Selvin celol ny Ss Chowdary, K.P.R. A LI NUL { 7465 = CHOW-7465 A 65 Pp.a annlinnenpriomentnbr tinea iqden) ycontesT AL Chapter 1 Drug Discovery, Development and Approval Process: An Overview Introduction In ancient time most of the drug used in the treatment of disease were derived from naturally Quinine from cinchona, occurring substances of plant origin, e.g. Opium from poppy, on ics agent are synthetic in digitalis from foxglove. Presently, the majority of new therapeut 1 a2 A Textbook of Clinical Research and Pharmacovigilance nature. Drug discovery and development is complex, time-consuming, costly process which carries commercial risk. Drug discovery and development is broadly divided into three main components: i) drug discovery, : ii) preclinical evaluation, iii) clinical trials. Drug Discovery Typically, researchers discover new drugs by the following methods: i) Through new insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease. ii) Through many tests of molecular compounds to find possible beneficial effects agains a disease : iii) Through existing treatments that have unanticipated effects. iv) Through new technologies that provide new ways to target products to specific diseases. At this stage in the process, thousands of compounds may be potential candidates for development in to an effective and safe drug. After initial pharmacological and toxicity testing only a small number of compounds look promising and call for further studies. Development: Once researchers identify a promising compound for development, they conduct experiments to gather information on: How it is absorbed, distributed, metabolized, and excreted. Its potential benefits and mechanisms of action. The best way to give the drug (such as by mouth or injection). Side effects or adverse events that can often be referred to as toxicity. How it affects different groups of people (such as by gender, race or ethnicity) differently. How it interacts with other drugs and treatments. Its effectiveness as compared with similar drugs. Methods for Drug Discovery Random screening Molecular manipulation Molecular designing Metabolites of drug Serendipity PewPenr Random screening: In this procedure new chemical entities are subjected to battery of screening test designed to determine diff. types of biological activity. Such test include studies on animal behaviour. Isolated tissues, intact animal and sometimes even af animal models of disease. Such studies are time consuming, expensive and have a !0¥ yield. It is possible that the new drug thus found may be ultimately turn out to be similat in extraction to already existing drugs, with no added advantages.Chapter 1 : Drug Discovery, Development and Approval Process: An Overview _3 2, Molecular manipulation: In this procedure analogues of existing drugs are synthesized and tested for their biological activity. This is more logical approach and may yield new compounds with certain advantages like better absorption, greater potency, more selective action, fewer side effects. 3. Molecular designing: This is the most rational form of drug R & D. It ends at designing of substances to fulfill of specific biological task. In its simplest form this may involve the synthesis of naturally occurring substance, a hormone, a vitamin o a precursor of a neurotransmitter. e.g. dopamine for cardiogenic shock, levodopa for parkinsonism. 4, Metabolites of Drug: Sometimes active metabolites of drug are found to posses therapeutic advantages Over parent compound. e.g. Paracetmol is metabolite of phenacetin and it is effective as an analgesic but does not cause renal damage. 5, Serendipity: it means “happy observation by chance” and has led to introduction of many remedies in the past. e.g. use of organomercurials for cardiac oedema, penicillin as an antibacterial agent, Drug Development Once a new chemical entity is discovered it has to be subjected to the development process. Chemical synthetic activity is mostly carried out in R&D divisions of p’ceutical lab by synthetic chemistry. After synthesis the structure of new compound and its purity is determine and confirmed by analytical chemist. Pharmacological evaluations can be divided into — i) preclinical pharmacology and ii) clinical pharmacology Steps Involved in Drug Development Preclinical synthesis and physiochemical analysis Preliminary biological evaluation Secondary and specific biological evaluation Rang finding toxicological studies Target organ toxicological studies Acute and subacute toxicological studies4 ATextbook of Clinical Research and Pharmacovigilance Metabolic studies § ‘Synthesis and quality control of bulk materials Phase 1 