Regulatory framework for new drug development
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The regulatory framework for new drug development involves a lengthy multi-step process including drug discovery, pre-clinical research, and clinical trials on humans to test safety and efficacy. Key aspects of the framework include guidelines from the International Conference on Harmonisation (ICH) to harmonize technical requirements globally, oversight of clinical trials by institutional review boards, and Good Clinical Practice (GCP) standards to ensure trials are scientifically sound and respect participants. The overall goal is to develop new medications efficiently and ethically while protecting human subjects.
Regulatory framework for new drug development
- 1. Regulatory Framework for New Drug Development
- 2. Drug Development • Drug discovery: is the process by which new candidate medications are discovered. • Historically: identifying the active ingredient from traditional remedies or by serendipitous discovery. • Modern drug discovery includes: • Identification of screening hits, • and optimization of those hits to increase the affinity, selectivity (to reduce the potential of side effect • Efficacy/potency, metabolic stability (to increase the half-life), and oral bioavailability.
- 3. • It is a lengthy, "expensive, difficult, and inefficient process" with low rate of new therapeutic discovery • Drug development: • It includes: • Pre-clinical research (microorganisms/animals) • Clinical trials (on humans) and may include the step of obtaining regulatory approval to market the drug.
- 4. • Pre-clinical Phase: • New chemical entities (NCE): compounds which emerge from the process of drug discovery. These have promising activity against a particular biological target thought to be important in disease; however, little is known about the safety, toxicity, pharmacokinetics and metabolism of this NCE in humans at that time. • The information gathered from this pre-clinical testing, and is submitted to regulatory authorities as an Investigational new drug application or IND. If the IND is approved, development moves to the clinical phase.
- 5. • Clinical phase: three or four steps: • Microdosing: • Phase I trials: In healthy volunteers, for safety and dosing. • Phase II trials: Initial understanding of efficacy and further explore safety in small numbers of sick patients. • Phase III trials: large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients. • Phase IV: These are post-approval trials also called post-market surveillance studies.
- 7. ICH • The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a project that brings together the regulatory authorities to discuss scientific and technical aspects of pharmaceutical product registration. • The purpose of ICH is to: • Reduce or obviate the need to duplicate the testing carried out during the research and • Development of new medicines by achieve greater harmonisation in the interpretation and application of technical guidelines
- 8. Benefits of ICH : It leads to more economical use of • human, • animal and • material resources and • elimination of unnecessary delay in new medicines while maintaining safeguards on – • quality, • safety, and • efficacy
- 9. Institutional Review Board/Independent Ethics Committee (IRB/IEC) ICH defines an Institutional review board (IRB) as • a group to protect the rights, • safety and • well-being of humans involved in a clinical trial. • IRBs can also be called independent ethics committees (IECs). • An IRB/IEC reviews the clinical trial protocol as well as the risks and benefits to study participants. • It ensures that clinical trial participants are exposed to minimal risks.
- 10. • Reviews all study-related materials. • Must operate in accordance with national and local regulations, as well as with ICH-GCP guidelines • An IRB/IEC should have: • At least five members. • Members with varying backgrounds. • At least one member must represent a non- scientific area (a lay member). • an independent member who must not be affiliated with the institution or the trial site.
- 11. • IRB/IEC Responsibilities Before, During and After a Trial • Before a site is allowed to start enrolling patients in a clinical trial, the IRB/IEC must review all study- related materials in an initial review. • The IRB/IEC also performs periodic reviews throughout the trial’s duration. • The IRB/IEC may also ask for additional information regarding payments and compensation to study participants, and informed consent process.
- 12. Good Clinical Practice guidelines Good Clinical Practice (GCP) is an international ethical and scientific quality standard for the- • Design, • Conduct, • Performance, • Monitoring, • Auditing, • Recording, • Analyses and Reporting of clinical trials.
- 13. • GCP provides assurance that the - • Data and reported results are credible and are • Accurate and that the • Rights, Integrity and Confidentiality of trial subjects are respected and Protected. • GCP is a legal obligation for all trials.
- 14. Historical Background • The concept of the ‘good physician‘ dates back to the Hippocratic Oath (460 BC). • In the United States, the first landmark in the regulation of drugs was the Food and Drugs Act of 1906. • Manufacturers were required to test drugs for safety and present the evidence of safety testing to the FDA prior to marketing. • In 1947, the Nuremberg Code was created as a result of the unethical and horrific experiments carried out during World War II at Nazi war camps by German physicians, who were subsequently tried and charged at the Nuremberg Military Tribunal.
