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Drug discovery, development and approval process: Need for an interdisciplinary approach.

Introduction

Universities, private institutes, governmental laboratories and industrial research all play a highly significant role in developing new knowledge which provides the basis for a new product development. Pharmaceutical products are defined as drugs, devices or biologicals that have a perceived impact on health-care systems. Products result from a recognized market need through a stepwise or evolutionary process based on incremental additions to knowledge or technology. The pharmaceutical industry is an outstanding example of successful collaboration between scientists of various disciplines with a common aim to develop new and effective products. It can take over ten years from the time a drug is discovered to complete all the mandatory clinical phases and obtain regulatory approval for the new medicine. Efficient information management can save valuable years and millions of dollars associated with the drug discovery & development process, and a collaborative approach among professionals of various fields can accelerate the process of expediting and approval of new drug entities.

New Drug Discovery Process: The Search for New Drugs

The research process is complicated, time-consuming, and costly. Thousands of chemical compounds must be made and tested in an effort to find one that can achieve a desirable result. U.S.F.D.A estimates that it takes approximately eight-and-a-half years to study and test a new drug before it can be approved for the general public. This estimate includes early laboratory and animal testing, as well as later clinical trials using human subjects.

There is no standard route through which drug development takes place. New drug research starts with an understanding of how the body functions, both normally and abnormally, at its most basic levels. The questions raised by this research help determine a concept of how a drug might be used to prevent, cure, or treat a disease or medical condition. This provides the researcher with a target. Sometimes, scientists find the right compound quickly, but usually hundreds or thousands must be screened. In a series of test tube experiments called assays, compounds are added one at a time to enzymes, cell cultures, or cellular substances grown in a laboratory. The goal is to find which addition shows some effect. This process may require testing hundreds of compounds since some may not work, but will indicate ways of changing the compound’s chemical structure to improve its performance.

However, in some instances, the etiology of a disease is unknown in spite of intensive investigation. In the latter situation, the pathway to a satisfactory cure or method of prevention cannot be foreseen or forecast. Products in such cases may be developed from careful investigations, from a “revolutionary” new approach or from a serendipitous finding.1

The earliest drug discoveries were made by the presumably random sampling of higher plants. Herbal remedies have been important throughout human history, and they still are.2 Although many natural products are used in pharmaceuticals in their original chemical structures, successful efforts have been made to improve their pharmaceutics and therapeutical properties by structural modifications. Some of these modifications are relatively simple, such as the formation of the phosphate ester of hydrocortisone. This derivative increases water solubility of the drug. Other modifications may be more substantial, as in the replacement of penicillin and cephalosporin side chains with new ones that modify the antibacterial spectrum. Another approach to improving therapeutic properties is to identify that portion of a natural molecule responsible for its biological activity and synthesize new molecules that are based on it. This active portion is known as the essential structural unit. The development of local anesthetics from cocaine is a prime example of this approach.2

Computers can be used to simulate a chemical compound and design chemical structures that might work against it. Enzymes attach to the correct site on a cell’s membrane, which causes the disease. A computer can show scientists what the receptor site looks like and how one might tailor a compound to block an enzyme from attaching there. But even though computers give chemists clues as to which compounds to make, a substance must still be tested within a living being.

Another approach involves testing compounds made naturally by microscopic organisms. Candidates include fungi, viruses and molds, such as those that led to penicillin and other antibiotics. Scientists grow the microorganisms in what is known as a “fermentation broth,” with one type of organism per broth. Sometimes, 100,000 or more broths are tested to see whether any compound made by a microorganism has a desirable effect.

Organic chemists in the pharmaceutical industry synthesize hundreds of new compounds every week. In most cases, the chemist has specific reasons for synthesizing a particular compound, usually based on theoretical considerations, medicinal chemistry, biological mechanisms or a combination of all three. One of the major factors leading to a more rational approach to new drugs has been improved knowledge of bio chemical mechanism.