clinical evaluation Final formulation and final physiochemical analysis Phase 2 clinical evaluation Phase 3 clinical evaluation Phase 4 clinical evaluation 4 Clinicat Fig-1.1. Various Stages in Drug Discovery Development and Approval Process. Preclinical Evaluation (Animal Studies) Before testing a drug in people, researchers must find out whether it has the potential to cause serious harm, also called toxicity. The two types of preclinical research are: -In Vitro, In Vivo. FDA requires researchers to use good laboratory practices (GLP), defined in medical product development regulations, for preclinical laboratory studies. Usually, preclinical studies are not very large. However, these studies must. provide detailed information on dosing and toxicity levels. After preclinical testing, researchersChapter 1 : Drug Discovery, Development and Approval Process: An Overview _5 review their findings and decide whether the drug should be tested in people. The experimental animals used for preclinical testing include mice, rats, guinea pigs dogs, and sometimes monkeys. The three major areas of preclinical evaluation are: 1. Acute, sub acute and chronic toxicity studies 2. Therapeutic index. 3. Absorption, distribution and elimination studies Clinical Evaluation (Human Studies) Preclinical data obtained from animal studies. provide a general pharmacological, toxicological, and pharmacokinetic profile of a new drug. The New Drug application in the prescribed format, with all relevant literature and preclinical data must be submitted to Drug Control Authority for scrutiny, and sanction obtained before clinical evaluation studies are initiated. ‘ Clinical pharmacology deals with the effect of drugs on body and the effect of body on drugs in man, i.e. the pharmacokinetic and pharmacodynamics studies in man. It has three distinct part: qe 1. Confirmatory pharmacology. 2. Human biotransformation studies 3. Clinical trials. Sir Bradford Hill (1966) defined a clinical trial as “A carefull and ethnically designed human experiment with the aim of answering some Precisely framed questions”. This definition is valid even today. Clinical Trials Here are some salient guidelines to design a perfect clinical trial: 1. [Link] patient selection: Criteria for selection of patient should be well thought out and defined. Special care must be taken if more than one doctor is involved in the selection of patient in the trial specially in multicentric trials 2, Response measurement: The erid point should be clearly defined. Side ‘effect should be carefully observed and recorded. 3. Experimental design: For the design of an experimental design preferably a biostatistician should be consulted.6 ATextbook of Clinical Research and Pharmacovigilance (a) In general, controlled clinical trials must include four safe guards against bias: double blind technique (b) Randomization of treatment (0) Matching of patient (@)_ Cross over techniques. Phases of Clinical Trials > Phase I: Clinical pharmacologic Evaluation > Phase Il: Controlled clinical evaluation > Phase II: Extended clinical Evaluation > Phases IV: Surveillance during post marketing Phase I: Phase’I are usually catried out on 20-50 healthy volunteers or patients, depending on class Of drug and it’s safety. This studies are mainly concemed with human toxicity, tolerated dosage range, pharmacological actions, and pharmacokinetics of drug. Phase II: ‘These studies are carried out on 50-300 patients. These studies mainly aim to ascertain the safety and efficacy of the new drug, and are strictly controlled. Phase III: Extended clinical Evaluation ‘These are formal therapeutic trials carried out in double blind Controlled manner in 250-100 patients. Efficacy and safety of the new drug is evaluated and even comparison with other drugs is undertaken. Phase IV: Surveillance during Post marketing ‘After the drug release for general clinical use, certain unusual type of adverse reactions may be observed even after years of clinical usage. Thus, an adverse reaction monitoring is carried out in Phase IV evaluation. = For Further Reading 1 Pharmacology, Essential of pharmacotherapeutics, By [Link] [Link] publication, 1" edition, 1985, Page no: 56-61 2 2. [Link] i i . Dee Maan tt -[Link]/subjects/drug.. discovery 3. [Link] hitps:f/www [Link]/mobile/rahu |_pharma/d"¥6 discovery-and-development- 10698574&grqid=dRB10k76&hI=en-INChapter 1: Drug Discovery, D DRUG APPROVAL PROCESS Developing a new drug requires great amount of research work in chemistry, molecular biology, biochemistry, preformulation and formulation development, process development and manufacturing, quality control, prectinical and clinical