Drug Discovery, Testing & Approval Process PDF

CHAPTER 8: HOW DRUGS ARE DISCOVERED, TESTED AND APPROVED  DRUG DISCOVERY The active ingredients of drugs are extracted from: Plants Mammalian, hormones, microorganisms, Semisynthetic and synthetic compounds. Plant Poisons: Morphine (Opium Poppy), Digitalis (Foxglove)...

CHAPTER 8: HOW DRUGS ARE DISCOVERED, TESTED AND APPROVED  DRUG DISCOVERY The active ingredients of drugs are extracted from: Plants Mammalian, hormones, microorganisms, Semisynthetic and synthetic compounds. Plant Poisons: Morphine (Opium Poppy), Digitalis (Foxglove) Inorganic Chemicals: Potassium, Sodium, Chloride, and Calcium Biologics: Insulin, Estrogen Hormones, Epineprhine, And Diphtheria Antitoxin Drugs from the Seas: Algae, Invertebrates, and Sponges.  DRUG RESEARCH & DEVELOPMENT TEAM Take a team of scientists from several disciplines:  Pharmaceutical Chemistry  Pharmaceutics  Clinical Toxicology  Clinical Pharmacology  Biopharmaceutics And Clinical Pharmacokinetics FDA DRUG APPROVAL PROCESS  FDA DRUG APPROVAL PROCESS I. Pre-clinical phase (Drug development & animal testing) Initial synthesis of substance Lab Studies Institutional Review Board meeting II. Investigational New Drug (IND) Application & IND Review III. Phases of Clinical trials - Phase 1,2 and 3 IV. New Drug Application (NDA) submission, filing, review & response by FDA  FDA DRUG APPROVAL PROCESS  Before filing an IND, the sponsor must develop a pharmacologic profile of the drug, determine its acute and sub-acute toxicity in at least two species of animals. After the preclinical testing is completed, the sponsor will file an IND with the FDA. IND should contain following information:  Clinical Protocol (IRB approved)  Introductory statement & general investigational plan  Chemistry, Manufacturing & Control (CMC) information  Animal Pharmacology and Toxicology Studies data  IND REVIEW  At this stage, the FDA decides whether it is reasonably safe for the company to move forward with testing the drug in humans. Drug studies in humans can begin only after an IND is reviewed by the FDA.  The FDA has 30 days after receipt of an IND to respond to the sponsor. The sponsor may begin clinical trials if there is no response from the FDA within 30 days.  The FDA delays the initiation of a new study or discontinues an ongoing study by issuing a clinical hold (when FDA identifies a risk to the subjects).  FDA DRUG APPROVAL PROCESS  Phase 1 studies are usually conducted in healthy volunteers. This phase emphasizes on safety. Subjects are healthy volunteers. (Sample size: Around 20 - 80)  The emphasis in Phase 2 is on effectiveness. Safety continues to be evaluated, and short-term side effects are studied. Subjects are patients (Sample size: Few dozens to few hundreds).  Phase 3 studies gather more information about safety & effectiveness, studying different populations and different dosages and using the drug in combination with other drugs. Subjects are patients (Sample size: Several hundreds to several thousands).  Review meeting before NDA.  FDA DRUG APPROVAL PROCESS  A NDA includes all animal, human data & analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured.  When a NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. The FDA can refuse to file an application that is incomplete.  The review goal is six months for priority drugs.  FDA DRUG APPROVAL PROCESS Drug Labelling FDA reviews drug’s professional labelling, to ensure appropriate information has been communicated to the health care professionals & consumers. Facility Inspection FDA inspects the facility where the drug will be manufactured. After completion of all these steps the FDA will either approve the drug or issue a complete response letter. Once the FDA approves the drug for marketing, PMS (Phase-IV) begins. The sponsor is required to submit periodic safety updates to FDA. FDA’s Medwatch voluntary system makes it easier to report ADR’s for physicians & consumers.  POSTMARKETING SURVEILLANCE OF NEW DRUGS All drugs have some degree of risks associated with them described as Side Effects or Adverse Drug Reactions (ADRs). Side effects are minor, predictable, unwanted effects of the drug. ADRs are moderate to severe, sometimes life threatening, unwanted, unpredictable effects of the drug When adverse events emerge and are confirmed, the FDA and drug manufacturers have several options: Change the directions for the product use, (or) warn  POST-MARKETING SURVEILLANCE OF NEW DRUGS  Post-market requirement & commitment studies are required or agreed by a sponsor, and are conducted after the FDA has approved a product for marketing.  Post-marketing requirements (PMRs) are the studies that the sponsors are required (Ijbaari) to conduct under one or more statutes (law) or regulations.  Post-marketing commitment (PMCs) are the studies that a sponsor has agreed to conduct, (Ikhtiyaari) but that are not required by a statutes (law) or regulation.  HOW & WHEN THE DRUGS ARE APPROVED FOR USE The FDA only approves drugs ONLY when the submitted data proves the efficacy and safety of the formulation. When the FDA’s advisory committees and the FDA feel the benefits of the drug outweigh its risks, only then the drug is approved. TIME AND COST OF DRUG DEVELOPMENT  Developing a new pharmaceutical agent may take more than a decade, but usually takes 8 to 15 years. Some high- priority drugs, have been approved much faster e.g. HIV drugs. The biggest item driving up research and development costs is contract studies mainly in the clinical and the preclinical areas such as toxicology studies or analytical sample costs. TIMELINE OF DRUG DEVELOPMENT  DRUG MANUFACTURING Once a drug company has their new drug application (NDA) approved by the FDA, they can start marketing and producing the drug.  