Drug discovery and development overview

1,307 views

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,307
On SlideShare
0
From Embeds
0
Number of Embeds
2
Actions
Shares
0
Downloads
29
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • New products grow out of problems and opportunities: Diseases without a cure (Cancer, AIDS) Difficulty in making a diagnosis - Pancreatic cancer New technologies - virtual reality that assists the blind to “see”
  • The Professorial Staff of the Caroline Institute has, therefore, decided to award the Nobel Prize this year to Elie Metchnikoff and to Paul Ehrlich for their work on the theory of immunity.
  • Ehrlich, Paul 1854-1915, German bacteriologist. For his work in immunology he shared with Élie METCHNIKOFF the 1908 Nobel Prize in physiology or medicine. He discovered salvarsan for the treatment of syphilis and made valuable contributions in hematology, cellular pathology, cancer study, and the use of dyes in microscopy and treatment of disease. Paul Ehrlich (1854-1915), German physician, considered the father of modern chemotherapy and immunology. Ehrlich was a staunch advocate of selective action in the treatment of infectious diseases. In the field of immunology he developed the "theory of side chains for the formation of antibodies", forming the basis of the theory of clonal selection . In 1908 Paul Ehrlich received the Nobel Prize for Medicine. Brains - One of the highest concentrations of brains in any segment of our modern society, exceeding that of many universities, is the brain power dedicated to basic science, administration, manufacture, and marketing of modern pharmaceutical agents. Capital - The process from discovery to approval by regulatory agencies and successful market introduction requires enormous sums of money. For a new chemical entity, the estimated cost ranges from $300 M to $ 1 billion with 10 to 15 years of concentrated effort consumed in the process. Luck - Louis Pasteur - chance favors the prepared mind. Prepared minds actively seeking a solution to one problem often serendipitously find the solution to another (Fleming and the discovery of penicillin.) Luck is becoming less of a factor as we focus on optimizing the development process. Persistence - 10 to 15 years to bring a new drug to the patient; being challenged in the current, highly competitive climate
  • Development Decision points: The pharmaceutical development process requires enormous sums of money as well as an extended period of concentrated effort. It is often necessary during this development period to make decisions regarding whether or not a program should be continued. To aid in this process, clear decision points are generally defined and made a part of the overall development plan. The purpose of these decision points is to identify key points at which management will assess the project’s likelihood for success vs the company’s exposure to risk, costs, and strategic need. The decisions are spread over the development period and generally correspond to points in the program where a company will commit to a new phase of development.
  • Discovery is the research phase of R&D. Research: The process of scientific investigation or inquiry; in this usage, it involves the work carried out to discover and bring new biomedical products to the market. It is often used in combination with many terms to distinguish among various types of research such as basic research, discovery research, applied research, preclinical research, etc. The drug discovery/development process is often considered to have two major components: research and development. In this context, research refers to the discovery aspects which deal with the synthesis of/search for compounds and the screening processes used to identify “lead” compounds.
  • Academic research Research institutes In-house research labs For example: University of California System National Institutes of Health Robert Wood Johnson Pharmaceutical Research Institute
  • Opportunities—and challenges—for pharmaceutical research are great. These include such uncured diseases as heart disease, cancer, Alzheimer's, diabetes, arthritis, depression, stroke, and osteoporosis—which afflict more than 100 million Americans and cost our society over $550 billion annually. In addition, age-old scourges such as bubonic plague and influenza threaten to return in more virulent forms resistant to antibiotics, while new and deadly viruses such as Ebola fever and Hantavirus continue to emerge. Success in meeting these challenges will depend in large measure on the continued vitality of the pharmaceutical industry.
  • The strategic plan is the company document that is ordinarily used to state the medical areas in which the company will be work, and the areas which will have priority for company funding. The plan should reach out 5 to 10 years. It states essentailly how far the research will have advanced in that period, states what the company thinks will be the “breakthrough” areas at that time and assesses what resources will be required to be a player. What Diseases? What approaches? In pharmaceutical research, strategy, or the strategic plan, might also refer to the decisions made (and generally documented) to help guide research efforts, Such a plan or document would describe the therapeutic areas for which efficacy will be developed, and which of these screens will have priority. The Strategic Plan is the document that is ordinarily used to state the therapeutic areas of interest. It can entail a scenario reaching out for 5 or 10 years. Resources include people, facilities and capital. Resource allocation is the decision making process whereby it is determined which activities and/or projects will receive the resources they require and in what quantity. Because the quantity of resources available is generally limited in some way, they must be proportioned (allocated) among the activities for which they are required. The demand for resources can come from multiple projects as well as normal operating requirements of the functional department which controls the resources pool.
  • The next step after Strategic Plan review and approval is usually to formulate a short term plan based on the Strategic Plan. This Prpgram Review concerns the screens that will run for that period, including previously initiated ones as well as new ones to be established, where they will be established, and the amount of support/resources for the new screens. The Strategic Plan is the document that is ordinarily used to state the therapeutic areas of interest. It can entail a scenario reaching out for 5 or 10 years. The basic components of the Strategic Plan originate from Senior Management of Basic Research. They are hired or promoted on the basis of their expertise in generating new ideas from their experience in new areas and from their knowledge of the relevant scientific literature.
  • Technology assessment groups may also be formed to provide input as to future screening opportunities/needs. Such groups would include representatives from marketing, basic research, and clinical research within a particular area.
  • What will the product be? Diagnostic: invasive or noninvasive? Therapeutic: route of administration Topical Oral Suppository Injectable IV IM SC Intralesional ID (intradermal) Intrathecal Cosmetic/Food Device
  • Who will use the product? Demographics will influence regulatory, development strategy · Age groups - geriatrics, pediatrics present different challenges · Ethnic groups - domestic or international market · Incidence of disease - orphan drug status? Who will pay for the product? · Health Care Financing Administration (HCFA); administers Medicare · Insurance carriers · Individuals Medical need Is the need significant? Is there another available product If yes, is that product effective Are there strong or dangerous side effects with the available product? Does treatment present the patient with a clinical benefit? Do the benefits out weigh the risks associated with the new drug?
  • Feasibility Study Objectives: to determine the biochemical or engineering feasibility of a product concept Process: explore research/design options that meet a given clinical need or purpose Discovery Research Computational Chemistry Medicinal Chemistry Separations Analytical Chemistry Biochemistry Biotechnology Pharmacology Microbiology Fermentation Design Engineering Develop prototype design for new device; establish component specifications Preliminary quality characteristics and functional parameters for prototype Document software source code Other Discovery Activities Legal, Industrial hygiene and Marketing
  • Biochemistry/Biotechnology - Set up appropriate in vitro screening tests (receptors, enzymes, subcellular organelles, signal transduction systems, cloned human receptors and enzymes, etc.) establish early criteria for mechanism of action” for drug candidates; initiate recombinant DNA and monoclonal antibody approaches to new molecules where appropriate
  • Decision Point One -- The Screen There are usually two sources of materials for screens. One is synthetic compounds, which are rationally based on the structure of the target. Molecular modeling with computers is used to propose novel structures that may be tested in the screen. Another source of samples is natural products, for example, soil samples from all over the world. There are other sources as well: from the oceans, from plants, from algae, etc. Several companies are screening herbs used in traditional Chinese medicine. All samples are fed into the screen and, with luck, an ACTIVE is produced. The ACTIVE can be defined as a substance that inhibits/stimulates at the concentration run in the screen. If the ACTIVE is a synthetic product, the next step will be to scale-up the production so that the activity can be confirmed. If the ACTIVE is a natural product, the challenge is to isolate or produce enough (by fermentation) to confirm activity.
  • A drug is generally envisaged as a chemical substance that can modify the response of a tissue to its environment. In a diseased or traumatized tissue where this response is modified in a manner detrimental to the long term survival of the organism, a drug is used to restore normal function. The conceptualization of a drug as a “key” fitting into a “lock” on a cell membrane arose from the seminal work of Langley and Ehrlich at the end of the 19th century. Major advances in technology in both the chemical and biological arenas have yet to negate the “lock and key” hypothesis, now a century old, as the seminal focus for compound design and drug targeting. For receptors, the recognition sites for hormones, neurotransmitters and neuromodulators, drugs may function as agonists or antagonists.
