DRUG DISCOVERY – NEW DRUG DEVELOPMENT PROCESS

DRUG DISCOVERY – NEW DRUG DEVELOPMENT PROCESS BY Dr. BASAVARAJ K. NANJWADE Department of Pharmaceutics K L E UNIVERSITY JN MEDICAL COLLEGE BELGAUM – 590010 E-mail: bknanjwade@yahoo.co.in Dept. of Pharmaceutics

DRUG • A substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication recognized or defined by the U.S. Food, Drug, and Cosmetic Act. • A drug is any chemical or biological substance, synthetic or non-synthetic Dept. of Pharmaceutics

A drug is anything that affects the way an organism works. • Drugs can be taken to enhance function, such as a student drinking caffeine to enhance alertness. • For now we only consider drugs which are used to cure a disease. Dept. of Pharmaceutics Continued

A disease is often thought of as an infection, where a bacteria, virus, or other living thing invades the body. • However, a disease is anything which affects the proper functioning of the body. • It can be an infection, a genetic disorder, or the result of environmental conditions such as malnourishment, poisoning, or stress. Dept. of Pharmaceutics Continued

Engineers often find it easy to see the body as a factory. • Individual organs can be seen as machinery. The actual nuts, bolts, screwdrivers, and wrenches that make up all the machinery are the equivalent of proteins, little chunks of organic material that move things around in the body and attach them together. • Most of the work in our body is done by proteins. Dept. of Pharmaceutics Continued

The body contains thousands of different kinds of proteins. • The construction of each is determined by the DNA in the nucleus of each cell. • DNA may be thought of as long strings of instructions which code for how each protein is too be built. • The DNA is just a long string of acids that serves as a message about how to make proteins. Dept. of Pharmaceutics

How Drugs are Developed • The processes of new drug discovery and development are long, complicated and dependent upon the expertise of a wide variety of scientific, technical and managerial groups. • If you are new to the industry, it can prove a significant challenge to understand the significance of your contribution, even if you belong to one of the teams directly involved; for those on the periphery, the problem is magnified to the point where team interactions and efficiency are adversely threatened. Dept. of Pharmaceutics

Differences and Similarities of Drugs and Medicinal Plants • Today there are at least 120 distinct chemical substances derived from plants that are considered important drug and are currently in use in one or more countries in the world • Some of these drugs are simply a chemical or chemicals extracted from plant materials and put into a capsule, tablet or liquid. • Eg. In Germany a Cynarin drug is manufactured and sold to treat hypertension, liver disorders and highly cholesterol levels. Dept. of Pharmaceutics

Differences and Similarities of Drugs and Medicinal Plants • The drug is simply this single chemical or an Artichoke liquid extract, that has been concentrated and chemically manipulated to contain a specific amount of this one chemical ; such a preparation is called a standardized extract. • However in the U.S artichoke extracts are available as natural products and sold in health food stores as “dietary supplements” • Some –U.S artichoke products are even standardized to contain a specific amount of cynarin, yet they can still be purchased here as a natural product without a prescription. • There may be little to no difference between the Cynarin drug produce in Germany and the artichoke standardized herbal supplements made in the U.S considering that the same amount of Cynarin is being delivered, dose for dose Dept. of Pharmaceutics

Need for consumer education about Herbal supplements & Drugs • Consumers find it very frustrating to sort through a lot of ambiguous information put out by natural product manufacturers who cannot legally label their goods with condition-specific. • Stop them in their tracks in the aisles at the health food store saying “ Hey, look at me, if you have high cholesterol. Dept. of Pharmaceutics

More is Not Always Better • Be careful about dosage amounts • Philosophy of excess: “ if some is good, more is better” Dept. of Pharmaceutics

Problem of One Vs Several Chemicals • While many drugs have originated from biologically active plant chemicals, and many plants, medicine uses can be attributed to various active chemicals found in them, there is a distinct difference between using a medicinal plant and a chemical drug. • The difference is one that scares most conventionally trained doctors with no training in plants. • Drugs usually consist of a single chemical, whereas medicinal plants can contain 400 or more chemicals. • It’s relatively easy to figure out the activity and side effects of a single chemical. Dept. of Pharmaceutics

Plant Based Drugs and Medicines Dept. of Pharmaceutics

The New Drug Development Process (Steps from Test Tube to New Drug Application Review) Dept. of Pharmaceutics