Newly approved drug (Patent Drug)  Generic Drug  Non-Prescription Drug NEWLY APPROVED DRUG (PATENT DRUG)  An extremely novel new drug produced by a drug company (innovator) that made the original research on the product.  The original innovator is allowed to patent and provide a trade name for its newly approved drug.  The patent gives the innovator about 20 years to market the drug without competition. At the end of patent period, other drug companies may develop a generic version of the innovator’s product.  DRUG MANUFACTURING GENERIC DRUG A drug that is an identical copy in active ingredients, formulation and strength that is marketed by a company other than the innovator company. NON-PRESCRIPTION DRUG The FDA has always applied the same standards to non-prescription drugs as it does to prescription ones when the proposed over-the- counter (OTC) drug meets criteria for a new drug  FUTURE OF DRUG DISCOVERY The human genome project is changing dramatically how drugs are discovered and developed.  The Human Genome Project is an international research project whose primary mission is to decipher the chemical sequence of the complete human genetic material (i.e., the entire genome), identify all 50,000 to 100,000 genes contained within the genome, and provide research tools to analyze all this genetic information (Collins & Fink, 1995)  Collins FS, Fink L. The Human Genome Project. Alcohol Health Res World. 1995; 19(3): 190-195.  FUTURE OF DRUG DISCOVERY  Using surrogate markers to predict long term results such as survival. A “surrogate marker” can be defined as “ …a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful endpoint that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy” (Temple, 1999) Temple R. 1999.Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 282: 790–795,  Studying Metabolomics to find unique patterns or profiles and a screening tool for disease  Metabolomics is the large-scale study of small molecules, commonly known as metabolites, within cells, bio-fluids, tissues or organisms. Collectively, these small molecules and their interactions within a biological system are known as the metabolome (Liu & Locasale, 2017) Liu, X., & Locasale, J. W. (2017). Metabolomics: a primer. Trends in biochemical sciences, 42(4), 274-284.  NEW METHODS OF DRUG DISCOVERY  RATIONAL DRUG DESIGN  USING POWERFUL COMPUTERS  COMPUTATIONAL CHEMISTRY  X-RAY CRYSTALLOGRAPHY  NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY  3-DIMENSIONAL STRUCTURE ACTIVITY RELATIONSHIP ANALYSIS These new methods should provide more efficacious, safer and more cost-effective drugs while lessening development time and cost.  NEW METHODS OF DRUG DISCOVERY RATIONAL DRUG DESIGN: Rational drug design can be broadly divided into two categories: A. Development of small molecules with desired properties for targets, biomolecules (proteins or nucleic acids), whose functional roles in cellular processes and 3D structural information are known. This approach in drug design is well established and is being applied extensively by the pharmaceutical industries (Mandal et al., 2009). B. Development of small molecules with predefined properties for targets, whose cellular functions and their structural information may be known  NEW METHODS OF DRUG DISCOVERY COMPUTATIONAL CHEMISTRY: Computational chemistry is a branch of chemistry that uses computer simulation to assist in solving complex chemical problems. It exploits methods of theoretical chemistry, incorporated into efficient computer programs, to calculate the structures, the interactions, and the properties of molecules (Lewars, 2011). Lewars, E. (2011). Computational chemistry. Introduction to the theory and applications of molecular and quantum mechanics, 318. X-RAY CRYSTALLOGRAPHY: X-ray crystallography is a tool used for determining the atomic and molecular structure of a crystal  NEW METHODS OF DRUG DISCOVERY NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY: Nuclear magnetic resonance (NMR) spectroscopy is an advanced characterization technique. It is used to determine the molecular structure at the atomic level of a sample. (Krishnan, 2019). Krishnan, V. V. (2019). Molecular thermodynamics using nuclear magnetic resonance (NMR) spectroscopy. Inventions, 4(1), 13.  NEW METHODS OF DRUG DISCOVERY 3-DIMENSIONAL STRUCTURE ACTIVITY RELATIONSHIP ANALYSIS Three-dimensional quantitative structure-activity relationships (3D-QSAR) permit correlations between a series of diverse molecular structures and their biological functions at a particular target (Ekins et al., 2002)  Structure-Activity Relationship (SAR) is an approach designed to find relationships between chemical structure (or structural-related properties) and biological activity (or target property) of studied compounds. Ekins, S., Kim, R. B., Leake, B. F., Dantzig, A. H., Schuetz, E. G., Lan, L. B.,... & Wrighton, S. A. (2002). Application of three- dimensional quantitative structure-activity relationships of P- glycoprotein inhibitors and substrates. Molecular