  • Alteration of receptor density and/or function is frequently associated with disease processes, and drugs acting as receptor agonists or antagonists are frequently employed to treat disease. For example, antihistamines are used to treat allergic reactions (agonist or antagonist?) and various beta-adrenergic receptor antagonists are used to treat hypertension. Hormones, such as estrogen, or insulin are examples of agonists.
  • There are usually two sources of materials for screens. One is synthetic compounds, which are rationally based on the structure of the target. Molecular modeling with computers is used to propose novel structures that may be tested in the screen..
  • Another source of samples is natural products, for example, soil samples from all over the world. There are other sources as well: from the oceans, from plants, from algae, etc. Several companies are screening herbs used in traditional Chinese medicine.
  • Decision Point One -- The Screen Screening is the process by which substances are evaluated in a battery of tests or assays (screens) designed to detect a specific biological property or activity. It can be conducted on a random basis in which substances are tested without any pre-selection criteria or on a targeted basis in which information on a substance with known activity and structure is used as a basis for selecting other similar substances on which to run the battery of tests. To be effective, screens must be capable of handling large numbers of candidates since the probability of finding an active substance by this random process is low.
  • At about this phase of the cycle the preliminary toxic potential of the LEAD is considered. The earliest test given for this purpose is the Ames test to determine the mutagenic potential of the LEAD. For most pharmaceutical companies, a positive Ames Test or other genetic predictor is usually of sufficient concern to preclude further development. There is sufficient correlation between mutagenicity and carcinogenicity to warrant this policy. Ordinarily, the time and resources required to run carcinogenicity studies do not justify working with a suspect mutagen. However, a true breakthrough product, one of high potential, may go through significant more genotoxicity, even if Ames positive, as well as an analogue program to find a less suspect lead. The Ames assay is also known as Salmonella typhimurium reverse mutation assay. This is a rapid, relatively simple and sensitive screen for detecting mutagenic potential. Simply stated, the bacteria Salmonella typhimurium is exposed to the test agent and grown on agar plates. The plates are incubated and examined for mutagenic activity by comparing bacterial colony growth of plates exposed to the test agent to control plates. A mutagenic response is indicated by a doubling or predefined statistically significant difference in colony counts between treated and control plates. Discovery teams are turning more and more to drug metabolism input to assist in the design of new molecules. Metabolism support at this stage must be based on utilization of computerized data banks to predict metabolism properties together with aggressive use of in vitro metabolism systems using animal and human source material to predict in vivo patterns.
  • This flow chart summarizes the use of the screen in Discovery. All samples are fed into the screen and, with luck, an ACTIVE is produced. The ACTIVE can be defined as a substance that inhibits/stimulates at the concentration run in the screen. If the ACTIVE is a synthetic product, the next step will be to scale-up the production so that the activity can be confirmed. If the ACTIVE is a natural product, the challenge is to isolate or produce enough (by fermentation) to confirm activity.
  • Records should be maintained in a laboratory notebook; notebooks should be numbered, issued and used by only one person. Notebooks are the intellectual property of the company and are legal documents. The experimental write-up should be signed and dated by the researcher, then verified by a second person. No formal quality requirements at the discovery phase BUT If you didn’t document it, you didn’t do it.
  • 1. Introduction giving background of the field and the candidate drug 2. Summary of entire submission highlighting the key elements from each section. 3. In vitro assays with emphasis on biochemical, pharmacological and physiological assays. Activity of drug on human biochemical targets s/b included; safety assessment studies 4. Whole animal assays emphasize experimental design characteristics as they relate to design of projected clinical studies. Blood levels for activity; bioavailability 5. Chemistry - syntheses; physical/chemical characterization; known analytical methodology; important related analogs as well as potential backups to candidate; Process cost and feasibility; Pharma stability, physical/chemical characteristics, salt or free acid, potential issues 8. Clinical Plan - parallel and non-parallel experimental designs with respect to pre-clinical studies; Regulatory commentary on preclinical data and any potential issues 9. Patent - written opinion; competition in field 10. Candidate potential and rationale for recommending development including advantages over current gold standard
  • The next step is a formal management review of the LEAD and a business decision whether to enter the Development phase with a Safety Assessment Candidate - a prototype product that will under go preclinical safety testing. This represents a major commitment by the company and should be carefully considered. Both a written report and a formal presentation are in order. 1. Introduction - giving background of the field and the candidate drug 2. Summary - a brief summary of the entire submission highlighting the key elements from each section 3. In Vitro Assays - emphasis on biochemical, pharmacological and physiologic assays. Legends for the tables and figures should allow an independent reviewer to reproduce the results. Activity of drug on human biochemical targets should be included. An emphasis should be placed on biochemistry and biology being done in same animal species 4. Whole Animal Assays - can be in vivo or ex vivo . Emphasizes experimental design characteristics as they relate to design of projected clinical studies. Blood levels of drug for activity. Bioavailability of the drug in animals used for tests. Relation of species for in vitro vs in vivo assays. 5. Chemistry - description of syntheses in such format that an independent chemist could reproduce them, including physical/chemical characterization and known analytical methodology for both preparative and pharmaceutical purposes. Also, a description of important related analogs as well as potential backups to the candidate may be included. 6. Process Chemistry - Written commentary on cost and feasibility of process. 7. Pharma R&D - stability, physical/chemical characteristics, salt or free acid, potential, etc. 8. Patent - written legal opinion; if patent application is feasibile, should plan for submission. Timing an important part of development planning. 9. Clinical Plan - parallel and non-parallel experimental designs with respect to preclinical studies. This should be part of the submission for Management approval. Plan to get initial go/no go point. 10. Regulatory Affairs - commentary on whether the preclinical data might present any unique or substantial regulatory issues which could affect clinical plans. 11. Potential Liabilities - this should encompass any potential problems found in safety, metabolism, formulation, etc. data that may be predictive of issues arising in Development. 12. Competition - competitive drugs within this target and other targets in this field. 13. Candidate Potential - future research plans to build and expand on the projected success of the Safety Assessment Candidate, and backup research plans in case the Safety Assessment Candidate is not successful. 14. Safety - Ames and Cytochrome P-450 induction test 15. Recommendation - a reasoned rationale of why the product candidate should be proposed for development including those potential attributes that could be found in a package insert indicating superiority over the current marketed drugs in the relevant theraputic area.
  • Drug quantity -- In research, the new compound is calculated in terms of micrograms to grams, and the drug is made by the bench chemist, often laboriously. In Development, however, kilograms of the drug are needed for the multiplicity of toxicity and human studies. This often requires the use of a chemical pilot plant. Safety -- Usually only the Ames Test, a cytochrome P450 analysis for enzyme induction, and perhaps an acute (up to one week) toxicity study in one or two species is all that is required for research. In Development the studies range from one week up to 105 weeks. Formulation -- In research, pre-formulation studies revolve around the initial presentation to the human clinical trial subject, which usually means the drug in a capsule or ampule. In development, there are a host of formulations considered, usually marketing-driven, being worked on simultaneously. And others are considered after initial marketing. Metabolism - In the Research phase, radiolobeling is usually sufficient to determine the metabolism of the drug. For development, however, non-radioactive assays are required. Budget - Research uses departmental or broad-based program budgets, but once the drug is in Development, each candidate, formulation or indication gets its own Project Accounting Number. Costs - Most Activities in Research are in the $100,000 range: in Development, most everything is over $1 million.
  • The scope of the regulations is clearly defined in Section 58.1. The regulations apply to all nonclincal laboratory studies that support or are intended to support research or marketing permits for FDA-regulated products. Subject to the regulations are human and veterinary pharmaceuticals, food and color additives, medical devices for human use, biologics and electronic products. The term does not include studies utilizing human subjects or clinical studies or field trials in animals. The term does not include basic exploratory studies carried out to determine whether a test article has potential utility or to determine physical or chemical characteristics of a test article. Similar regulations exist to cover submissions of chemical data to the EPA under TSCA (Toxic Substances Control Act) and FIFRA (Federal Insecticide, Fungicide, and Rodenticide Act).
