SESSION 2 Development Strategy For Pharmaceutical Project

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SESSION 2 DEVELOPMENT STRATEGY FOR PHARMACEUTICAL PROJECT

General Principles of Pharmaceutical Project Development The quality and quantity of preclinical data provided by discovery groups to support the development of a new compound is often suboptimal. It is important to establish appropriate selection criteria for development because much time and resource can be wasted, subsequently, by the development organization in inefficient strategies which more thought (and training) in discovery could obviate. There has to be a reasonable balance between responsibility for discovery to provide a basic array of technical data to justify development, and needs of project development that must show maturity and reasonable flexibility. Specific data gaps in a development proposal may exist for good reasons and can be addressed in development. Establishing reasonable criteria for development is also valuable to discovery groups . The selection criteria can be used to better discriminate between alternative lead candidates prior to development. Generally, lead candidates are selected on the basis of structural activity studies focused on one or more biological activities. It also makes good sense to optimize development candidate selection by examining other preclinical data which will be critical for development. In each of the nonclinical development disciplines (chemistry, pharmaceutics, drug metabolism, pharmacokinetics and toxicology) key pieces of data may be obtainable at modest cost and to aid in selecting the best development candidate. Basic stability and solubility studies of a drug substance, at an early stage may reveal the need to select a better salt or an alternative candidate. Characterizing the basic pharmacokinetics may highlight a best option candidate. In vitro genotoxicity testing should certainly be undertaken early. Although additional resources are required to more fully profile a limited selection of development lead candidates, the payback in improved input quality to development will more than justify the effort. Drug research. The administration of any medicament, especially a new drug, to a patient is fundamentally an experiment: particularly if it involves a modification to an established technique or a completely new procedure. Concern for the patient, careful observation, accurate recording, and a detached mind are the keys to this kind of investigation, as indeed to all forms of clinical study. Because patients are individuals reacting to a situation in their own different ways, the data obtained in groups of patients may well require statistical analysis for their evaluation and validation. One of the striking characteristics in the medical field in the 20th century has been the development of new drugs, usually by pharmaceutical companies. Until the end of the 19th century, the discovery of new drugs was largely a matter of chance. It was in that period that Paul Ehrlich, the German scientist, began to lay down the principles for modern pharmaceutical research that made possible the development of a vast array of safe and effective drugs. Such benefits, however, bring with them their own disadvantages: it is estimated that as many as 30 percent of patients in, or admitted to, hospitals suffer from the adverse effect of drugs prescribed by a physician for their treatment (iatrogenic disease). Sometimes it is extremely difficult to determine whether a drug has been responsible for some disorder. An example of the difficulty is provided by the thalidomide disaster between 1959 and 1962. Only after numerous deformed babies had been born throughout the world did it become clear that thalidomide taken by the mother as a sedative had been responsible. In hospitals where clinical research is carried out, ethical committees often consider each research project. If the committee believes that the risks are not justified, the project is rejected. After a potentially useful chemical compound has been identified in the laboratory, it is extensively tested in animals, usually for a period of months or even
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years. Few drugs make it beyond this point. If the tests are satisfactory, the decision may be made for testing the drug in humans. It is this activity that forms the basis of much clinical research. In most countries the first step is the study of its effects in a small number of health volunteers. The response, effect on metabolism, and possible toxicity are carefully monitored and have to be completely satisfactory before the drug can be passed for further studies, namely with patients who have the disorder for which the drug is to be used. Tests are administered at first to a limited number of these patients to determine effectiveness, proper dosage, and possible adverse reactions. These searching studies are scrupulously controlled under stringent conditions. Larger groups of patients are subsequently involved to gain a wider sampling of the information. Finally, a full-scale clinical trial is set up. If the regulatory authority is satisfied about the drug's quality, safety, and efficacy, it receives a license to be produced. As the drug becomes more widely used, it eventually finds its proper place in therapeutic practice, a process that may take years. An important step forward in clinical research was taken in the mid-20th century with the development of the controlled clinical trial. This sets out to compare two groups of patients, one of which has had some form of treatment that the other group has not. The testing of a new drug is a case in point: one group receives the drug, the other a product identical in appearance, but which is known to be inert--a so-called placebo. At the end of the trial, the results of which can be assessed in various ways, it can be determined whether or not the drug is effective and safe. By the same technique two treatments can be compared, for example a new drug against a more familiar one. Because individuals differ physiologically and psychologically, the allocation of patients between the two groups must be made in a random fashion; some method independent of human choice must be used so that such differences are distributed equally between the two groups. In order to reduce bias and make the trial as objective as possible the double-blind technique is sometimes used. In this procedure, neither the doctor nor the patients know which of two treatments is being given. Despite such precautions the results of such trials can be prejudiced, so that rigorous statistical analysis is required. It is obvious that many ethical, not to say legal, considerations arise, and it is essential that all patients have given their informed consent to be included. Difficulties arise when patients are unconscious, mentally confused, or otherwise unable to give their informed consent. Children present a special difficulty because not all laws agree that parents can legally commit a child to an experimental procedure. Trials, and indeed all forms of clinical research that involve patients, must often be submitted to a committee set up locally to scrutinize each proposal.

