety and well-being of the trial participants are the most important consideration and should prevail over the interests of science and society.
Information on the medicinal product
The available non-clinical and clinical information on an investigational medicinal product should be adequate to support the proposed clinical trial.
Good quality trials
Clinical trials should be scientifically sound, and be described in a clear, detailed protocol.
Compliance with the study protocol
A trial should be conducted in compliance with the protocol that has received ethics committee and regulatory approval.
Medical decision
The medical care given to, and medical decisions made on behalf of trial participants should always be the responsibility of a qualified physician or when appropriate, of a qualified dentist.
Trial staff
Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective task(s).
Informed consent
Freely given informed consent should be obtained from every participant prior to recruitment to a clinical trial.
Clinical trial data
All clinical trial information should be recorded, handled and stored in a way that allows accurate reporting, interpretation and verification.
Confidentiality
The confidentiality of records that could identify trial participants should be protected, respecting the privacy and confidentiality rules in accordance with regulatory requirements.
Good Manufacturing Practice
Investigational products should be manufactured, handled and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.
Quality assurance
Trial sponsors should have systems and procedures in place that assure the quality of every aspect of the trial is maintained.