studies, Drug regulatory agencies globally bear the responsibility of evaluating whether the research data support the safety, effectiveness and quality control of a new drug product to serve the public health, Every country has its own regulatory authority, which is responsible to enforce the rules and regulations and issue the guidelines to regulate the marketing of the drugs, Different countries have different regulatory requirements for approval of new drug. For IND, NDA of marketing authorization application (MAA) a single regulatory approach applicable to various countries is almost a difficult task, not available at present. Therefore it is necessary tohave knowledge about regulatory requirements for drug approval process of each country. The new drug approval process consists of two stages, the first stage is for IND and the second stage is for NDA and marketing authorization of drug, Firstly, non-clinical studies of drug are completed to ensure safety and efficacy. The next step is the submission of application for conduction of clinical trials to competent authority of respective country. In next step, clinical trials are carried out in four phases i.c. phase I to phase 4 study. These studies are carried out for the assurance of safety, efficacy and for optimization of dose of drug in human being. Then application for marketing of drug is verified by competent authorities. The competent authority review the application and approve the drug for marketing purpose, only if that drug is found to be safe and effective with desired therapeutic effect. The drug approval process in various countries is reviewed below. Drug Approval Process in United States evelopment dl Appre I Process: An Overview 7 The United States has the world’s most stringent standards for approving new drugs. Drug approval standards in the United States are considered to be the most demanding in the world") Investigational New Drug (IND) Application It’s an application filed to the FDA in order to start clinical trials in humans if ‘the drug was found to be safe from the reports of Preclinical trials. A firm or institution, called a Sponsor, is responsible for submitting the IND application." A pre - IND meeting can be arranged with the FDA to discuss a number of issues like the design of animal research, which is required to lend support to the clinical studies, the intended Protocol for conducting the clinical trial, the chemistry, manufacturing, and control of the investigational drug. Such a meeting will help the Sponsor to organize animal research, gather data, and design the Clinical protocol based on suggestions by the FDA. New Drug Application (NDA) If clinical studies confirm that a new drug is relatively safe and effective, and will not pose unreasonable risks to patients, the manufacturer files a New Drug Application (NDA), the actual request to manufacture and sell the drug in the United States" °”25 Q fibjigilance 8 A Textbook of Clinical Research and Pharmacovig! IDA) Si Drug Application (AN) . Abbreviated New Drug App! of Generic Drugs. The sponsor is not Tequired to done for the original, brand oF ee Instead, ; t is the ic di manufacturers must demonstrate that ae Foci iestine as, and Benen eteat to_a previously approved brand name product. Pantin Gout 7 IN Clinical ee Stadies (typically involve 20-80 people) Phase 2 si typically involve a ials Phase I s ies (typically involve several hundred to ap et st Oe Sa hate at 3,000 people). The pre DA and drug sponsors to meet Submission of an NDA is the formal step FDA ‘takes to consider a drug for marketing approval 8. After an NDA ig formal step ine has 60 days to decide whether to file it so it can be reviewed 9. If the Saat wie NDA aan FDA review team is assigned to evaluate the sponsor’ research on tie drug's safety and effectiveness. The FDA reviews information ia goes ona dr fessional labeling (information on ow to use the drug) The FDA inspects the facilis Wihere the drug will be manufactured as part of the approval process. FDA reviewers wil approve the application or find it either “approvable” or “not approvable jinical: ter simulations, experimental animal studies, or in vitro studies are ae PTS a promising drug, test for promising biologic effects and test for adverse effects. A drug company may test many related compounds to identify 1 or 2 to take further in development. The FDA is not involved in this aspect of drug development but will review the study results for any compounds that are planned for clinical (human) testing, New Drug Application (NDA): The IND is the formal process by which a sponsor requests approval for testing of a drug in humans