- 16. Historical background of GCP • 460BC Oath of Hippocrates • 1930 U.S. Food, Drugs and Cosmetic Act • 1947 Nuremberg Code • 1948 Declaration of Human Rights • 1962 Kefauver-Harris Amendment • 1964 Declaration of Helsinki • 1979 The Belmont Report • 1982 International Guidelines for Biomedical Research Involving Human Subjects • 1996 ICH-GCP guidelines issued • 1997 ICH-GCP guidelines becomes law in some countries
- 17. • In 1964, the Declaration of Helsinki was developed by the World Medical Association, forming the basis for the ethical principles that underlie the ICH-GCP guidelines we have today.It is widely regarded as the cornerstone document of human research ethics • In 1962 Kefauver-Harris Amendments was passed in response to the reports of severe foetal limb deformities linked to the use of maternal Thalidomide use, which required the FDA to evaluate all new drugs for safety and efficacy. • In 1979 Belmont report was issued by the National Commission for Protection of Human Subjects of Biomedical and Behavioural Research.The principles of this report are as follows:
- 18. Respect for Persons: • Dignity and freedom of every person. • It requires obtaining informed consent Beneficence: • Researchers maximise benefits and minimise harms associated with research. Justice: • Equitable selection and recruitment and fair treatment of research subjects.
- 19. • The Indian GCP Guidelines: • Central Drugs Standard Control Organisation (CDSCO), has formulated the Indian GCP guideline in 2002. • The Drug Technical Advisory Board (DTAB), has endorsed adoption of this GCP guideline to streamline clinical studies in India. • CDSCO’s Head quarter is located at New Delhi and the present the current DCGI is Dr. G.N. Singh.
- 20. The 13 Core principles of ICH-GCP are: • Clinical trials should be conducted in accordance with the Declaration of Helsinki. • foreseeable risks and inconveniences should be weighed against anticipated benefit. A trial should be initiated and continued only if the anticipated benefits justify the risks. • The rights, safety and well-being of the trial subjects should prevail over interest of science and society.
- 21. • The available non-clinical and clinical information on an investigational product should support the proposed clinical trial. • Clinical trials should be scientifically sound, and described in clear, detailed protocol. • A trial should be conducted in compliance with the protocol of institutional review board (IRB)/ independent ethics committee (IEC) • The medical care given to, subjects should always be the responsibility of a qualified physician.
- 22. • Each individual involved in conducting a trial should be qualified and experience. • Freely given informed consent should be obtained from the subject. • All trial information should be recorded, handled, and stored to allows its accurate reporting, interpretation and verification. • The confidentiality of records that could identify subjects should be protected.
- 23. • Investigational products should be manufactured, handled and stored in accordance with applicable Good Manufacturing Practice (GMP). • Systems with procedures that assure the quality of every aspect of the trial should be implemented.
- 24. Participants of GCP in clinical trials and their respective responsibilities • Regulatory Authorities - Review submitted clinical data and conduct inspections • The sponsor - Company or institution/organization which takes responsibility for initiation, management and financing of clinical trial • The project monitor - Usually appointed by sponsor • The investigator - Team leader. Responsible for conduct of clinical trial at the trial site.
- 25. • The pharmacist at trial location - Responsible for maintenance, storage and dispensing of investigational products. • Patients - Human subjects • Ethical review board or Committee for protection of subjects - Appointed by Institution or if not available then the Authoritative Health Body in that Country will be responsible. • Committee to monitor large trials - Overseas Sponsors eg. Drug Companies
- 26. • Summary of GCP Guidelines: • All clinical trials should be conducted in accordance with the • Ethical principles, • Sound scientific evidence and • Clear detailed protocols. • The benefits of conducting trials should outweigh the risks. • The rights, safety and wellbeing of trial participants are of paramount importance and these should be preserved by obtaining informed consent and maintaining confidentiality. • The care must be given by appropriately qualified personnel with adequate experience. • Records should be easily accessible and retrievable for accurate reporting, verification and interpretation • Investigational products should be manufactured according to Good Manufacturing Practice.
- 27. • The events that led up to the culmination of the ICH-GCP guidelines • brought forth public awareness that there was a need to control and regulate clinical trials dealing with drugs and human subjects. • The ICH-GCP guidelines are therefore considered the ‘bible’ of clinical trials, and have become a global law which safeguards humanity as we know it today.
- 28. GUIDELINES FOR GOOD CLINICAL LABORATORY PRACTICES (GCLP) • In biomedical research , achieving a set standard of quality produces credible results and allows comparison between studies carried out at different institutes nationally and internationally. • GLP embodies a set of principles that provides a framework within which laboratory studies are • planned • performed, • monitored, • reported and • archived.