The search for new drugs still involves a generous measure of serendipity, but a more rational approach has developed gradually. For example, a discovery in basic biological research may lead to a hypothesis that a certain chemical mediator, a particular enzyme or perhaps specific receptor plays a key role in a pathological condition. Candidate drugs are designed with the aid of computers and synthesized partly on the basis of known mediators, hormones, metabolites or substrates. Initial screening of hundreds, or perhaps thousands, of compound may be accomplished rapidly by use of in vitro enzymatic or receptor test systems. Typically, several unique active lead compounds emerge, which are studied in a variety of biological systems, either confirming or refuting the original hypothesis. Whether or not promising new drug is born, the extensive biological characterization often reveals an unexpected action for one or more of the compounds. This unusual finding frequently leads to a new biological concept, a new series of compounds and another promising new drug.

More recently, emphasis has been placed on rational design of new pharmaceuticals. This is a difficult thing to do because detailed knowledge of the macromolecular receptor is important, and considerations of bioavailability and pharmacokinetics must be addressed. Some notable successes have resulted from the design of specific inhibitors of important enzymes. For example, the antithypertensive drug captopril was designed to inhibit peptidyl dipetidase, an enzyme that cleaves angiotensin I to the potent vasoconstrictor angiotensin II. Another example is the design of the anticancer drug, 5-fluorouracil, as an inhibitor of thymidylate synthetase. Even if the receptor is not known in detail, rational design can be applied to selective modification of the structure of a neurotransmitter or hormone to limit its spectrum of activity (decrease side effects) or convert it into an antagonist. Thus, adrenergic agents, such as terbutaline, provide relief of bronchoconstriction in asthmatics, without unduly stimulating the heart. The development of cimetidine as an antiulcer drug was based on antagonizing H2 receptors for histamine. It involved a combination of chemical intuition and careful attention to changes in pharmacologic activity induced by varying the physico-chemical properties of lead antagonists, based on the histamine structure.2

A new drug substance may be produced by chemical synthesis, recovery from a natural product, enzymatic reaction, recombinant DNA technology, fermentation, or a combination of these processes. Further purification of the drug substance may be needed before it can be used in a drug product.

Involvement of different branches of Biological Sciences in New Drug Development

Organic Chemistry involved in Synthesis & Purification

Organic chemists synthesize new drug compounds as well as isolate and characterize natural products, such as alkaloids. In each case, there is interest in the complex relationships between chemical structure and pharmacological action. The pharmacological activity of a compound is an involved function of the structure, and very small changes may pro-foundly modify the pharmacological effect. These structural modifications may involve replacing one group with another at a specific point in the molecule, shifting the same group from place to place in the parent molecule, saturating valence bonds or modifying the acidity or basicity. Total synthesis is made possible by knowledge of chemical structures and, in many instances, is important economically in reducing the cost of the drug.1 Chromatographic techniques have been widely used for the purification of newly synthesized compounds.

Instrumental Techniques for Product Characterization

The first step in product characterization is to establish the precise chemical identity of the product. It is important to determine whether the material is a compound, i.e. a single chemical entity, a mixture of closely related compounds, mixture of isomers, or merely a loose molecular complex of readily dissociable components. Such information is fundamental to a proper evaluation of the biological properties of the material.
For compounds of synthetic origin, identity is usually clearly defined in the great majority of cases by the synthetic route employed. However, it is essential not only that identity be confirmed by alternative means but that the means employed should be capable of providing rapid verification whenever this may be required at any stage of the development program. Modern spectroscopic techniques, such as as1H and 13C NMR and infrared spectroscopy are sensitive tools for such purposes. They are invaluable in the resolution of ambiguities where two or more alternative products may result from synthesis, and in the precise characterization of complex natural products.4

The interpretation of spectroscopic data obtained from compounds, however, is wholely dependent on the knowledge that the material under study is homogeneous. Powerful separative techniques, particularly chromatography in all its many forms, provide sensitive methods for both purification liquid chromatography, which make use of electronic recorders, are also eminently suitable and widely used for quantitative determination of the composition of mixtures of related compounds such as mixtures of isomers. The speed and high separative power of capillary gas chromatography make it particularly useful, if highly specialized, technique for the separation of complex mixtures during the research phase of drug development.