Non-clinical Drug Development • Non-clinical drug development is a complex, regulatory-driven process designed primarily to assess the safety and viability of new molecular entities. • Non-clinical, or preclinical, services encompass toxicology, pharmacology, metabolism, bioanalysis, pharmaceutical analysis and biosafety testing in support of non-clinical drug development. Dept. of Pharmaceutics

Non-clinical Drug Development • A sponsor must first submit data showing that the drug is reasonably safe for use in initial, small-scale clinical studies. • Depending on whether the compound has been studied or marketed previously, the sponsor may have several options for fulfilling this requirement. 1. Compiling existing non-clinical data from past in vitro laboratory or animal studies on the compound 2. Compiling data from previous clinical testing or marketing of the drug in the U.S or another country whose population is relevant to the U.S population 3. Undertaking new preclinical studies designed to provide the evidence necessary to support the safety of administering the compound to humans. Dept. of Pharmaceutics

Non-clinical Drug Development • During preclinical drug development, a sponsor evaluates the drug’s toxic and pharmacologic effects through in vitro and in vivo laboratory animal testing. • Genotoxicity screening is performed, as well as investigations on drug absorption and metabolism, the toxicity of the drug’s metabolites and the speed with which the drug and its metabolites are excreted from the body. Dept. of Pharmaceutics

FDA will generally ask • Develop a pharmacological profile of the drug • Determine the acute toxicity of the drug in at least two species of animals • Conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on the proposed duration of use of the substance in the proposed clinical studies. Dept. of Pharmaceutics

Subpart E • CFR (Code of Federal Regulations) establishes procedure to expedite the development, evaluation and marketing of new therapies intended to treat people with life-threatening and severely-debilitating illnesses, especially where no satisfactory alternatives exist. Dept. of Pharmaceutics

Sponsor/FDA Meetings ( Pre-IND) • Prior to clinical studies, the sponsor needs evidence that the compound is biologically active, and both sponsor and the FDA need data showing that the drug is reasonably safe for initial administration to humans. • Meeting at such an early stage in the process are useful opportunities for open discussion about testing phases, data, requirements, and any scientific issues that may need to be resolved prior to IND submission • At these meeting, the sponsor and FDA discuss and agree upon the design of the animal studies needed to initiate human testing Dept. of Pharmaceutics

Synthesis and Purification • The research process is complicated, time-consuming, and costly and the end result is never guaranteed. • Literally hundreds and sometimes thousands of chemical compounds must be made and tested in an effort to find one that can achieve a desirable result. • FDA estimates that it takes approximately eight and half years to study and test a new drug before it can be approved for the general public. • Computers can be used to simulate a chemical compound and design chemical structures that might work against it. • Enzymes attach to the correct site on a cell’s membrane, which causes the disease. • A computer can show scientists what the receptor site looks like and how one might tailor a compound to block an enzyme from attaching there. Dept. of Pharmaceutics

Animal Testing • Drug companies make every effort to use as few animals as possible and to ensure their humane and proper care. • Generally two or more species ( one rodent, one non-rodent). • Animal testing is used to measure how much of a drug is absorbed into the blood, how it is broken down chemically in the body, the toxicity of the drug and its breakdown products metabolites, and how quickly the drug and its metabolites are excreted from the body Dept. of Pharmaceutics

Short and Long Term Animal Testing • Short-term testing in animals ranges in duration from 2 weeks to 3 months, depending on the proposed use of the substance. • Long-term testing in animals ranges in duration from a few weeks to several years. - Some animal testing continues after human tests begin to learn whether long-term use of a drug may cause cancer or birth defects. Dept. of Pharmaceutics

Institutional Review Board • Institutional review boards (IRB) are used to ensure the rights and welfare of people participating in clinical trials both before and during their trial participation. • An IRBs at hospitals and research institutions throughout the country make sure that participants are fully informed and have given their written consent before studies ever begin. • An IRBs are monitored by the FDA to protect and ensure the safety of participants in medical research. • An IRBs must be composed of no less than five experts and lay people with varying background to ensure a complete and adequate review of activities commonly conducted by research institutions. • An IRBs must be composed of people whose concerns are in relevant areas. Dept. of Pharmaceutics

IND Submitted • Introduction • Current requirements and practices • Clarifications of present IND regulation • Cover Sheet (FDA Form – 1571) • Table of contents • Introductory statement and general investigational plan • Investigator's brochure • Protocols Dept. of Pharmaceutics

