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Topic:1 Overview of the steps involved in the discovery and development of a new drug ( with schematic representation) The following events takes place between the birth of a new drug substances & its marketing--A newly discovered drug substance is tested in a pharmacological screen. In pharmacological screening the drug may be found sufficiently interesting to warrant further study. If so, the sufficient quantity of the drug substances is synthesized/ isolated to--a. perform initial toxicity studies b. do initial analytical works & c. do initial preformulation. Once past initial toxicity studies, phase I clinical testing (clinical pharmacology) begins & there is need of actual formulation.(although dose level may not yet be determined) Phase ii & iii clinical testing then begins & during this phase (preferably phase ii) an order of magnitude of formula is finalized. After completion of the above, an NDA is submitted. After approval of the NDA, production can start (product launch). New Chemical Entity sources: Preclinical Studies including: Chemistry Investigational New Drug Application (IND) Clinical Trials Preclinical Studies (continued) plus: -term animal toxicity New Drug Application (NDA) Postmarketing Toxicology FIGURE: The new drug development process from discovery through preclinical and clinical studies, FDA review of the new drug application, and post marketing activities. Topic: 2 Schematic representation of the time course for the discovery and development of a new drug New drug discovery Preclinical studies Clinical trials NDA review Post-marketing surveillance i)Initial physico-chemical Phase I characterization. Phase II Phase III ii)Animal testing ii)Molecular (pharmacology and modification toxicology) i)Formulation short term ii)Manufacture and iii)Isolation from long term control plants iii)Package & label design iii)Preformulation Average 6.5 years Average 7 years Average 1.5 years i)Organic synthesis IND submitted FDA 30- days safety review NDA submitted Figure: New drug development process (FDA approach Topic: 3 Sources of new drugs with examples 1)Natural Sources i) ii) iii) iv) v) vi) Plant Animal Micro organism Minerals Venoms and toxins Marine sources i)Phase iv clinical studies ii)Adverse reaction report iii)Product defect reporting iv)Product line extension. NDA approved 2)Synthetic Sources 3)Semi Synthetic Sources 4)Recombined DNA technology and monoclonal antibodies 5)Gene Therapy (1) Natuaral Sources i) ii) Plant materials: these include leaves, flowers, fruits, seeds, roots, bark, stem Example: a) The chemical reserpine isolated from Rauwolfia serpentina is a tranquilizer and a hypotensive agent b) Plant extracts (vinblastin and vincristine) from Vinca rosea exhibit antitumor capabilities Animals have served humans in their search for drugs in a number of ways. Example: a) Hormonal substances such as thyroid extract insulin and pituitary hormone obtained from the endocrine glands of cattle, sheep and swine b) The urine of pregnant mares is a rich source of estrogens c) Poliomyelitis vaccine is prepared in cultures of renal monkey tissue (iii) Microbial Sources: Bacterial, Fungi, Moulds important source of many live serving drug. Drug Microorganism Penicillin Penicilium notatum Griseofulvin Penicillin griseofullivum (iv) Mineral Sources: Iron in iron deficiency anemia mercurial salts in syphilis Gold salts in rheumatoid arthritis (v) Venom and Toxins Teprotide from Brazilian viper has antihypertensive effect (vi) Marine Sources: Bryostatins, dolastatins are antitumor agents. (2) Synthetic Sources: When the nucleus of the drug from natural source as well as its chemical structure is altered, we call it synthetic Example: a series of quinolone- 3- carboxamide intermediates were found to have antiviral activity. (3) Semi Synthetic Sources When the nucleus of drug obtained from natural source is retained but the chemical structure is altered we call it synthetic. For example: The various species of Dioscorea, popularly known as maxican yams, are rich in the chemical steroid from which cortisone and estrogens are semi synthetically produced. (4) Recombinant DNA technology and Monoclonal antibodies: Drug products as human insulin, human growth hormone, hepatitis B vaccine, epoetinalpha and interferon are being produced in Recombinant DNA technology Monoclonal antibodies are used in home pregnancy testing produces. (5) Gene Therapy: A medical intervention based on modification of the genetic material of living cells Application of gene therapy to treat _ sickle cell anemia _ malignant melanoma Topic:4 Various Methods Of Drug Discovery With Example Random or untargeted screening: Random or untargeted screening involves the testing of large numbers of synthetic organic compounds or substances of natural origin for biologic activity. To detect and evaluate biologic activity, bioassays are used to differentiate the effect and potency (strength of effect) of the test agent from those of controls of known action and effect. High-throughput screening: Newer methods, such as high-throughput screening, are capable of examining 15,000 chemical compounds a week using 10 to 20 biologic assays (23). To be effective, this requires a sizable and chemically diverse collection of compounds to examine, which many pharmaceutical and chemical companies have in chemical libraries. Molecular modification: Molecular modification is a chemical alteration of a known and previously characterized organic compound (frequently a lead compound; see next section) for the purpose of enhancing its usefulness as a drug. The molecular modifications may be slight or substantial, involving changes in functional groups, ring structures, or configuration. The molecular modifications that led to the discoveries of the first commercial beta-blocker, propranolol, and the first commercial histamine H2-receptor blocking agent, cimetidine. Mechanism-based drug design: Mechanism-based drug design is molecular modification to design a drug that interferes specifically with the known or suspected biochemical