  • GLP Facility audit : Are facilities adequate to support the workload? Are written SOPs available to laboratory personnel? Equipment: General condition of equipment; Availability of operating instructions; Calibrations procedures; Schedule of calibration; Maintenance and repair record Specimen handling: History of sample storage; Length of time in shipment; Method of shipment; Off-hours receipt procedures; personnel handling sample receipt; documentation of condition upon arrival; Storage conditions; sample integrity Personnel: Number and type; Qualifications, training and experience
  • Affected Labs Public, private, government nonclinical laboratories conducting safety studies Subcontractor/off-site labs are required to be in compliance with those parts of the GLPs that are appropriate to the nature of their contributions to a study
  • For some, a nonclinical study is synonymous with a toxicological study. Although a toxicological evaluation is an important component of safety assessment, the scope of safety evaluation goes beyond toxicology. Examples of other aspects of safety assessment include metabolism studies certain pharmacological studies animal tissue residue studies, and environmental safety studies The physical and chemical evaluations that are integral parts of these studies must also comply with regulations. At minimum, one should be concerned with GLP compliance in studies of characterization of the chemical substance being evaluated, its purity and stability, and its concentration and homogeneity in the carrier used for administration.
  • Absorption (Oral) The transfer of compound across the intestinal lumen. The intestinal vasculature feeds into the portal vein which goes to the liver. Hence, total absorption does not mean all compound will reach the systemic circulation (see First Pass). Absorption (General) The transfer of compound across an external physiological barrier. Compared to oral absorption, first pass metabolism through the liver is avoided but extra-hepatic first pass metabolism may occur. Distribution The transfer of compound from the site of administration to the total systemic circulation and then to extracellular and intracellular water and tissues is called distribution. Drug distribution is usually a rapid and reversible process. Drug metabolism or biotransformation refers to the biochemical transformation of a compound to another chemical form; one that is usually more polar (water soluble) than the original parent molecule Excretion The removal of compounds from the body is excretion. Drugs may be excreted, unchanged or as metabolites, in urine via the kidneys or in faeces via the bile. Volatile compounds are often excreted in expired air by the lungs. Excretion via other body fluids such as saliva, sweat, or sexual fluids is well documented.
  • Decision 5: The Regulatory Submission that will allow the initiation of human clinical trials. The IND is not an application for marketing approval. Rather, it is an application for an exemption from the statute that prohibits an unapproved drug from being shipped in interstate commerce. Current law requires that a drug be the subject of an approved New Drug Application (NDA) before it is transported or distributed between states. Because the sponsor must ship the experimental drug to each clinical investigator, it must seek an exemption from that legal requirement. The IND is the vehicles through which this exemption is obtained from the FDA. Both drugs and biologics file IND’s prior to beginning clinical trials; devices file IDE’s. FDA is authorized to exempt devices intended solely for investigational use from certain requirements of the FD&C Act to allow for their shipment and use on human studies. This provision applies to investigational studies undertaken to develop safety and effectiveness data for a medical device when these studies use human subjects CTC - for use in UK/EU; some thought that it is easier to start clinical trials in Europe.
  • 1.12 Clinical Trial/Study Any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.
  • GCP is a term of convenience used by government and industry to identify a collection of loosely-realated regulations that define the responsibilities of the key figures involved in a clinical trial. These responsibilities are found primarily in the following: a 1981 final regulation on the informed consent of patients a 1981 final regulation on the responsibilities of IRBs the 1987 IND Rewrite regulations which define the responsibilities of the investigator and sponsor. the 1988 Guideline for the Monitoring of Clinical Investigations , which outlines the monitor’s responsibilities
  • World Medical Association Declaration of Helsinki: Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects Adopted by the 18th World Medical Assembly, Helsinki, Finland, June 1964 and amended by the 29th World Medical Assembly, Tokyo, Japan, October 1975, 35th World Medical Assembly, Venice, Italy, October 1983, and the 41st World Medical Assembly, Hong Kong, September 1989 Introduction It is the mission of the physician to safeguard the health of the people. His or her knowledge and conscience are dedicated the fulfillment of this mission. The Declaration of Geneva of the World Medical Assembly binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient." The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of disease. In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies especially to biomedical research. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. In the field of biomedical research a fundamental distinction must be recognized between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research. Special caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected. Because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as a guide to every physician in biomedical research involving human subjects. They should be kept under review in the future. It must be stressed that the standards as drafted are only a guide to physicians all over the world. Physicians are not relieved from criminal, civic and ethical responsibilities under the laws of their own countries. It is the mission of the physician to safeguard the health of the people. His or her knowledge and conscience are dedicated the fulfillment of this mission. The Declaration of Geneva of the World Medical Assembly binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient." The purpose of biomedical research involving human subjects must be to improve diagnostic, therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of disease.
  • 2.1 Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. 2.3 The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. 2.4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. 2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol. 2.6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion. 2.7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
  • 1.53 Sponsor An individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial. 1.54 Sponsor-Investigator An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.
  • 5.4.1 The sponsor should utilize qualified individuals (e.g., biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRF's and planning the analyses to analyzing and preparing interim and final clinical trial/study reports. 5.5 Trial Management, Data Handling, Recordkeeping, and Independent Data Monitoring Committee 5.5.1 The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports. 5.5.2 The sponsor may consider establishing an independent data monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. 5.6 Investigator Selection 5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected.. 5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator's Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided. 5.6.3 The sponsor should obtain the investigator's/institution's agreement: (a) To conduct the trial in compliance with GCP, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the IRB/IEC; (b) To comply with procedures for data recording/reporting: and (c) To permit monitoring, auditing, and inspection (see 4.1.4). (d) To retain the essential documents that should be in the investigator/institution files (see 8.) until the sponsor informs the investigator/institution these documents are no longer needed 5.9 Financing The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
  • Federal regulators define “sponsor” as: “...a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization or other organization.” Investigator selection: the sponsor must select investigators - physicians contracted by the sponsor to conduct the clinical study - qualified by training and experience as appropriate experts to investigate the drug. The sponsor is responsible for keeping all investigators involved in the clinical testing of its drug fully informed about the invstigational drug and research findings. The sponsor must closely monitor the conduct and progress of its clinical trials for (1) investigator noncompliance and (2) unreasonable and significant drug risks A sponsor must maintain adequate records showing the receipt, shipment or other disposition of the investigational drug. The records must include, as appropriate, the name of the investigator to whom the drug is shipped, the date quantitiy and lot identification of each shipment. The sponsor must ensure the return of all unused supplies of the drug from each investigator whose participation ceases.
  • 5.1 QA/ QC 5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOP's to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). 5.1.2 The sponsor is responsible for securing agreement from all involved parties to ensure direct access (see 1.21) to all trial-related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities. 5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. 5.1.4 Agreements, made by the sponsor with the investigator/institution and/or with any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement. 5.2 Contract Research Organization (CRO) 5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control. 5.2.2 Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing. 5.2.3 Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor. 5.2.4 All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the trial-related duties and functions of a sponsor. 5.3 Medical Expertise The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial-related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.
  • 5.10 Notification/Submission to Regulatory Authority(ies) submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission to begin the trial(s). 5.11 Confirmation of Review by IRB/IEC 5.12 Information on Investigational Product(s) 5.12.1 ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied. 5.12.2 update the Investigator's Brochure as significant new information becomes available. 5.13 Manufacturing, Packaging, Labeling, and Coding Investigational Product(s) 5.13.1 is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labeled in a manner that protects the blinding, if applicable. In addition, the labeling should comply with applicable regulatory requirement(s). 5.13.2 acceptable storage temperatures, storage conditions (e.g., protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. 5.13.3 packaged to prevent contamination and unacceptable deterioration during transport and storage. 5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding. 5.13.5 If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials. 5.14 Supplying and Handling Investigational Product(s) 5.14.1 The sponsor is responsible for supplying the investigator(s)/ institution(s) with the investigational product(s). 5.14.2 The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g., approval/favorable opinion from IRB/IEC and regulatory authority(ies)). 5.14.3 The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).
  • 1.38 Monitoring The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOP's), GCP, and the applicable regulatory requirement(s). 1.39 Monitoring Report A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor's SOP's.