IND Submitted F. Chemistry, Manufacturing, and Control information • Chemistry and manufacturing introduction • Drug substance • A description of the drug substance, including its physical, chemical, or biological characteristics • The name and address of its manufacturer • The general method of preparation of the drug substance • The acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug substance. • Information to support the stability of the drug substance during the toxicology studies and the proposed clinical study Dept. of Pharmaceutics

IND Submitted 3. Drug product • A list of all components, which may include reasonable alternatives for inactive compounds, used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear, but which are used in the manufacturing process. • Where applicable, the quantitative composition of the investigational new drug product, including any reasonable variations that may be expected during the investigational stage. • The name and address of the drug product manufacturer Dept. of Pharmaceutics

IND Submitted d. A brief, general description of the method of manufacturing and packaging procedures as appropriate for the product. e. The acceptable limits and analytical methods used to assure the identity, strength, quality, and purity of the drug product. f. Information to support the stability of the drug substance during the toxicologic studies and the proposed clinical study(ies) Dept. of Pharmaceutics

IND Submitted 4. A brief general description of the composition, manufacture, and control of any placebo to be used in the proposed clinical trial. 5. A copy of all labels and labeling to be provided to each investigator. 6. A claim for categorical exclusion from or submission of an environmental assessment. Dept. of Pharmaceutics

IND Submitted G. Pharmacology and Toxicology information • Pharmacology and drug distribution. 2. Toxicology: Integrated summary. 3. Toxicology- Full data tabulation. H. Previous human experience with the investigational drug Dept. of Pharmaceutics

Phase 1 Clinical Studies • Phase 1 includes the initial introduction of an investigational new drug into human. • Phase 1 studies usually conducted in healthy volunteer. • Phase 1 studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and if possible to gain early evidence on effectiveness. Dept. of Pharmaceutics

Phase 1 Clinical Studies • Phase 1 studies also evaluate drug metabolism, structure-activity relationships, and the mechanism of action in humans. • The total number of subjects included in Phase I studies varies with the drug, but is generally in the range of 20 to 80 Dept. of Pharmaceutics

Phase 2 Clinical Studies • Phase 2 includes the early controlled clinical studies conducted to obtain some preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. • This phase of testing also helps determine the common short-term side effects and risks associated with the drug. • Phase 2 studies are typically well-controlled, closely monitored, and conducted in a relatively small number of patients usually involving several hundred people. Dept. of Pharmaceutics

Sponsor/FDA Meeting (End of Phase 2) • One month prior to the “end of the Phase 2”, the sponsor should submit the background information and protocols for phase 3 studies. • This information should include data supporting the claim of the new drug product, chemistry data, animal data and proposed additional animal data, results of Phase 1 and 2 studies, statistical methods being used, specific protocols for phase 3 studies, as well as a copy of the proposed labeling for a drug, if available. • This summary provides the review team with information needed to prepare for a productive meeting. Dept. of Pharmaceutics

Phase 3 Clinical Studies • Phase 3 studies are expanded controlled and uncontrolled trials. • They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase 2 and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. Dept. of Pharmaceutics

Phase 3 Clinical Studies • Phase 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. • Phase 3 studies usually include several hundred to several thousand people. • Great care is taken to ensure that this determination is not made in isolation, but reflects current scientific knowledge, agency experience with the design of clinical trials, and experience with the class of drugs under investigation Dept. of Pharmaceutics

Accelerated Development/ Review • Accelerated development/review is a highly specialized mechanism for speeding the development of drugs that promise significant benefit over existing therapy for serious or life-threatening illnesses for which no therapy exists. • The fundamental element of this process is that manufacturers must continue testing after approval to demonstrate that the drug indeed provides therapeutic benefit to the patient. • If not, the FDA can withdraw the product from the market more easily than usual. Dept. of Pharmaceutics

Treatment IND • Treatment investigational new drug are used to make promising new drugs available to desperately ill patients as early in the drug development process as possible. • An immediately life-threatening disease means a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment. • Treatment INDs are made available to patients before general marketing begins, typically during Phase 3 studies. • Treatment INDs also allow FDA to obtain additional data on the drug’s safety and effectiveness. Dept. of Pharmaceutics

Long – Term Testing • Long-term testing in animals ranges in duration from a few weeks to several years. • Some animal testing continues after human tests begin to learn whether long-term use of a drug may cause cancer or birth defects. • Much of this information is submitted to FDA when a sponsor requests to process with human clinical trials. • The FDA reviews the preclinical research data and then makes a decision as to whether to allow the clinical trials to proceed Dept. of Pharmaceutics

DRUG DISCOVERY – NEW DRUG DEVELOPMENT PROCESS