Where the product consists of more than one isomer, the isomers must be capable of separate identification and measurement to establish means of ensuring batch-to-batch consistency of isomer composition. For most optically active compounds, a simple polarimetric measurement of the specific optical rotation at the wavelength of the sodium D-line will suffice. Occasionally, however, where the measured rotation is small, measurements on a more sensitive instrument at other wavelengths either directly or after derivatisation may be necessary to secure adequate control of the product.

In exceptional cases, the identification of optical isomers differing in only one of several chiral centers may call for the use of optical rotatory dispersion or circular dichroism to provide a degree of sensitivity that cannot be obtained from simple measurements of optical rotation.

NMR is particularly valuable in distinguishing geometrical isomers.
It is important not only to establish the chemical identity of any new drug substance but also to identify and quantify potential impurities at an early stage in development. These impurities relate to the source materials (i.e. the substance itself if it is a natural product, or starting materials for synthesis), the manufacturing process and the stability of the product.

Relatively unsophisticated techniques such as those of thin-layer chromatography are in widespread use for the detection and quantitation of organic impurities, but in the development phase formulation of such tests necessarily rests on the formal identification of the chemical structure of each impurity, and this calls for the same heavy dependence on spectroscopic techniques as is required for the characterization of the investigational drug itself. Inorganic impurities that might interfere with the assessment of toxicological profiles are confined to residues from toxic elements arising from catalysts and reagents used in synthesis.

Trace amounts of toxic metal catalysts, such as nickel and platinum, are readily determined directly at parts per million levels by atomic absorption spectrophotometry. Traces of toxic non-metals such as boron, derived from the use of borohydride reagents, are not amenable to direct measurement in this way, and require preliminary treatment to destroy the organic matter before determination by some suitable spectroscopic means.4

Statistical approaches in Drug Discovery

Once a new pharmaceutical lead compound has been discovered, extensive and costly efforts usually are made to prepare a series of analogues in the hope that even better activity will be found. In an effort to improve the efficiency of analogue development, a variety of statistical methods have been introduced. They range from the Hansch approach, in which analysis of variance is used to derive an equation expressing the quantitative relationships between functional group changes and biologic activity, to pattern recognition and factor analysis methods. Nonquantitative methods, such as the Topliss approach, also are popular.2

Computer –Aided Drug Designs

Computer-aided design, including quantitative energy calculations and graphical methods, has been rapidly introduced in the pharmaceutical industry.2 It is too early to evaluate its effect on drug discovery.
Techniques such as computer-assisted drug design are employed to elucidate the three-dimensional structure of a particular biological target and to design a molecule that interacts specifically with that target. Drug researchers also have access to libraries containing large numbers of molecules, which are screened against multiple in vitro biological targets using high-throughput computerized processes looking for a significant receptor-ligand reaction.5

A high-tech approach is to use computers to simulate an enzyme or other drug target and to design chemical structures that might work against it. A computer can show scientists what the receptor site looks like and how one might tailor a compound to block an enzyme from attaching there. However, while computers give chemists clues to which compounds to make, they don’t give any final answers. Compounds made based on a computer simulation still have to be put into a biological system to see whether they work. [17]

Compound libraries have an important role in the drug discovery process. Various computational methods are available as decision support tools for medicinal chemists involved in compound library synthesis programs. These methods can be used to assemble a flexible library design scheme consisting of a structure-based library design followed by property-biased library refinement and final selection according to structure-activity-relationship considerations.

Compound libraries have an important role in the hit identification, hit-to-lead and earlier lead optimization phases of the drug discovery process. Considering the large number of possible structures accessible via modern automated synthesis and purification technologies, the selection of compounds to be synthesized for a program is crucial. In addition to requirements such as building block availability, synthesis economics and intellectual property considerations, the selected compounds need to show appropriate druglikeness, solubility and bioavailability. Various computational models have been developed to enable the classification of virtual compounds according to these requirements before synthesis. [14]

Biotechnology revolutionized the Drug Discovery Process

More recent advances in biotechnology have provided drug researchers with new biological targets such as cell membrane channels, as well as active complex biological proteins such as hormones. An example of this is the discovery that erythropoietin is a key regulator of red blood cell production. The identification of the gene encoding its amino acid sequence, and the subsequent insertion of this human gene into a non-human mammalian cell, allowed erythropoietin to be mass-produced for the treatment of anaemia in patients with renal failure.5

Role of Pharmacology in Drug Development and Research

Once a new compound shows potential for clinical development, extensive studies on its pharmacology and toxicology are undertaken. Dosage forms are optimized to provide appropriate solubility and bioavailability, and the pharmacokinetics are determined.