  • FDA’s Guideline for the monitoring of Clinical Investigations, 1988 Selection of a Monitor. A sponsor may designate one or more appropriately trained and qualified individuals to monitor the progress of a clinical investigation. Physicians, clinical research associates, paramedical personnel, nurses and engineers may be acceptable monitors depending on the type of product involved in the study. Written Monitoring Procedures. A sponsor should establish written procedures for monitoring clinical investigations to assure the quality of the study and to assure that each person involved in the monitoring process carries out his or her duties. Preinvestigation site visits. Through personal contact between the monitor and each investigator, a sponsor must assure that the investigator, among other things, clearly understands and accepts the obligations involved in undertaking a clinical study. The sponsor must also determine whether the investigator’s facilities are adequate for conducting the investigation and whether the investigator has sufficient time to honor his/her responsibilities in the trial. Periodic visits. A sponsor must assure, throughout the clinical investigation, that the investigator’s obligations are being fulfilled and that the facilities used in the clinical investigation continue to be acceptable. The monitor must visit the clinical site frequently enough to provide such assurances. Review of subject records. A sponsor must assure that safety and efficacy data submitted to the FDA are accurate and complete. The FDA recommends that the onitor review subject records and other supporting documentation and compare these records with the reports prepared by the investigator for submission to the sponsor. Record of on-site visits. The monitor or sponsor should maintain a record of the findings, conclusions, and actions taken to correct deficienciesf or each on-site visit to an investigator.
  • 1.34 Investigator A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Subinvestigator. 1.35 Investigator/Institution An expression meaning ``the investigator and/or institution, where required by the applicable regulatory requirements.''
  • Institutional Review Board (IRB) An independent body constituted of medical, scientific, and nonscientific members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trials, of protocols and amendments, and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
  • 1.1 Adverse Drug Reaction (ADR) In the preapproval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase ``responses to a medicinal product'' means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. Regarding marketed medicinal products: A response to a drug that is noxious and unintended and that occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function 1.2 Adverse Event (AE) An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product
  • Observe effects of drug upon first administration to human beings Studies investigate safety as opposed to efficacy Initial dose ranging studies to investigate drug tolerance and preliminary theraputic effects
  • Phase I studies are carried out in normal volunteers as opposed to patients. One exception to performing these studies in normal human volunteers is in the cancer and AIDS areas where the drugs are potentially very toxic compounds. In this instance, Phase I trials are conducted in patients with the targeted disease, not in normal human subjects.
  • REM: Clinical trials are carefully outlined in clinical protocols which have been reviewed (and commented on) by FDA. The main elements of a clinical trial are given here.
  • Drug metabolism Study how the drug is absorbed, distributed throughout the body, metabolized and excreted (ADME) determine pharmacokinetic parameters Pharmacology The science that pertains to the effect of drugs on living organisms. Toxicology The science that concerns the nature and effects of poisons (including all drugs), their detection and the treatment of poisoning.
  • During the initial stage of clinical development, the manufacturing process will not be fully validated (e.g., all manufacturing steps and yields optimized, storage times and conditions for intermediates fully addressed, etc.) Consequently, ample characterization data must be generated to show that the type and amount of active substance in the test article is present. At minimum: Have a highly characterized active substnace demonstrating that it was produced as intended Be able to quantify the amount of active substance(s) in the final product; Demonstrate that the test article is stable for the duration of the clinical trials; and Have assays to generate data that are mandated by federal regulations If sufficient data are available, generally from several lots, one can establish initial active substnace and final product specifications. These specifications may be acceptably broad but scientifically defensible. If data are not available, it is acceptable not to set specifications and to simply report the results. If any assay is not listed in compendia or commonly known, a “mini-validation” on key parameters should be initiated to assure that the assay provides accurate and reproducible results.
  • Preformulation commences the dosage form development stage. During this phase, the physical chemistry of the drug is studied by itself and in relation to other potential formulation ingredients. In selecting the final formulation for a specific drug form, many factors must be taken into consideration, such as: which formulation provides the highest level of bioavailability; what is the most flexible drug delivery system; what formulation provides the best stability; and how palatable these formulations are for topical formulations, the formulation must also be cosmetically acceptable to the patient Dosage form development normally progresses from preformulation through preliminary stability. This stage can involve a number of decision loops until a formulation demonstrating acceptable stability and activity is developed. When such a formulation is in hand, package selection and the formal stability can commence. Throughout this process, supplies must be manufactured and packaged for clinical and other studies. To simulate manufacturing conditions, increasingly larger btches are produced. Toward the end of this pphase, technology must be transferred to the selected manufacturing site or sites that will be used once the drug is approved for marketing.
  • In the area of metabolism it is necessary to study the pharmacokinetics of the drug or ADME. Investigators correlate the duration of drug effects against drug blood levels, and examine the bioequivalence and bioavailability of alternate drug dosage forms. It is necessary also to study the transfromation of the drug in the body..
  • And, since there may be differences in the way the drug is handled by various individuals, studies must be conducted in special populations, such as specific age groups, patients with renal/hepatic impairment, etc
  • A new compound must surmount a major hurdle consisting of acute, subacute, and chronic toxicology studies. It is at this point that the benefit-to-risk ratio comes into play. If the new compound is of breakthrough caliber where no therapy exists to treat the disease, there can be a willingness to accept more side effects. If, on the other hand, the condition is not life-threatening or if several alternative therapies exist with few side effects, then the toxicology/safety ratio becomes more critical. Early decisions are based upon subacute and chronic studies that entail administering repeated doses over time to identify potential side effects. In the clinic it is important to design the studies in such a way as to obtain information that facilitates decision making. The Phase 1 studies obviously provide data about safety and side effects. In order to evaluate these results in a realistic way, it is necessary to know the safety/side effect profile of the competition. There is no point in developing a drug with an inferior safety profile unless the activity of the drug is significantly superior.
  • This stage of clinical trials involves patients with the targeted disease. The purpose is to determine if the drug has the desired theraputic effect. This stage involves dose ranging in patients to determine the dose strength and the frequency of administration in order to provide the optimal theraputic benefit. Patients are carefully monitored for all side effects in order to gain an initial assessment of the benfit-to risk ratio. These trials are also generally done against a placebo as well as a drug active in the targeted disease, if such is available.
  • End-of-Phase 2 meetings with FDA are a vital element in the development of drug products. This type of meeting assists a drug company in planning well-designed Phase 3 studies that will most effectively confirm a drug’s effectiveness, and also determines what additional information is necessary to support a marketing application. Desired Outcome: Sponsor and FDA agree on plans for conduct and design of Phase 3
  • Phase 3 consists of controlled and uncontrolled trials conducted to determine additional safety and efficacy data to provide a benefit to risk assessment and a basis for labeling. This phase may incorporate from several hundred to several thousand patients.
  • controlled: A controlled trial compares a group of patients treated with a placebo or standard therapy against a group of subjects treated with the investigational new drug. blinded design: Blinded trials are those in which both the patients and the investigators are kept from knowing which subjects are receiving the experimental drug and which are receiving the placebo/standard therapy. This double blinding procedure ensures that treatment evaluations are as objective as possible. randomized: This means that clinical subjects are assigned randomly to the investigational drug and the placebo/standard. Therefore, each patient is given an equal chance of being in the control or the experimental group. Randomization prevents the investigator from influencing the outcome by assigning patients with a better prognosis to the preferred treatment. adequate size: The study must involve enough patients to provide statistically significant evidence that a new drug offers a therapeutic or safety advantage over existing therapies. Sample size calculation requires many assumptions about the result to be obtained with the treatment and population being studied. Because considerable clinical judgment is employed in making these assumptions, FDA warns that faulty presumptions frequently result in studies of inadequate statistical power. Trial sample size is said to be the most common clinical trial design flaw.
  • Pharmacological studies generally fit into the category of generation of data suitable for publication in accordance with a defined publication strategy. Tox studies being completed - 24-month rat and mouse carcinogenicity studies, 12-month chronic rat, 12-month chronic dog; ADME Prescribing : key clinical data which will be incorporated into the pkg insert emerges from Phase 3 data A world-wide registration strategy is developed. Where and what indications in what countries? Pricing is cmplx, highly competitive; based upon many interrelated international factors. During Phase 1 trials a clinical formulation was prepared which could be a modification of the dosage form used in toxicology studies. Later in the course of the Phase 1 study and on into Phase 2, efforts were directed at formulating and developing the commercial (sales) dosage form. Usually during Phase 3 the final stability studies on the sales dosage form are undertaken. Marketing :Plan must be reviewed re changes during development. New competition? Newer theraputic approach? Rethink drug life re changes. Trials provide data for new indications, potential future development of new compound.