pathway or mechanism of a disease process. The intention is the interaction of the drug with specific cell receptors, enzyme systems, or the metabolic processes of pathogens or tumor cells, resulting in a blocking, disruption, or reversal of the disease process. An example of mechanism-based drug design is the compound enalaprilat, the active metabolite of enalapril (Vasotec), which inhibits the angiotensin-converting enzyme (ACE) that catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Inhibition of the enzyme results in decreased plasma angiotensin II, leading to decreased vasopressor effects and lower blood pressure. Topic: 9 International Conference On Harmonizition Of Technical Requirments For Registration Of Pharmaceuticals For Human Use The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a tripartite organization formed in 1991 by the FDA, the European Union and Japan and geographical representatives to discuss, identify, and address relevant regulatory issues. areas quality, safety, and efficacy. With ICH success, -duplicative technical requirements for registering pharmaceuticals would be eliminated; -new drug approvals would occur more rapidly; -the quality, safety, and efficacy of imported products would be improved; and -there would be an increase in information transfer between participating countries Examples of specific ICH- developed guidelines: products -derived Pharmaceuticals atrics tissue distribution studies response information to support drug regist Investigational New Drug Application (IND) Definition: An Investigational New Drug Application (IND) is a request for Food and Drug Administration (FDA) authorization to administer an investigational drug to humans. Such authorization must be secured prior to interstate shipment and administration of any new drug that is not the subject of an approved new drug application. An IND is required for a clinical study if it is intended to support a: New indication. Change in the approved route of administration or dosage level. Change in the approved patient population (e.g. pediatric) or a population at greater or increase of risk (Elderly, HIV positive, Immunocompromised). Significant change in the promotion of an approved drug. Purpose of IND: FDA approval is needed to bring a new drug to market, and IND is a preliminary step in that process. It is against federal law to transport an unapproved, unlabeled drug across state lines. Most clinical trials require participation from patients in various locations, and that presupposes sending the new drug to various states. An IND is exempt from this distribution restriction. An IND can also be used for early permission to use a drug for treatment. Once a drug enters the clinical research phase, it is deemed safe for people with reasonable certainty. Although it is not legal to sell a drug at this point, some patients may not be able to wait for final approval. Content of The IND: The content of an IND is prescribed in the Code of Federal Regulations and is submitted under a cover sheet (Form FDA-1571). These are: Name, address, and telephone number of the sponsor of the drug Name and title of the person responsible for monitoring the conduct and progress of the investigation Names and titles of the persons responsible for the review and evaluation of the information relevant to the safety of the drug Name and address of any contract research organization involved in the study Introductory statement and general investigational plan: the name of the drug and all formulation of the dosage form and route of administration, and the broad objectives and planned duration of the study Description of the investigational plan: the rationale for the drug or research study, the indication or indications to be studied, the approach to evaluating the drug, the types of studies to be conducted, the estimated number of subjects to be given the drug, and any serious risks anticipated based on animal studies or other human experiences with the drug Brief summary of previous human experience with the drug (domestic or foreign), including the reasons if the drug has been withdrawn from any other investigation and/or marketing CMC information: a complete description of the drug substance, including its physical, chemical, and biologic characteristics; its method of preparation and analytical methods to ensure its identity, strength, quality, purity, and stability; a quantitative list of the active and inactive components of the dosage form to be administered; the methods, facilities, and controls employed in the manufacture, processing, packaging, and labeling of the new drug to ensure appropriate qualitative and quantitative standards; and product stability during the clinical investigation acute, sub-acute, chronic, and reproductive and developmental toxicity studies If the new drug is a combination of previously investigated components, a complete preclinical and clinical summary of these components when administered singly and any data or expectations relating to the effect when combined Clinical protocol for each planned study Commitment that an Institutional Review Board (IRB) has approved the clinical study and will continue to review and monitor the investigation Investigator brochure Commitment not to begin clinical investigations until the IND is in effect, the signature of the sponsor or authorized representative, and the date of the signed application IND Submission Process: Step 1: Pre-IND teleconference with FDA Highly recommended for new products Step 2: Submission of complete IND package All forms, all sections Step 3: IND Review FDA will notify Sponsor within 30 calendar days of receipt of the IND whether the study may proceed or is placed on clinical hold Studies may not begin until 30 day review is complete or FDA notifies Sponsor studies may proceed IND Review Process: Figure: IND Review Process The Clinical Protocol: As a part of the IND application, a clinical protocol must be submitted to ensure the appropriate design and conduct of the investigation. Clinical protocols include: Statement of the purpose and objectives of the