Pharmacological research plays two important roles in its contribution to new drug development. The pharmacologist designs and operates model systems for detecting and evaluating the activity of compounds for control of diseases such as those of the CNS, the GI tract, the cardio-vascular bed and the endocrine organs. Following the discovery of a new drug, the dosage, toxicity, mode of action, metabolism and fate of that drug in the body must be determined with the help of pharmacological designs. Intact animals, whole organs, isolated tissue or purified enzyme and receptor systems may be used in modern pharmacological experiments. The classic pharmacological methods are undergoing rapid changes to more automated and more bio-chemically oriented methods. The elevation or depression of such important metabolic substances such as acetylcholine, histamine and catecholamines is used as a guide for drug studies. The pharmacologist, on the basis of experimental work on a variety of species of laboratory animals, must predict an effective human dose, which hopefully will produce minimal side effects.1

The profiling of new drug candidates for general pharmacological properties requires a systematic examination of the functional effects of agents in a variety of in vitro and in vivo assays. Broad functional profiling provides valuable information to the preclinical pharmacologist with respect to the selectivity of new agents and may serve to identify new and useful therapeutic indications of investigational drugs. At the same time, knowledge of the effects on these physiological systems can also play an important role in safety assessment. [11]

Toxicological examination to establish safety profile

Pharmacological activity of a new agent that is both unintended and undesirable & can be referred to as “pharmacological toxicity.” In general, the spectrum of toxicities disclosed in pharmacological effects which are not life threatening and are readily reversible. On rare occasions, unanticipated and life-threatening pharmacological effects (e.g., convulsions, arrhythmias) are detected which can seriously detract from the usefulness of a new agent and may therefore deter the drug development process. It should also be noted that repeated exposure to acute pharmacological effects may lead to less obvious chronic findings, such as target organ effects or tumour formation in animals. The interpretation of pharmacological toxicity with respect to the safety profile of a new drug candidate is dependent not only upon the types of reactions observed and the doses at which they occur but also upon the nature of the effects elicited as to whether they represent expected extensions of the primary mechanism of action of a compound or constitute reactions unrelated to the primary pharmacological activity. The ultimate impact of pharmacological toxicity, as with all adverse findings in preclinical assessment, is dependent upon the projected therapeutic margin of safety as well as the risk-to-benefit ratio for new drug entities. In addition to supplement the existing armamentarium of preclinical safety studies, pharmacological profiling can also play an important role in
(1) The selection of new drug candidates with reduced toxic potential.
(2) The design and conduct of preclinical toxicology studies.
(3) The investigation of preclinical and clinical safety issues.
(4) The identification of potential functional effects to be monitored most closely in clinical trials of new drug entities. [11]

In order to be certain that a new drug is safe, detailed studies are made of the effects of varying doses and prolonged administration of that drug. The pharmacologist provides acute toxicity data. The toxicologist then must refine the acute toxicity measurement in laboratory animals and begin subacute and chronic studies. The latter are conducted in a variety of species, at several dosage levels of the drug and over periods of time ranging up to 30 months. During the test period, animals are observed carefully for all adverse symptoms. At the end of this period, and occasionally during its progress, animals are sacrificed, and their vital tissues, such as liver, heart, kidney, intestine, brain, etc, are removed and studied grossly and microscopically by a pathologist. In addition to gross and microscopic pathology, biochemical and physiological responses are measured as an indication of liver function, kidney function, endocrine function, etc. 1

Animal tests are designed to determine:
1. The relative toxicity of the new chemical. These tests would include acute toxicity and LD50 tests to determine toxic dosage, as well as median and long-term toxicity tests for harmful effects on the animal and on various specific organs, such as the eyes, liver, and brain.
2. The probable or possible effect of the chemical in human drug use, including areas of interest for study, dosage, and probable side effects.
Animal tests or “preclinical investigations,” as they are also termed, are designed with particular regard to possible future testing of the drug in humans, or “clinical investigation.”3

Preclinical Pharmacokinetics

A compound with favorable pharmacokinetics is more likely to be efficacious and safe. Therefore, the preclinical pharmacokinetic evaluation should be comprehensive enough to ensure that compounds do not fail in the clinic. Preclinical ADME screening facilities early elimination of weak candidates and directs the entire focus of the drug development program towards fewer potential lead candidates.