  • Phase 2 Early Development Establish Technology Transfer Team 15 - 23 Months
  • Phase 3 Full Development 10 - 16 Months
  • Phase 3 Full Development 10 Months NDA Bioequivalence : Scientific basis on which generic and brand-name drugs are compared. To be considered bioequivalent, the bioavailability of two products must not differ significantly when the two products are given in studies at the same dosage under similar conditions. Some drugs, however, are intended to have a different absorption rate. FDA may consider a product bioequivalent to a second product with a different rate of absorption if the difference is noted in the labeling and doesn't affect the drug's safety or effectiveness or change the drug's effects in any medically significant way.
  • 15 Months Launch
  • The validation protocol defines what is to be done. The process whould be stated succinctly with little or no reference to actual specific devices. Guideline: Purpose or objective
  • Process performance qualification - Establishing confidence that the process is effective and reproducible. Product performance qualification - Establishing confidence through appropriate testing that the finished product produced by a specified process meets all release requirements for functionality and safety. Worst case - A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, which pose the greatest chance of process or product failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure. The basic principles of quality assurance have as their goal the production of articles that are fit for their intended use. These principles may be stated as follows: (1) quality, safety, and effectiveness must be designed and built into the product; (2) quality cannot be inspected or tested into the finished product; and (3) each step of the manufacturing process must be controlled to maximize the probability that the finished product meets all quality and design specifications. Process validation is a key element in assuring that these quality assurance goals are met.
  • History section identifies the biobatches and batches used for pivotal clinical trials.
  • Raw material inventory records will be reviewed to evaluate the use of the drug substance in the biobatch, clinical, and/or test batches. The investigator will evaluate the quantities of materials used, the testing performed and their sources. Raw laboratory data validation, data procedures, equipment and methods will be reviewed Equipment should be in place and qualified. Manufacturers must validate their cleaning processes for the new drug/dosage form. SOPs Process change QA/QC investigations/problems/defects/failures Field alerts Cleaning validation
  • (a) Description. (1) Under this section heading, the labeling shall contain: (i) The proprietary name and the established name, if any, as defined in section 502(e)(2) of the act, of the drug; (ii) The type of dosage form and the route of administration to which the labeling applies; (iii) The same qualitative and/or quantitative ingredient information as required under Sec. 201.100(b) for labels; (iv) If the product is sterile, a statement of that fact; (v) The pharmacological or therapeutic class of the drug; (vi) The chemical name and structural formula of the drug; (vii) If the product is radioactive, a statement of the important nuclear physical characteristics, such as the principal radiation emission data, external radiation, and physical decay characteristics. (2) If appropriate, other important chemical or physical information, such as physical constants, or pH, shall be stated.
  • (b) Clinical Pharmacology. (1) Under this section heading, the labeling shall contain a concise factual summary of the clinical pharmacology and actions of the drug in humans. The summary may include information based on in vitro and/or animal data if the information is essential to a description of the biochemical and/or physiological mode of action of the drug or is otherwise pertinent to human therapeutics. Pharmacokinetic information that is important to safe and effective use of the drug is required, if known, e.g., degree and rate of absorption, pathways of biotransformation, percentage of dose as unchanged drug and metabolites, rate or half-time of elimination, concentration in body fluids associated with therapeutic and/or toxic effects, degree of binding to plasma proteins, degree of uptake by a particular organ or in the fetus, and passage across the blood brain barrier. Inclusion of pharmacokinetic information is restricted to that which relates to clinical use of the drug. If the pharmacological mode of action of the drug is unknown or if important metabolic or pharmacokinetic data in humans are unavailable, the labeling shall contain a statement about the lack of information. (2) Data that demonstrate activity or effectiveness in in vitro or animal tests and that have not been shown by adequate and well-controlled clinical studies to be pertinent to clinical use may be included under this section of the labeling only under the following circumstances: (i) In vitro data for anti-infective drugs may be included if the data are immediately preceded by the statement ``The following in vitro data are available but their clinical significance is unknown.'' (ii) For other classes of drugs, in vitro and animal data that have not been shown by adequate and well-controlled clinical studies, as defined in Sec. 314.126(b) of this chapter, to be pertinent to clinical use may be used only if a waiver is granted under Sec. 201.58 or Sec. 314.126(b) of this chapter.
  • The National Drug Code (NDC) System was originally established as an essential part of an out-of-hospital drug reimbursement program under Medicare. The NDC was to serve as a universal product identifier for prescription drugs.. The directories were considered essential for 3rd party reimbursement programs by some segments of the health care industry. The NDC System contained information for the most frequently prescribed drugs. However, the System did not meet the Food and Drug Administrations's (FDA) needs for a complete inventory of all commercially distributed drug products. In 1972, the Federal Food, Drug, and Cosmetic Act was amended (Drug Listing Act of 1972) to make the submission of information on all commercially distributed drugs mandatory. . National Drug Code (NDC) Each drug product is assigned a unique 10-digit, 3-segment number. This number, known as the National Drug Code (NDC), identifies the labeler/vendor, product, and trade package size. The first segment, the labeler code, is assigned by the FDA. A labeler is any firm that manufactures, processes, or distributes a drug product. The second segment, the product code, identifies a specific strength, dosage form, and formulation for a particular labeler. The third segment, the package code identifies trade package sizes. Both the product and package codes are assigned by the labeler. The NDC will be in one of the following configurations: 4-4-2, 5-3-2, or 5-4-1.
  • Part of CDER's mission is to assure that prescription drug information provided by drug firms is truthful, balanced, and accurately communicated. This is accomplished through a comprehensive surveillance, enforcement, and education program, and by fostering better communications of labeling and promotional information to both health professionals and consumers. This work is accomplished primarily through CDER's Division of Drug Marketing, Advertising and Communications (DDMAC).
  • In a very real sense the drug development process continues long after a product’s approval. Adverse drug reaction (ADR) and other reporting and recordkeeping requirements provide the sponsor and the FDA with a continuing flow of information so a drug’s safety and effectiveness can be periodically reassessed in light of new data. According to federal regulations, sponsors of approved NDAs are required to submit to the FDA several different types of general reports - field alert reports, annual reports, and advertising and other specials reports. These submissions, as well as adverse drug reaction (ADR) reports, allow the FDA to continue to monitor the use of the drug, and to determine if there are any grounds for suspending or withdrawing the approval of the drug.
  • Phase 4 program . This is part of the Product Extension strategy. Phase 4 is market oriented since, periodically, new marketing facts or studies are needed for continued growth or to attain a competitive edge. Phase 4 is conducted under the original IND. This phase is designed to expand upon an already approved claim. Expansion of Claim Structure . In the US, any claim for a new indication or indications requires a new IND as well as a supplemental NDA that entails a longer review process. An example would be a claim that a product not only is effective for the approved indication, for example hypertension, but can also serve as an anti-anginal agent.
  • However, a successful NDA does not assure a successful product.
  • Drug discovery and development overview

    1. 1.  Description  Clinical Pharmacology  Indications and Usage  Contraindications  Warnings  Precautions  Adverse Reactions  Drug Abuse and Dependence  Overdosage  Dosage and Administration  How Supplied  Clinical Studies  References
    2. 2.  Immunologist  Tissue staining  1908 Nobel Prize for Medicine  “Magic Bullet”  Salvarsan
    3. 3. Paul Ehrlich: All who are about to embark on developing a new drug must bring to the task four essentials: › brains › persistence › capital › luck
    4. 4. Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12 Discovery The Screen  The Lead  Development R R Safety Assess Cand  Patents  Dosage Form Dev  IND/IDE  Clinical Trials Phase 1 Review Safety Data  Phase 2 End Phase 2 Clin Rev  Phase 3 NDA/BLA/PMA  FDA Review Approval  Product Launch 
    5. 5. The term includes basic and applied research as well as development activities carried on or supported in the pharmaceutical, biological, chemical, medical, and related sciences, including psychology and psychiatry, if the purpose of such activities is concerned ultimately with the utilization of scientific principles in understanding diseases or in improving health.
    6. 6. The term “Discovery” is used to describe the early phases of the overall biomedical discovery process, that is, the synthesis of or the search for compounds and the screening processes developed to identify “lead” compounds.