study Outline of the investigational plan and study design, including the kind of control group and methods to minimize bias on the part of the subjects, investigators, and analysts Estimate of the number of patients to be involved Basis for subject selection, with inclusion and exclusion criteria Description of the dosing plan, including dose levels, route of administration, and duration of patient exposure Description of the patient observations, measurements, and tests to be used Clinical procedures, laboratory tests, and monitoring to be used in minimizing patient risk Names, addresses, and credentials of the principal investigators and coinvestigators Locations and descriptions of the clinical research facilities to be use Approval of the authorized IRB Treatment IND: A treatment IND or a treatment protocol permits the use of an investigational drug in the treatment of patients not enrolled in the clinical study but who have a serious or immediately life- threatening disease for which there is no satisfactory alternative therapy. The objective is to make promising new drugs available to desperately ill patients as early as possible in the drug disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is lik . This includes such conditions as advanced cases of AIDS, herpes simplex encephalitis, advanced metastatic refractory cancers, bacterial endocarditis, Alzheimer disease, advanced multiple sclerosis, advanced Parkinson disease, and others. For products to be considered for a treatment IND, the drug must be under active investigation in cacy demonstrated to data, a drug may be approved for treatment use during Phase 2 or Phase 3 of the clinical trials. In sponsor must submit a treatment protocol in addition to the information normally included in an IND application. In making its decision, the FDA renders a risk the treatment IND, the law provides for the emergency use of an investigational drug in rare IND For an Orphan Drug: or condition that affects fewer than 200,000 people in the United States and for which there is no reasonable expectation that costs of research and development for the indication can be recovered by sales of the product in the United States. Examples of such illnesses are- chronic lymphocytic leukemia, elopment was established to identify and facilitate the development of orphan products, including drugs, biologics, and medical devices. To foster the necessary research and development, the FDA provides support grants to conduct clinical trials on safety grants are awarded for Phase 2 and Phase 3 clinical studies based on preliminary clinical research. Regular and treatment IND protocols may be included in orphan drug clinical trials. An incentive to orphan product development is a provision for a 7-year period of exclusive marketing rights after regulatory approval of a product. Clinical Investigation / Trial Definition: A clinical trial is a carefully designed study which tests the benefits and risks of a specific medical treatment or intervention, such as a new drug or a behavior change (e.g., diet). Once researchers have completed a rigorous screening and preclinical testing process, the company files an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA). This application allows the investigational medicine to be tested in human volunteers in clinical trials. Purpose of Clinical Trial: Assess safety and efficacy of: Experimental treatments New combinations of drugs New approaches to surgery or radiation therapies Better disease prevention approaches Better diagnostic approaches Phases of Clinical Trial: ic questions. The different phases of clinical trials are given below below: Phase I: These trials are used to test brand new drugs, devices or procedures to find out how safe they are, including safest dose, and identify possible side effects. They usually involve 20 to 80 people. Phase II: These trials are used to further evaluate the effectiveness of a drug, device or procedure. The researchers keep track of any medical benefits, as well as side effects. They usually involve 100 to 300 people. At the end of Phase II trials, the U.S. Food and Drug Administration (FDA) and trial sponsors determine how Phase III trials will be conducted. Phase III: These trials compare a new treatment or procedure to current treatments to figure out which works better. Safety and level of effectiveness continued to be monitored, as well as side effects. They usually involve 1,000 to 8,000 people. Phase IV: Once a drug or procedure is approved by the FDA and made available to the public, researchers continue to study its safety to figure out the best use of the new treatment. Information is -term effectiveness in various populations, as well as adverse side effects associated with long-term use. Purposes of Different Phases: Controlled Clinical Study: Controlled clinical study is a research strategy that calls for two samples: an experimental sample of patients receiving a pharmaceutical, and a second sample of control patients receiving a placebo (placebo control) or an active drug (positive control), a standard or comparator drug product. Both a placebo and an active drug may be used as controls in the same study. Neither the patient nor the researcher knows which is receiving the pharmaceutical and which the placebo. Blinded Study: A study done in such a way that the patients or subjects do not know (is blinded as to) what treatment they are receiving to ensure that the results are not affected by a placebo effect (the power of suggestion). Two types: Single-blinded Study Double-blinded Study Single-blinded Study: A type of clinical trial in which only the researcher doing the study knows whether a patient is receiving the standard treatment or the new treatment being tested. This helps to prevent bias in treatment studies. Double-blinded study: A medical study in which both the subjects participating and the researchers are uaware of when the experimental medication or procedure has been given. Open-labelled Study: A type of study in which both the health providers and the patients are aware of the drug or treatment