Candidates with the desired in-vivo pharmacokinetic profile may be further profiled in-vitro, using assays such as metabolic stability, reaction phenotyping, CYP-450 inhibition and induction, plasma protein binding etc. in human microsomes, human recombinant CYP-450 enzymes and human plasma. This also provides an early indication of whether the compound which worked in animals would works in humans as well. Extensive metabolism is generally considered a liability as it limits the systemic exposure and shortens the half-life compound. Several strategies such as reduction of lipophilicity, modification and/or blocking of metabolically soft spots and use of enzyme inhibitors have been developed to combat metabolism. Inspite of several concerns the fact that active metabolize of several marketed drugs have been developed as drugs with better efficacy, safety and pharmacokinetics profile cannot be denied. Therefore instead of considering metabolic instability a liability it can be exploited as a tool for discovering better drugs. It is equally important to identify the metabolic pathways of the drug candidates by conducting in-vitro CYP-450 reactions phenotyping assays. It is known that only unbound drug is pharmacologically active and therefore the assessment of bound fraction by the estimation of plasma protein binding of a compound is another important parameters to be explored in-vitro. Toxicity study is the foundation of an INDA (Investigational New Drug Application) and therefore the final selection of a compound can be performed only after proper toxicological evaluation in animal models. Toxicokinetics forms an integral part of toxicity study and is used to assess the exposure of candidates in toxicity models and correlate the drug levels in blood and various tissues with the toxicological finding. [12]

Pharmacokinetics (ADME Studies)

An important part of Pharmacology is the study of drug absorption, distribution, metabolism and excretion i.e.pharmacokinetics.The metabolism of drugs is an important topic in drug development and considerable effort is spent on detailed analysis of the bioconversions that a new drug undergoes. Modern analytical methods, such as mass spectrometry, permit the identification of minute amounts of metabolites. The usual effect of metabolism is to convert drugs into compounds that are less active, less toxic, and more readily excreted. However, there are examples in which metabolism sustains or increases the activity.2

Pharmacogenomics Revolution: A new tool for drug discovery

Pharmacogenomics has recently become an integral part of the drug development process. The pharmacogenomics revolution comes at a time when pharmaceutical companies are faced with mounting pressures to lower the cost of drugs despite the continued rise in research and development spending needed to bring new drugs to market.
Pharmaceutical companies want to avoid late stage failures or drugs labeled for restricted use following approval. More than twenty years of pharmacogenetic studies have established many of the genetic traits responsible for interindividual differences in the way patients metabolise drugs. The genetic polymorphisms found in the major drug metabolizing enzymes (DMEs) and their associated phenotypes are well established. These monogenetic traits have a predictable influence on the pharmacokinetic and pharmacological effects of a large number of commonly prescribed drugs. This knowledge has been used to develop affordable, robust, clinical genotyping methods that can be used by pharmaceutical companies to screen patients prior to drug therapy. Prospective screening of Phase I volunteers for DME polymorphisms is done routinely at a number of pharmaceutical companies. As the pharmacogenomic initiatives at these companies evolve, more and more patients enrolled in Phase II-III clinical trials are genotyped to correlate efficacy with genetic markers that predict pharmacodynamic effects. There are a number of pharmacogenemic markers that provide useful diagnostic tools to prospectively evaluate treatment regimens, including the genetics of the host, cancerous tumours or infectious agents. The incorporation of pharmacogenomics into clinical drug development offers the opportunity for pharmaceutical companies to evaluate drugs with a better understanding of the effect that specific genetic variants will have on drug response. Prospective testing can ensure the inclusion of important phenotypic subgroups, thus impacting the efficiency of drug development. [13]