    7. 7. Uncured Diseases Approximate Annual Prevalence Approximate Economic Cost (billions) Cardiovascular 56,000,000 $128 Cancer 10,000,000 $104 Alzheimer’s 4,000,000 $100 Diabetes 16,000,000 $ 92 Arthritis 40,000,000 $ 65 Depression 17,400,000 $ 44 Stroke 3,000,000 $ 30 Osteoporosis 28,000,000 $ 10
    8. 8.  National Cancer Institute  National Heart, Lung and Blood Institute  National Institute on Aging  National Institute of Arthritis and Musculoskeletal and Skin Diseases  National Institute of Diabetes and Digestive and Kidney Diseases
    9. 9.  American Cancer Society  American Heart Association  Howard Hughes Medical Institute  Salk Institute for Biological Studies
    10. 10.  Select area of therapeutic or diagnostic interest  Establish long term (5 to 10 year) goals for program  Commit needed resources
    11. 11.  Short term plans, 1 to 3 years  Identifies areas for discovery research  Allocates resources to carry out the plan › people › space › equipment › money
    12. 12.  Discovery research  Marketing  Clinical research
    13. 13.  Product  Market  Proprietary Aspects  Technologies used  Mechanism of action  Regulatory agencies involved  Clinical trials
    14. 14.  Diagnostic  Therapeutic  Device  Combination
    15. 15.  Who will use the product?  What special needs does that group have?  Who will pay for the product?
    16. 16.  Basic Research  Feasibility  Explore research/design options  Lead candidate
    17. 17.  Cloning  Protein purification  Monoclonal antibodies  Carbohydrate technology  In vivo genetic modification  Transgenic manipulation  Cell culture
    18. 18.  Tool to identify new drug candidates  Usually a subcellular component (enzyme, receptor, etc.) removed from a living system and studied in vitro  ACTIVES: agents that stimulate or inhibit normal function
    19. 19. Receptor: any biological macromolecule which can be activated by a drug to cause a biological response or effect.
    20. 20.  Agonist: a drug which binds to a receptor and elicits a biological response  Antagonist: occupies (or blocks) a receptor but does not elicit a response  Intrinsic activity: the measure of a drug’s ability to elicit a response
    21. 21.  Synthetic program  High through-put screening program  Compound libraries
    22. 22.  Fermentation/microbial sources  Plant/herbal sources  Arachnid and amphibian sources  Marine sources
    23. 23.  Tool to identify new drug candidates  Usually a subcellular component (enzyme, receptor, etc.) removed from a living system and studied in vitro
    24. 24. An active is a substance that causes inhibition or stimulation in a screening model, thereby indicating the substance may have pharmacological effect.
    25. 25. A compound that exhibits pharmacological properties which suggest its value as a starting point for drug development.
    26. 26. The process of synthesizing chemical variations, or analogs, of a lead compound, with the goal of creating those compounds with improved pharmacological properties.
    27. 27. From WSJ Jan 27, 2000: Three teams of researchers have discovered a gene for a protein that appears to prevent nerves in the brain and spinal cord from growing back after being damaged by injury or disease.
    28. 28. By studying the protein, researchers hope they can design drugs that might help regenerate damaged nerves
    29. 29. Scientist are looking for the receptor for the protein. Once it is found, drug companies may be able to design antagonists to block the effect of the protein, allowing damaged nerves to regenerate.
    30. 30. Ames Test In vitro metabolism  microsomes  hepatocytes  liver slices
    31. 31. Compoundfromsyntheticprogram, combinatoriallibrary,chemicallibrary, naturalproductsource,etc. Invitroevaluation-human/mammal receptor/enzymeassay;reporter system Active Biochemical,tissueoranimalmodelof function Active Animalmodeloftheraputictarget Pharmacokinetics,formulation,acute toxicology Approvalforclinicaldevelopment Yes Yes No No
    32. 32. For every experiment the researcher should record: › each item, source, lot number and quantity used › experimental conditions, e.g., times, temperatures, pressures, etc. › all calculations › sampling schedule, results
    33. 33.  Safety and Efficacy  Chemistry/Pharmacy  Clinical/Regulatory  Marketing/Legal  Potential Ups and Downs
    34. 34.  Process not well controlled; nonreproducible results  Insufficient experience to adequately predict critical parameters  Process not scaleable “as is”  Documentation incomplete, poorly recorded, poorly organized, or does not support claims
    35. 35.  Introduction and Summary  Assays  Chemistry  Pharmacy  Patents  Clinical Plan  Regulatory Affairs  Potential Liabilities  Competition  Candidate Potential  Safety  Recommendation
    36. 36. Research Development Overall objective Select a development candidate Submit an NDA Corporate Mandate Broad, Loosely defined Narrow, focused Compounds tested Many, diverse One Types of studies Few Many
    37. 37. Research v. Development Research Development Regulatory Little or none Extensive Timetable Loose, flexible Strict, constrained Recognition Innovation Speed Culture Chaotic Structured Workstyle Entrepeneurial Interdependent
    38. 38. Research Development Quantity µg →mg →g g →kg Safety Ames, P450 1 w →105 w Formulation Capsule Tablet, inject. Metabolism Radiolabeled Assay Budget Departmental Proj. Acct. No. Costs <$100,000 >$1,000,000
    39. 39. 1. Establish raw material specifications 2. Scale-up production processes 3. Establish critical process control parameters 4. Establish final product specifications 5. Validate analytical methods 6. GLP preclinical studies 7. Prepare clinical trial material 8. Initiate stability/reliability studies 9. Establish document systems
    40. 40. New Chemical Entities (NCE) or New Molecular Entities (NME) - active ingredients never before used as drugs
    41. 41. The active ingredient intended to diagnose, treat, cure, or prevent disease or affect the structure or function of the body, excluding other inactive substances used in the drug product.
    42. 42.  Identity: normally two identity tests required  Strength/potency  Sensitivity  Specificity  Purity: normally 98+% for NCE’s  Stability  Safety and efficacy
    43. 43. The finished dosage form (tablet, capsule, etc.) that contains a drug substance--generally, but not necessarily, in association with other active or inactive ingredients.
    44. 44. Establish specifications and specification testing requirements for: •identity •potency/strength •purity •stability
    45. 45. United States Pharmacopoeia and National Formulary - designated as the official compendia pursuant to federal and some state statutes, and containing enforceable standards and specifications for strength, quality, purity, packaging, labeling, and where applicable, bioavailability of drugs
    46. 46. Nonclinical laboratory study - in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety.