The ways how does Drug Discovery happens:

Accidental Discoveries Some drugs have been discovered by accident. (For example Warfarin (Coumadine) firstly the substance has been used as a rat poison. Rats have died of bleeding. Now, it is used as per oral anticoagulant.) Herbal medicaments and other substances that could be derived from plants. (For example digitalis) or from fungi or other natural sources. Perform structure/activity/function computations of computer-readable chemical libraries with huge number of chemical compounds. Creation of chemical structures that are likely to solve medical problems. Firstly, there is a problem that should be solved. The researches are looking for pharmaceutical solution. The aim is to improve the existing medicaments. To eliminate side effects. To change the way of drug delivery (Per oral P.O., intramuscularly I.M., intravenous I.V. or other) . For example, in order to avoid undesirable allergic reactions to insulin produced from pigs, there was genetically included human gene of insulin into one cell organisms that started to produce human insulin

Natural Substances Computer Technology - Molecular Structuring Direct Research

Changing of Known Molecular Compounds

Genetic Engineering

Molecular Biology applies key technologies such as bioinformatics, cloning, gene expression analysis and cellular high-throughput assays to discover drug
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targets in novel disease areas. A proprietary gene-array system allows simultaneous gene-expression profiling of hundreds of possible drug targets. Intracellular signal transduction pathways are investigated to develop innovative cellular assays for high-throughput screenings and for early lead compound validation. Gene-expression systems are established in collaboration with the biochemistry and structural biology to produce recombinant proteins for in vitro assays and x-ray crystallography.

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Simple biochemical assays, such as radioligand binding assays or protease assays, are crucial tools for drug discovery. The drug targets to be assayed are proteins that are purified or enriched from natural or recombinant sources. The screening assays are developed in microtiter plates, the preferred assay format for HTS. Automated HTS allows testing of tens of thousands of chemical compounds per day for their effect on the activity of a drug target. The test compounds are stored (in microtiter plates) in a Special Storage System, which is physically linked to the HTS system. This proprietary setup provides instant, random access to every compound available for screening . Immunological assays provide sensitive tools to quantify proteins or signaling molecules in man and animal models. Such assays are used to identify and quantify molecules whose levels differ in healthy and diseased individuals. Quantification of such disease markers allows one to monitor the severity of a disease, as well as drug mediated improvements of the disease state. Structural information on target proteins is used in molecular modeling to guide chemists and biologists in their daily work. For insight into the active centers of enzymes and receptors , the three-dimensional structure must be determined either via X-ray crystallography or NMR. In structure-based molecular design, the three-dimensional structures of drug targets are used to guide drug discovery. The spatial visualization of protein-small-molecule complexes greatly facilitates the creation of ideas for new molecules. Automated positioning of small fragments in the active site of a target protein additionally speeds up the improvement of Structure Activity Relationship (SAR) as well as the design of new molecules with higher affinity or good pharmacokinetic properties (ADME). In the case of unavailability of the three-dimensional structures of a target protein, homology models can be built if suitable target proteins with high sequence identity are available. Automated Chemistry.The major objective of the automated chemistry group is to deliver small focused libraries of purified compounds for lead optimization. This implies that the methodology used is restricted to solution-phase chemistry, which allows the synthesis of some hundred compounds per library. The purification of all compounds represents the bottleneck in the whole process of synthesis, purification and analytics, but there are some significant advantages to be gained. For example, purification reduces the rate of decomposition of stored compounds, and the quality and comparability of all chemical and biological data are improved. Synthesis. The equipment used for the synthesis of small focused libraries are as varying as the chemistry, which has to be handled in a parallel approach. The available tools range from a simple 96-deep-well plate in combination with a multichannel pipette to completely automated liquid-handling systems. Purification. One of the most important but time-consuming stages of every synthesis is the purification of products. To handle this bottleneck automated preparative HPLC systems are used that are able to purify up to 80 mixtures per day at a scale of 100 - 500 mg. Analytics . For the rapid analysis of compounds and reaction mixtures, automated system is used. The use of an autosampler in combination with short run-times allows the analysis of up to 720 samples per day In Pharmacology, the research focuses on discovering new drugs for new therapeutics in different medical areas. General Pharmacology. Monitoring of blood pressure, heart rate and function, as well as drug distribution are performed routinely. The most challenging task still remains to develop new experimental approaches to understand the physiological mechanisms involved in the efficacy of clinical candidates. Pre-clinical drug metabolism and pharmacokinetics is the science that describes the fate of a substance in the body. Drug discovery process includes
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medicinal chemistry already in the early phase of a project in design of new molecules which have a good chance of oral activity and reaching the site of action. Bioanalytics is the science of quantifying drug concentrations in plasma and tissue and is a fundamental support for monitoring experiments. Detailed understanding of the processes between pharmacokinetic behavior and pharmacological action is necessary to define a dosing regimen that will achieve the desired therapeutic objective. Drug metabolism and pharmacokinetics is an integral part of the pre-clinical development process. Selected drug candidates are studied in a number of in vivo and in vitro experiments to characterize the physiological and molecular processes that govern the drug's absorption, distribution, metabolism and elimination. Together with data from pharmacology and toxicology, a safety profile of the drug candidate is created in order to identify any potential risk before the drug is first given to man and to streamline the design of the early clinical trials. Metabolism is the science describing the (bio)chemical modification of a drug which is part of the removal process from the body but which might also have toxicological consequences. Subcellular and cellular systems, such as recombinant liver enzymes, liver microsomes and hepatocytes, are useful tools to study in vitro the nature and rate of metabolic processes in different animals species and man. Drug-Drug interaction. An increasingly important aspect in this field is the early evaluation of potential drug-drug interactions on the level of drug metabolizing liver enzymes, in particular cytochrome P450s. Drug discovery and development process follows an approach of combining experimental screening methods with computer modeling in order to understand the molecular basis of potential interactions and to advise medicinal chemists how to synthesize molecules that are devoid of such interactions. Protein crystallography aids in drug discovery and lead optimization by providing 3-D structures of target-lead complexes at the atomic level. By revealing the interactions between a drug or lead and its protein target, X-ray crystallography provides the means to improve lead compounds rationally using experimental data rather than predictions as a starting point. Using structural information on the 3-D shape of a reactive site helps in the design of new compounds that bind better, more specifically and more potently to targets. Target proteins are produced in large amounts and high quality, and co-crystallized with lead compounds. Crystals are tested for diffraction and datasets are collected. Structures are refined to determine the atomic structure of our target-lead complexes.