New Strategies for Effective Drug Candidate Selection

Strategies to improve the quality of decisions in drug development are: the use and integration of new tools and technologies such as pharmacogenemics to improve our knowledge about the origin of the disease and to identity new therapeutic strategies; modeling and simulation of preclinical and clinical trials to bridge the gap between the early stages of the development of a new drug and its potential effect in humans; more sophisticated clinical pharmacokinetics to answer the question if the drug is present at the disease site for a sufficient time and to provide information on concentration-effect-relationships; selecting and evaluating surrogates/biomarkers for safety and efficacy; involvement of the target population as soon as possible; using information technologies to make better use of existing data. The more thorough and profound studies have been carried out during this exploratory stage of development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patient and increasing the success-rate of the project in the later confirmatory effectiveness trial. [15]

Transgenic Systems for Innovative Drug Discovery and Development

Those pharmaceutical companies whose goal is to come out with novel innovative drugs are faced with the challenge that only a fraction of the compounds tested in clinical trials eventually become a registered drug. This problem of attrition is compounded by the fact that the clinical trial or development stage is by far the most costly phase of bringing a new drug to market, consuming around 80 per cent of the total spend. Transgenic technology represents an attractive approach to reduce the attrition rate of compounds entering clinical trials by increasing the quality of the target and compound combinations making the transition from discovery into development. Transgenic technology can impact at many points in the discovery process, including target identification and target validation, and provides models designed to alert researchers early to potential problems with drug metabolism and toxicity, as well as providing better models for human diseases.

Transgenic animals can also be used to generate better disease models. Predictive animal models to test new compounds and targets will significantly speed up the drug discovery process and, more importantly, increase the quality of the compounds taken further in the research and development process. [19]

Role of Regulatory Agency in Drug Development & Approval Process

USFDA7

The United States Food and Drug Administration (best known as the FDA) is an agency within the U.S. Public Health Service, which is a part of the Department of Health and Human Services. Approval of new drugs is one of the main functions of FDA. The FDA requires that drugs--both prescription and over-the-counter--be proven safe and effective. In deciding whether to approve new drugs, FDA does not itself do research, but rather examines the results of studies done by the manufacturer. The FDA must determine that the new drug produces the benefits it's supposed to without causing side effects that would outweigh those benefits. The enforcement of the Federal Food, Drug and cosmetic Act in the United States is the responsibility of the Food and Drug Administration. FDA maintains a headquarters building in the District of Columbia, but its main headquarters activities are at 5600 Fishers Lane, Rockville, MD 20852.3

Preclinical stage

Pre-clinical development is a stage in the development of a new drug that begins before clinical trials (testing in humans) can begin, during which important safety and pharmacology data is collected.

The main goals of pre-clinical studies are to determine a drug’s pharmacodynamics, pharmacokinetics, ADME, and toxicity through animal testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans. Pre-clinical studies must adhere to Good Laboratory Practices (GLP) in ICH Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in the United States. [6]

During preclinical drug development, the drug development team/company/ sponsor evaluates the drug's toxic and pharmacologic effects through in vitro and in vivo laboratory animal testing. Genotoxicity screening is performed, as well as investigations on drug absorption and metabolism, the toxicity of the drug's metabolites, and the speed with which the drug and its metabolites are excreted from the body.
At the preclinical stage, the FDA will generally ask, at a minimum that sponsors:
(1) Develop a pharmacological profile of the drug;
(2) Determine the acute toxicity of the drug in at least two species of animals, and
(3) Conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on the proposed duration of use of the substance in the proposed clinical studies.
Preclinical tests, therefore, are designed with the following considerations:
(1) The expected duration of administration of the drug to human beings.
(2) The age groups and physical status of the intended human subjects with special consideration for infants, pregnant women, or the aged.
(3) The expected effects of the drug in humans.