    47. 47. Regulations established in the U.S. in 1976 to ensure the quality and integrity of bioresearch and animal test data submitted to the FDA
    48. 48.  Regulations on facilities and equipment  Regulations involved in tests and controls  Regulations on personnel and organization
    49. 49.  Verify the quality and integrity of data submitted to FDA  Inspect nonclinical laboratories engaging in safety studies for regulated products  Audit ongoing and completed lab safety studies  Determine degree of compliance with GLP regulations
    50. 50.  Toxicology › Acute toxicity › Subacute and chronic toxicity › Reproductive and developmental studies › Mutagenicity  Metabolism  Pharmacology  Tissue residue  Environmental
    51. 51.  Study of how the drug is absorbed, distributed throughout the body, metabolized and excreted (ADME)  Determination of the rate constants (kinetics) for ADME
    52. 52.  Engineering: Determine pilot plant requirements for preparation of clinical trial material  Clinical Affairs: Begin the design of clinical studies to establish efficacy and tolerance of the new drug candidates in human beings  Regulatory Affairs › Prepare IND/IDE › Pre-IND/IDE meeting with the FDA to discuss plans for Phase I clinical trials
    53. 53.  Drug/Biologic/Component Characteristics  Description of actives, excipients, components, and solvents required for formulation or assembly  Analytical test methods  Process or assembly instructions  Processing equipment incompatibilities
    54. 54. Regulatory Affairs  Regulatory status of drug substance and finished product  History or status of communications with FDA  World wide regulatory strategy
    55. 55. Engineering  Equipment/environmental/facility requirements for manufacture  Special handling requirements
    56. 56.  The scaled-up version of the product is ineffective or uncharacteristic when compared to the research version  Facilities are inadequate for aseptic handling of product, microbiological testing and/or quality control
    57. 57.  Quality specifications for raw materials, drug substance and processing intermediates  Stability of raw materials  Preliminary product specifications  Storage requirements
    58. 58. Marketing and Medical  Product name  Initial dose levels  Packaging configurations  Projected initial market demand (units per month)
    59. 59. Regulatory Affairs  Regulatory status of drug substance and finished product  History or status of communications with FDA  World wide regulatory strategy
    60. 60. Engineering  Equipment/environmental/facility requirements for manufacture  Special handling requirements
    61. 61. Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12 Discovery The Screen  The Lead  Development R R Safety Assess Cand  Patents  Dosage Form Dev  IND/IDE  Clinical Trials Phase 1 Review Safety Data  Phase 2 End Phase 2 Clin Rev  Phase 3 NDA/PLA/PMA  FDA Review Approval  Product Launch 
    62. 62.  Investigational New Drug Applications, or Notice of Claimed Exemption for a New Drug
    63. 63.  Brief (1 - 2 hours) conference with FDA to get pre-submission feedback from FDA  Project Manager; FDA staff person that serves as liaison between sponsor and FDA; a Project Manager is assigned to each IND
    64. 64.  Preclinical testing:Pharm/tox data including ADME, carcinogenicity and mutagenicity screening  Protection of human subjects
    65. 65.  General Investigational plans  Investigator’s Brochure  Clinical Protocols  Chemistry, Manufacturing and Controls  Animal Pharmacology and Toxicology  Previous Human Experience
    66. 66.  FDA review time: 30 days  Submission size: 4 to 10 (400 page) volumes
    67. 67. Any study in humans intended to › verify effects › identify adverse reactions › determine ADME for an investigational drug
    68. 68. Good Clinical Practices  establish procedures to assure the quality and integrity of data obtained during clinical testing  protect the rights and safety of clinical trial subjects
    69. 69. GCP Requirements GCP Requirements Sponsor MonitorInvestigator IRB Informed Consent
    70. 70.  In research on man, the interest of science and society should never take precedence over considerations related to the well-being of the subject  Biomedical research involving humans must be scientifically sound
    71. 71.  Declaration of Helsinki  Benefits justify the risks  Preserve rights, safety, and well-being of subjects  Adequate information to support trial  Clear, detailed protocol  Prior IRB/IEC approval  Medical care by qualified physician
    72. 72.  Qualified personnel  Informed consent  Record keeping  Confidentiality  GMP investigational products  Quality systems
    73. 73. An individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.
    74. 74.  Trial design  Trial management, Data handling and Recordkeeping › Independent Data Management Committee  Selecting Investigators  Financing
    75. 75.  selecting investigators and monitors  informing investigators  reviewing ongoing investigations  record keeping and record retention  ensuring disposition of unused drug supplies
    76. 76.  Quality Assurance/Quality Control › SOPs to assure compliance › access to sites and documents › data reliability › contracts with investigators  Contract Research Organization  Medical Expertise
    77. 77.  Notification/Submission to Regulatory Authorities  Confirmation of IRB Approval  Investigator’s Brochure  Clinical Trial Material  Ensuring disposition of unused drug supplies  Monitoring
    78. 78. Sponsors must monitor trials to  ensure the quality and integrity of the clinical data  ensure that the rights and safety of human subjects involved in the clinical study are preserved
    79. 79. The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOP's), GCP, and the applicable regulatory requirement(s).
    80. 80.  selection of a monitor  written monitoring procedures  preinvestigation site visits  periodic site visits  review of subject records  record of on-site visits
    81. 81. A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator
    82. 82.  control of drug  record keeping and record retention  investigator reports  assurance of IRB review  handling of controlled substances
    83. 83.  Provide adequate resources  Medical care of Trial Subjects  Communication with the IRB  Compliance with the protocol  Control of investigational product  Informed Consent  Records and reports
    84. 84. An independent body constituted of medical, scientific, and nonscientific members, whose responsibility it is to ensure the protection of the rights, safety, and well- being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trials, of protocols and amendments, and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
    85. 85.  Institutional Review Board/Independent Ethics Committee  Minimize risk to subjects  Risk v. Benefit must be reasonable  Subject selection must be equitable  Informed consent  Adequate monitoring for safety  Subject Privacy
    86. 86. A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed, and dated informed consent form.
    87. 87.  Adverse Drug Reaction (ADR): all noxious and unintended responses to a medicinal product related to any dose  Adverse Event (AE): any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.
    88. 88. Unexpected, Fatal or Life Threatening and Associated with the Use of the Drug Serious, Unexpected and Associated With the Use of the Drug Serious, Expected and Nonserious ↓ ↓ ↓ To FDA by Telephone Within 3 Working Days To FDA and all Participating Investigators in a Written Report Within 10 Working Days To FDA in Next IND Annual Progress Report Written Report Within 10 Working Days Written Report to all Participating Investigators
    89. 89. Number of Subjects: Length: Purpose: 20 to 80 Several months Primarily safety
    90. 90. FDA General Considerations for the Clinical Evaluation of Drugs • normal volunteers • generally, no concomitant drug therapy • generally excludes women of childbearing potential and children • pretreatment physical exams and follow-up studies
    91. 91.  objectives of study  investigator; IRB approval  patient selection/exclusion  study designs  dosing schedules  description of observations and measurements  clinical procedures and lab tests
    92. 92.  metabolism  pharmacology  toxicology  dose ranging  side effects
    93. 93. Case Report Form  Baseline information on patient’s existing medical condition and personal characteristics  drug related changes e.g., blood pressure  adverse events (side effects)  patient feedback
    94. 94.  Evaluation of Phase I data for safety  Prepare Phase II Protocol  Update Investigator’s Brochure  Recruit Phase II clinical sites
    95. 95. Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12 Discovery The Screen  The Lead  Development R R Safety Assess Cand  Patents  Dosage Form Dev  IND/IDE  Clinical Trials Phase 1 Review Safety Data  Phase 2 End Phase 2 Clin Rev  Phase 3 NDA/PLA/PMA  FDA Review Approval  Product Launch 
    96. 96.  Clinical trials  Formulation development/Stability  Chemical process development  Metabolism/ Pharmacokinetics  Toxicology
    97. 97.  Well characterized drug substance  Broad specifications  Stability indicating assays developed  Start assay validations  Stability studies
    98. 98.  Preformulation  Formulation  Preliminary stability  Package selection  Formal stability  Manufacture and Packaging for clinical supplies  Technology transfer
    99. 99.  Pharmacokinetics - ADME  Duration of effect v. drug blood levels  Bioequivalency/bioavailability of alternate dose forms  Biotransformation of the drug
    100. 100.  Studies in special populations › Age › Gender › Hepatic/renal impaired › Metabolic interaction › Ethnic groups
    101. 101.  Acute studies  Rangefinding studies  Subacute studies  Genetic Toxicity  Reproductive Toxicity  Chronic Toxicity (6 months, 1 year)  Carcinogenicity Studies (2 year dosing)
    102. 102. Number of patients: Length: Purpose: 100 to 300 patient volunteers 2 years Initial trials in patients to determine efficacy
    103. 103.  Dose ranging to determine optimal effect  Strength  Frequency of administration  Acceptable level of side effects  Initial determination of risk-to-benefit ratio
    104. 104.  Pilot scale to larger scale-up batches  Start process validation  Assay Development › Set or tighten specifications as needed › Continue assay development › Continue stability studies  shelf-life  storage requirements  primary packing materials
    105. 105.  Determine the safety of proceeding to Phase 3  Evaluate Phase 3 plan and protocols  Identify any additional information necessary to support marketing application
    106. 106. Patients: Length: Purpose: 1,000 to 3,000 patient volunteers 3 years PIVOTAL Verify safety and effectiveness Monitor adverse reactions from long- term use
    107. 107.  Larger patient pool  Genetic, lifestyle and physiologic diversity  Concomitant therapies and conditions permitted  Out-patient population, less rigorously monitored
    108. 108. At least two pivotal (adequate and well controlled) studies are required to provide “substantial evidence” supporting claims of effectiveness for new drugs and antibiotics.