- 29. • The Organization for Economic Cooperation and Development (OECD) evolved Good Laboratory Practice (GLP) guidelines. India is a signatory to OECD. • Government of India, provides GLP compliance certification to the test facilities involved in conducting safety studies on chemicals. • These guidelines should be adopted by all ICMR laboratories engaged in research as well as patient care.
- 30. Mission of GLP • Test systems • Archiving of records and materials • Apparatus, material and reagent facilities. • Quality assurance programs. • Performance of the study. • Reporting of study results. • Standard operating procedures (SOP)
- 31. • Scope: Good Clinical Laboratory Practices should be used by all laboratories where tests are done on: • Microbiology & Serology • Hematology & Blood Banking • Molecular Biology and Molecular Pathology • Clinical Pathology • Clinical Biochemistry • Immunology (Immunohematology and Immunobiochemistry) • Histopathology/Pathology and Cytology • Levels of laboratories: • Primary Level: PHC and urban health centres. • Hb and routine urine analysis
- 32. • Secondary Level: District hospitals, • Pathology, clinical pathology, biochemistry, serology, microbiological investigations. • Tertiary Level: Medical colleges hospitals and non- teaching large hospitals, receive referrals from primary as well as secondary levels • Reference Laboratories, Research Laboratories and Specific Disease Reference Laboratories: Provide services in a specialized field or area of importance.
- 33. • Guidelines of GCLP: • Infrastructure • Personal training and development • Equipment • Reagents and Materials • Specimen Collection • Reporting test results • Specimen rejection record • Data Management
- 34. • Standard operating procedure (SOP): • It is a document, which contains detailed, written instructions describing the stepwise process and technique of performing a test or procedure in the laboratory. • SOP helps to ensure • uniformity, • consistency and • control over the processes • It ensures that the procedures are done in exactly the same way each time irrespective of the operator.
- 35. • Safety in laboratories • Biosafety Precautions: • Four levels of biosafety laboratories (BSL) - 1, 2, 3 and 4, have been designed for handling biohazardous material. • Ethical Considerations • Quality Assurance • Quality Assurance Programme (QAP) • Internal Quality Control (IQC) • External Quality Assessment (EQA) • Internal Audit
- 36. Good Manufacturing Practices Purpose and Principles of GMP • The first WHO draft text on good manufacturing practices (GMP) was prepared in 1967 by a group of consultants at the request of the Twentieth World Health Assembly. • Provides a high level assurance that medicines are manufactured in a way that ensures their safety, efficacy and quality. • GMP applies to both Active Pharmaceutical Ingredients (APIs) and Finished Pharmaceutical Products (FPPs)
- 37. GMP Guidelines: • Quality assurance: ensuring that pharmaceutical products are of the quality required for their intended use. • Good manufacturing practices for pharmaceutical products (GMP): aimed primarily at diminishing the risks inherent in any pharmaceutical production like cross- contamination and mix-ups. • Sanitation and hygiene: A high level of sanitation and hygiene should be practised in every aspect of the manufacture of drug products.
- 38. • Qualification and validation: what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled. • Complaints: All complaints and other information concerning potentially defective products should be carefully reviewed. • Product recalls: There should be a system to recall from the market, products known or suspected to be defective. • Self-inspection and quality audits: to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control.
- 39. • Personnel: there must be sufficient qualified personnel to carry out all the tasks • Training: manufacturer should provide training for all personnel whose duties take them into manufacturing areas or into control laboratories • Personal hygiene: A high level of personal hygiene should be observed by all those concerned with manufacturing processes • Premises: Premises must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out.
- 40. • Equipment: Equipment must be located, designed, constructed, adapted, and maintained to suit the operations to be carried out. • Documentation: Good documentation is an essential part of the quality assurance system and, as such, should exist for all aspects of GMP. • Good practices in production • Good practices in quality control
- 41. Committee for the Purpose of Control and Supervision of Experiments on Animals -CPCSEA • A number of animals are used for conducting a variety of experiments. • There has been a long felt need to prescribe guidelines and procedures for animal experimentation covering all aspects. • The goal of these Guidelines is to: • promote the humane care of animals used in research. • provide specifications that will enhance animals well being and quality of research
- 42. The Guiding Principal of Three "R“ 1. Replace - replace animals with non animal methods. 2. Reduce - reduce the number animals used. 3. Refine - refine experimental techniques to make them less painful. 4. Rehabilitation - of laboratory animals.
- 43. • CPCSEA guidelines include: • Adequate veterinary care. • Quarantine, Stabilization and Separation. • Surveillance, Diagnosis, Treatment and Control of disease. • Location of animal facilities to laboratories . • Anaesthesia • Euthanasia • Animal ethics.