Prior to the institution of clinical testing in humans, a Notice of Claimed Investigational Exemption for a New Drug must be filed with the Food and Drug Administration by the sponsor. This form is also referred to as an IND, or investigational new drug application.
The IND must feature the following information:
1. The best available descriptive name of the drug including to the extent known, the chemical name and structure of any new drug substance (a new chemical entity).
2. A complete list of components of the drug.
3. The quantitative composition of the drug.
4. The name and address of the supplier of any new drug substance if other than the sponsor (the person or firm submitting the IND) and a description of the preparation (chemical synthesis or other method of manufacture) of any new drug substance.
5. A statement of the methods, facilities, and controls used for the manufacture, processing, and packaging of the new drug.
6. A statement covering all information available to the sponsor derived from preclinical investigations and any clinical studies and experience with the drug.
7. Copies of labels for the drugs and informational material that will be supplied to investigators. This material must describe the preclinical studies with the drug and describe all relevant hazards, side effects, contraindications, and other information pertinent to use of the drug by the investigator.
8. A description of the scientific training and experience considered appropriate by the sponsor to qualify an investigator as a suitable expert to investigate the drug.
9. The names and curriculum vitae of all investigators.
10. An outline of the planned investigations of the drug in humans.

Investigational New Drugs

The factor of “newness” that requires the greatest amount of work is the presence of a new chemical entity. After its synthesis, a new chemical entity is normally subjected to a “screening” process, which involves initial testing of the drug in a small number of animals of different species (usually three) plus microbiologic tests to detect any beneficial effects of the chemical. In addition to the usual LD50 and acute and chronic toxicity studies, tests involving teratogenicity, mutagenicity, and carcinogenicity are often conducted.
If the initial screening proves the new chemical to be worthy of further investigation, more extensive animal tests for its suspected properties are conducted. If the properties are similar to those of a drug already on the, market, the two compounds may be tested against each other to determine their relative merits.

Animal pharmacology and toxicology data are obtained to determine the safety and efficacy of the drug. An investigational new drug (IND) application for human testing is submitted to the Food and Drug Administration (FDA). Specific information on the planned studies for all phases of the investigation must be submitted to the Food and Drug Administration in the IND before work is begun.

Clinical Investigational Phase

Some common terminologies used in this phase of development are[20]:
1. Clinical Investigation: means any experiment in which a drug is administered or dispensed to one or more human subjects.
2. Investigator: means an individual under whose immediate direction the drug is administered or dispensed to a subject.
3. Sponsor: means a person who takes responsibility for and initiates a clinical investigation.
4. Sponsor-Investigator: means an individual who both initiates and conducts an investigation and under whose immediate direction the investigational drug is administered or dispensed. The term does not include any person other than an individual.
These investigations are divided into three phases. The first two phases are termed “clinical pharmacology” studies.

Phase 1 is the initial introduction of the drug into humans for the purpose of determining toxicity, metabolism, absorption, elimination, safe dosage range, and other pharmacological action. The Phase I studies are carried out most often in healthy male volunteers in order to study the safety and pharmacokinetics of a new drug.
The first trial of a drug in man is done with great caution and on a very limited basis. When dosing limits have been established and are found acceptable, the drug is made available to a larger number of practicing specialists for the Phase 2.

Phase 2 covers the initial trials for specific therapeutic effect and is conducted on a limited number of patients. Phase2 study is principally concerned with the determination of safety and efficacy in patients having the primary disease for which the drug is to be tested. The minimum effective dose, the maximum tolerated dose and the dose response (intermediate doses), also must be determined

Phase 1 and 2 studies are limited in nature and should be very closely controlled by the sponsor.

Phase 3 is termed the “clinical trial” of the new drug and is intended to assess its safety and effectiveness in one or more particular indications. If, after Phase 2, the drug still looks promising, it is distributed more widely to selected practicing physicians in the Phase 3 study. The purpose at this stage is to secure data from a large number of patients on efficacy and incidence of side effects.1Phase 3 studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained in Phase 2, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug. This phase is also known as the therapeutic confirmatory phase. It consists of large-scale studies designed to find the efficacy and safety of the new drug relative to already accepted drugs. Phase 3 studies also provide an adequate basis for extrapolating the results to the general population and transmitting that information in the physician labeling. Phase 3 studies compare specific doses of the investigational drug with an alternative therapy, usually the current therapeutic standard for the indication in question. The new drug may also be tested against a placebo at this stage. It is common for these studies to enroll more than 1,000 patients.9 Phase 3 studies usually include several hundred to several thousand people. Thousands of subjects are involved at this point, including people from different populations, such as those with concomitant illnesses who receive other drugs, so that we can learn about drug interactions. These studies are usually controlled with a placebo or with drugs that are universally accepted for treating that specific condition. Phase 3 studies allow us to build a good profile of how the drug behaves when it is used in large populations. The drug is eventually submitted to health authorities and if it is approved, the next phase, Phase 4, begins.10