    109. 109.  adequate size  must be a controlled trial  must have a blinded design (when practical and ethical)  must be randomized
    110. 110.  Degree of response sought  Desired assurance against false positive  Acceptable risk of failure to demonstrate response
    111. 111.  Clear statement of objectives  Design that permits valid comparison with control  Method of subject selection that provides adequate assurance that subjects have the disease or condition being studied
    112. 112.  Adequate measures to minimize bias by subjects, observers and analysts of the data  Well-defined and reliable methods of assessment of subject’s responses  Adequate analysis of the study results to assess the effects of the drug.
    113. 113.  Dangerous adverse effect is found  Drug lacks significant effects or has an effect less advantageous than that of an existing therapy  Drug has a significant effect, but that effect does not justify the risks associated with its use  Drug shows clear evidence of being safe and effective
    114. 114.  Pharmacology/Toxicology Completion  Prescribing Information  Registration/Pricing  Sales Formulation  Marketing plan/support trials
    115. 115.  70% of INDs successfully complete Phase I Clinical Trials  33% of INDs successfully complete Phase 2 Clinical Trials  27% of INDs successfully complete Phase 3 Clinical Trials and continue to NDA
    116. 116. Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12 Discovery The Screen  The Lead  Development R R Safety Assess Cand  Patents  Dosage Form Dev  IND/IDE  Clinical Trials Phase 1 Review Safety Data  Phase 2 End Phase 2 Clin Rev  Phase 3 NDA/PLA/PMA  FDA Review Approval  Product Launch 
    117. 117. NDA Phase 2 Phase 3 Launch Full Development Production ExperienceEarly Development Process Optimization Process Validation Preformulation Report Biobatch (>10% Full Scale Process Validation Batches (3) Final Validation Report Development Report Biobatch Qualification Validation Activities Production Acceptance of the Process (10 batches or 1 year) FMI, including packaging Provisional Scale-up Preliminary Release Notification Final Transfer Report Specifications Full Scale Process Optimization Provisional Transfer Document Pre-approval Inspection Pilot scale stability Provisional Scale-up Report Full Scale Packaging Preliminary process parameters Validation Protocol Full Scale Stability Specifications for dose form Assessment of Bio- /Validation Batch Equivalence Establish Technology Transfer Team 15 -23 Months 10 - 16 Months 10 Months 15 Months
    118. 118.  Preformulation Report  Development Report  FMI, including packaging  Specifications  Pilot Scale stability  Preliminary process parameters  Specifications for dose form
    119. 119.  Biobatch (>10% Full Scale)  Biobatch Qualification  Provisional Scale up  Full Scale Process Optimization  Provisional Scale up Report  Validation Protocol
    120. 120.  Process Validation Batches (3)  Validation Activities  Preliminary Release Notification  Provisional Transfer Document  Full Scale Packaging  Full Scale Stability  Assessment of Bio-/Validation Batch Equivalence
    121. 121.  Final Validation Report  Production Acceptance of the  Process (10 Batches or 1 Year)  Final Transfer Report  Pre-Approval Inspection
    122. 122.  The defining and testing of processes, specifications and/or equipment used, and to prove the capability and suitability of achieving required results consistently  A requirement of GMP’s for drugs and devices  “Organized, documented common sense”
    123. 123. A written plan stating how validation will be conducted, including test parameters, product characteristics. production equipment, and decision points on what constitutes acceptable test results.
    124. 124.  Suitability of building  Services  Materials of construction  Suitability, positioning, accuracy and calibration of instruments
    125. 125.  Consistent operation  System failsafes  Maintenance program  Equipment records  Equipment and system service records
    126. 126.  Demonstrate control of process within defined limits  Demonstrate consistent performance  Demonstrate consistent results
    127. 127. FDA reviewers must determine  Whether drug is safe and effective for intended use  Whether benefits outweigh risks  Whether proposed labeling is appropriate  Whether manufacturing methods and controls are adequate
    128. 128.  Application Form FDA-356h  Index  Summary  Pharmacologic Class, Scientific Rationale  Proposed Label  Foreign Marketing History
    129. 129.  Chemistry, Manufacturing and Controls  Human Pharmacokinetics and Bioavailability  Nonclinical, Pharmacology, Toxicology  Microbiology (anti-infective)
    130. 130. Clinical Data Summary  List of Investigators  Background/Overview of Clinical Investigators  Clinical Pharmacology  Controlled Clinical Trials  Uncontrolled Clinical Trials
    131. 131. Clinical Data Summary  Integrated Summary of Effectiveness  Integrated Summary of Safety  Drug Abuse and Overdose  Benefits/Risks
    132. 132. Clinical Data Summary  Review of Literature for Analogs  Bibliography for Compound  Statistical Section  Case Report Forms and Tabulations
    133. 133.  150 volumes  50,000 pages  12 to 48 months of review and negotiations  record: 42 days
    134. 134. Prior to NDA approval, the FDA will inspect the proposed manufacturing facility to assure that the conditions presented in the NDA do exist and have been adequately documented.
    135. 135.  CMC Section of NDA  Master Formula › specific manufacturing instructions for full scale commercial lots › in process specifications › product specifications  History section of NDA
    136. 136.  Raw materials  Laboratory  Equipment qualification  Cleaning validation  SOPs
    137. 137.  Batch record for first full scale production run  Validation protocols and reports  History of production  Failure investigation reports  All complaints  Microbiological data
    138. 138.  Report to pilot plant detailing R&D formulation development  Report covering pilot plant experiences during scale-up  Report setting product specification
    139. 139. US Package Insert Sections • Description • Clinical Pharmacology • Indications and Usage • Contraindications • Warnings • Precautions • Adverse Reactions • Drug Abuse and Dependence • Overdosage • Dosage and Administration • How Supplied • Clinical Studies • References
    140. 140.  proprietary name and established name  dosage form and route of administration  quantitative ingredient information  pharmacological or therapeutic class  chemical name and structural formula
    141. 141.  Actions of the drug in humans  Pharmacokinetic data (ADME)  Clinical Trial Results
    142. 142.  Clinical Adverse Experiences  Concomitant Therapy  Laboratory Abnormalities  Hypersensitivity Reactions
    143. 143.  General Recommendations  Dosage in Patients with Renal Insufficiency  National Drug Code
    144. 144.  Post-marketing surveillance  Prescription drug advertising and promotional labeling  Pharmaceutical industry surveillance  Drug shortages  Therapeutic inequivalence reporting  Medication errors
    145. 145.  Phase 4 Clinical Trials  General Reporting Requirements › Field Alert Reports › Annual Reports › Adverse Drug Reaction Reporting (ADR) › Special reports  cGMP Requirements
    146. 146.  Satisfy pre-approval FDA request  Evaluate safety and effectiveness in general use  Cost/benefit analysis  Augmentation of original indication  Marketing implications  Expansion of claim structure
    147. 147. Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12 Discovery The Screen  The Lead  Development R R Safety Assess Cand  Patents  Dosage Form Dev  IND/IDE  Clinical Trials Phase 1 Review Safety Data  Phase 2 End Phase 2 Clin Rev  Phase 3 NDA/PLA/PMA  FDA Review Approval  Product Launch 
    148. 148.  70% of INDs successfully complete Phase I Clinical Trials  33% of INDs successfully complete Phase 2 Clinical Trials  27% of INDs successfully complete Phase 3 Clinical Trials and continue to NDA
    149. 149. FDA reviewers must determine  Whether drug is safe and effective for intended use  Whether benefits outweigh risks  Whether proposed labeling is appropriate  Whether manufacturing methods and controls are adequate
    150. 150. Advisory Committee - a panel of outside experts convened periodically to advise FDA on safety and efficacy issues about drugs and other FDA-regulated products. FDA isn’t bound to take committee recommendations, but usually does.
    151. 151.  Learn as much as possible about the committee members  Fully understand the issues the review division presents  Understand how the committee functions  Don’t over do the presentation; keep it short
    152. 152.  Approval letter  Approval letter  Not approvable letter
    153. 153. 20% of IND’s result in successful NDA’s
    154. 154. Stage Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 11 Year 12 Discovery The Screen  The Lead  Development R R Safety Assess Cand  Patents  Dosage Form Dev  IND/IDE  Clinical Trials Phase 1 Review Safety Data  Phase 2 End Phase 2 Clin Rev  Phase 3 NDA/PLA/PMA  FDA Review Approval  Product Launch 

    ×