being given. Parallel Study Design: A parallel design, also called a parallel group study, compares two or more treatments. Participants are randomly assigned to either group, treatments are administered, and then the key element of a parallel design. Figure: Some Clinical Trial Parallel Study Design Crossover Study Design: A crossover design is a repeated measurements design such that each experimental unit (patient) receives different treatments during the different time periods, i.e., the patients cross over from one treatment to another during the course of the trial. Figure: Some Clinical Trial Crossover Study Design Crossover designs are useful in comparing different treatments within individuals since following one treatment, a patient is crossed over to a different treatment. Between treatment periods, subjects may be given no drugs as a washout period to allow return to baseline. New Drug Application (NDA) Definition: The NDA application is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. If the three phases of clinical testing during the IND(Investigational New Drug Application) period demonstrate sufficient drug safety and therapeutic effectiveness, the sponsor may file an NDA with the FDA. This filing may be preceded by a pre-NDA meeting between the sponsor and the FDA to discuss the content and format of the NDA. Purpose: package insert) is appropriate. adequate to preserve the drugs identity, strength, quality, and purity. After all ,to gain permission to market the drug product in the United States. General Content of the NDA: nonproprietary, code, and proprietary names of the drug, the dosage form, its strength, and route of administration . as an OTC product . intended labeling, CMCs, nonclinical and clinical pharmacology and toxicology, human pharmacokinetics and bioavailability, statistical analysis, clinical trial data, benefit and risk considerations, and proposed additional or planned post marketing studies. chemical characteristics, methods of identification, assay, and controls, and the drug product, including its composition, specifications, methods of manufacture and equipment used, inprocess controls, batch and master production records, container and closure systems, stability, and expiration dating. for nonclinical pharmacology and toxicology in relation to the proposed therapeutic indication, including acute, subacute, and chronic toxicology, carcinogenicity, reproductive toxicology, and animal studies of absorption, distribution, metabolism, and excretion. microbiology for antibiotic applications. to the proposed indication, a copy of the study protocol, effectiveness and safety data including any updates on safety information, comparison of human and animal pharmacology and toxicology data, and support for the dosage and dose intervals and modifications for specific subgroups such as pediatric, geriatric, and renally mpaired subjects. oposed for marketing, reference standards, and finished market package, as requested. Submission: The applicant submits three copies of the NDA: An archival copy, maintained by the FDA as the reference document; A review copy, used by the FDA review division; and A field copy, used by the FDA district office and field inspectors in an on-site preapproval inspection . FDA Review and Action Letters : The completed NDA is carefully reviewed by the FDA. By regulation, the FDA must respond within 180 days of receipt of an application. This 180-day period is called the review clock and is often extended by agreement between the applicant and the FDA, as additional information, studies, or clarifications are sought. The NDA is reviewed by the same FDA division that recommendation of an outside advisory review committee composed of persons of recognized the entire review of the application is completed. The FDA can respond to a sponsor of an NDA with one of the following types of letters: 1. Approval, meaning the drug has met agency standards for safety and efficacy and the drug can be marketed for sale in the United States. 2. Complete response, letting a company know that the review period for a drug is complete and that the application is not yet ready for approval. The letter will describe specific deficiencies and, when possible, will outline the recommended actions the applicant might take to get the application ready for approval. After an NDA is approved and the product marketed, the FDA requires periodic safety and other reports, schedules plant inspections, and requires continued compliance with control and quality standards and current good manufacturing practices. Supplemental New Drug Application (SNDA): A sponsor of an approved NDA may make changes in that application through the filing of an SNDA. Examples of changes that may be made without prior approval are minor editorial or other changes in the labeling that add to or strengthen an approved label section, any analytical changes made to comply with the USP on full shelf-life data obtained from a protocol in the approved application, and a change in the size (not the type of system) of the container for a solid dosage form. Abbreviated New Drug Application (ANDA): An ANDA is an application for a U.S. generic drug approval for an existing licensed medication or approved drug. An ANDA is one in which nonclinical laboratory studies and clinical investigations may be for duplicates (generic copies) of drug products previously approved under a full NDA and for which the FDA has determined that information on the exempted nonclinical and clinical studies is already available at the agency. Biologics License Application (BLA): products, vaccines, and toxins. The applications for biologics approvals follow the regulatory requirements as stated specifically for these products in the relevant parts of the CFR (4). Animal Drug Applications: The Federal Food, Drug, and Cosmetic Act, as amended, contains specific regulations pertaining to the approval for the marketing and labeling of drugs intended for animal use .It allows veterinarians to prescribe extra label uses of approved animal drugs and approved human drugs for animals.