The Product Profile - A Strategic Tool for Pharmaceutical Project Development The key strategic tool which guides drug development is the Target Product Profile (TARGET PRODUCT PROFILE ). The TARGET PRODUCT PROFILE describes the specifications of the product intended to be introduced into the market . It defines the required efficacy and side effect profile of the product, how it is supplied, how it is to be used, in which patient groups, and for what purpose. It specifies the cost of goods and the time of market introduction. It is the key design template for creating the development plan. It defines the performance requirements which enables the commercial organization to assess the market impact and estimate the commercial return. Teams sometimes confuse what they hope to see in the performance of a development compound with the minimum performance that would provide for a viable commercial opportunity. It is essential to define a minimum TARGET PRODUCT PROFILE specifying the minimum performance for commercial viability. Performance can also be defined alongside the minimum TARGET PRODUCT PROFILE , and commercial forecasts can be provided for both. The specific attributes within the TARGET PRODUCT PROFILE constitute a package. If a change is made in one attribute, the whole TARGET PRODUCT PROFILE must be reviewed again to ensure that the impact of the change is fully understood. The TARGET PRODUCT PROFILE has to be set in a specific time frame for launch because any change in schedule may result in an important change in the market environment, e.g., competitor launch. The TARGET PRODUCT PROFILE is dynamically affected by internal and external factors. Internal factors can include clinical and nonclinical development findings. External factors include, for example, new competitor clinical results just released. Therefore, the TARGET PRODUCT PROFILE is generally reset in development. The TARGET PRODUCT PROFILE is a contract between R&D and the commercial organization. The development
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investment is endorsed by the commercial organization on the basis that the TARGET PRODUCT PROFILE specifications are delivered at an agreed time and cost. If the TARGET PRODUCT PROFILE "contract" is to be changed, this must be renegotiated and an endorsement for the new contract secured to ensure that further investment is justified. The TARGET PRODUCT PROFILE is the target on which the development plan is focused. The TARGET PRODUCT PROFILE is valuable only if it is specific and quantitative. The TARGET PRODUCT PROFILE enables setting development checkpoints based on the minimum performance established in the TARGET PRODUCT PROFILE . The TARGET PRODUCT PROFILE should be defined by the project team because it is a multidisciplinary task. To frame the TARGET PRODUCT PROFILE , the team must define how the drug is intended to be used in the disease state. A good start for the project team is to attempt a pictorial (disease cartoon) depiction of the patient flow in a disease. This would highlight how the disease is detected and how the disease progresses both acutely and chronically. The types of invention possible (current and expected) should be assessed including both prophylactic approaches, surgical intervention and drug intervention. The outcomes of intervention and their problems should be considered. This holistic approach takes time (generally this analysis will reveal important information gaps, a need to collect information, and a need to secure external expertise to help understand the treatment context), but its reward is a TARGET PRODUCT PROFILE of substance and not a "jump to conclusion" profile that simply adds 5 percent to an efficacy parameter of what may be an irrelevant competitive product. One benefit for a company in focusing on selected franchise disease areas is that good information bases and good understanding of specific diseases should already be in place with strong links to health care professionals who understand patient needs in these diseases.

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