and includes information developed during preclinical testing regarding safety and effectiveness. There are 3 phases in clinical testing of anew drug ‘ Phase I studies are usually conducted in healthy volunteers. The emphasis in Phase | is on safety. The goal is to determine what the drug's most frequent side effects are often, to determine how the drug is absorbed, distributed, and excreted. The number of subjects typically ranges from 20 to 80. It’s an application made for approval reproduce the clinical studies that were The emphasis in Phase II is on effectiveness. The goal of a Phase II study is to obtain Preliminary data on whether the drug works in people who have a specific disease ot condition. For controlled trials, patients receiving the drug are compared with similar Patients receiving a placebo or a different drug. Safety continues to be evaluated and short- term side effects are studied. Typically, the number of subjects in Phase II studies ranges from a few dozen to about 300 after Phase II. __ At the end of Phase II, the FDA and sponsors negotiate about how the large-scale studies in Phase III should be done. The FDA usually meets with a sponsor several times, including Prior to Phase III studies, and pre-NDA right before a new drug application is submitted. All biologic agents or other products made using high-technology procedures. Products ,for HIV/AIDS, cancer, diabetes, neurodegenerative diseases, auto-immune and other “immune dysfunctions and viral diseases. Products for orphan conditions.Chapter 1 : Drug Discovery, Development and Approval Process: An Overview 9 Drug Approval Process in Europe National authorization procedure: Each country within the EU has its own procedures for authorizing a marketing application for a new drug. A sponsor can consult the website of the regulatory agency in each country in which it is interested in obtaining marketing approval to obtain details of the approval process. A sponsor can also seek approval of several EU countries simultaneously using the decentralized or mutual recognition procedure. Decentralized procedure: For products that fall outside the scope of the European Medicines Agency (EMA) with regard to centralized procedures, a sponsor can submit under the decentralized procedure. Using this process, a sponsor can apply for simultaneous authorization in more than one EU country for products that have not yet been authorized in any EU country. Mutual recognition procedure. With the mutual recognition procedure, a product is first authorized by one country in the EU in accordance with the national Procedures of that country. Later, further marketing authorizations can be sought from other EU countries, who, rather than conducting their own review, agree to recognize the decision of the first country. Centralized procedure: European drug approvals are overseen by the European Medicines Agency. The EMA is a decentralized body of the EU, with headquarters in London, England. It is responsible for the scientific evaluation of applications for authorization to market medicinal products in Europe (via the centralized procedure). Marketing applications for drugs for use in humans are evaluated by the Committee for Medicinal Products for Human Use (CHMP). Products that are eligible for review under the centralized procedure must meet the following criteria. 1. Biologic drugs developed by recombinant technology, coding for biologically active proteins in prokaryo transformed mammalian cells, and hybridoma and medicinal products containing new active substances AIDS, cancer, neurodegenerative disorders, immune dysfunctions, and viral diseases controlled expression of genes tes and eukaryotes including monoclonal antibody methods for the following indications: diabetes, autoimmune diseases and other Orphan medicinal products other new active substances may, at the request of the applicant, be accepted for consideration under the centralized procedure when it ean be shown that the product constitutes a significant therapeutic, scientific or technical innovation, or the granting of a Community authorization is in the best interests of patients at the Community level. Pre-submission process: At least seven months prior to. submi authorization application (MAA), submit and the month of submissio: including a document outlining thi under the centralized procedure. Sponsor of its decision regarding i a marketing @ sponsor must notify the EMA of their intention to n. This pre-submission involves a variety of information fe reasons the sponsor believes the application should fall The EMA will consider the pre-submission and notify the acceptance of the MAA.