Phase 4. Even after the regulatory authorities have granted marketing authorization for the new drug, systematic studies are still carried out to provide information on the long-term safety and efficacy of the product. These post-marketing studies involve several thousand patients.9There is no pre-determined end-point for Phase 4. Research on the new drug stops only when we no longer seek new information about it. Basically, Phase 4 consists of studies that differentiate the investigational drug from other drugs in its class; studies that compare the drug’s efficacy and demonstrate the drug’s benefits in terms of pharmacoeconomics. Phase 4 can be a never-ending process for the collection of post- marketing data.

Post Approval Studies

Post approval studies are experimental studies and surveillance activities undertaken after a drug is approved for marketing. Clinical trials conducted after a drug is marketed (referred to as phase IV studies in the United States) are an important source of information on as yet undetected adverse outcomes, Especially in populations that may not have been involved the premarketing trials (e.g., children, the elderly, pregnant women) and the drug’s long-term morbidity and mortality profile. Regulatory authorities can require companies to conduct Phase IV studies as a condition of market approval. Companies often conduct post-marketing studies in the absence of a regulatory mandate. [16]
Post-approval studies test a marketed drug in new age groups or patient types. Some studies focus on previously unknown side effects or related risk factors. As with all stages of drug development testing, the purpose is to ensure the safety and effectiveness of marketed drugs. [21]

An important part of any clinical testing under an IND is its supervision by Institutional Review Boards (IRBs). To assure, so far as possible, that all humans subjected to the investigational testing are protected from unnecessary risk, the FDA requires that the sponsor of any such test have it reviewed and approved by a board of nongovernmental employees. This board is directed to assure the protection of the rights and welfare of any humans subject to such a test.[3, 20]

Institutional Review Boards (IRBs) are used to ensure the rights and welfare of people participating in clinical trials both before and during their trial participation. IRBs make sure that participants are fully informed and have given their written consent before studies ever begin. IRBs are monitored by the FDA to protect and ensure the safety of participants in medical research.[20]

An IRB must be composed of no less than five experts and lay people with varying backgrounds to ensure a complete and adequate review of activities commonly conducted by research institutions. In addition to possessing the professional competence needed to review specific activities, an IRB must be able to ascertain the acceptability of applications and proposals in terms of institutional commitments and regulations, applicable law, standards of professional conduct and practice, and community attitudes. Therefore, IRBs must be composed of people whose concerns are in relevant areas.7

Registration Filing

Once Phase III has been concluded, the manufacturer can submit an application for approval to the regulatory authorities. Before the new drug can be marketed, a New Drug Application (NDA) must be filed with the FDA and approval obtained. The NDA contains most of the information included in the IND, which has been revised and updated, as well as the results of the clinical studies proving safety and efficacy. It usually takes at least six months to process. The new medicine cannot be brought onto the market until marketing authorization has been granted.
New drug application (NDA)
A drug may be considered “new” because of its composition, its use, its dosage, or its dosage form. It can readily be understood that a drug that contains as its active ingredient a new chemical entity would be considered to be a new drug; however, a drug may be new owing to the composition of its inactive ingredients, the proportion of ingredients, active or inactive, or the combination of ingredients, active or inactive. A drug’s recommended new use or change in recommended dosage, dosage form, or route of administration also can cause it to be considered a new drug. The basis for a drug’s “newness” determines what steps must be taken to obtain an approved new drug application.3

“USFDA describes NDA as: the new drug application (NDA) is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale in the United States. To obtain this authorization, a drug manufacturer submits in an NDA nonclinical (animal) and clinical (human) test data and analyses, drug information, and descriptions of manufacturing procedures.”

An NDA must provide sufficient information, data, and analyses to permit FDA reviewers to reach several key decisions, including:
• Whether the drug is safe and effective for its proposed use(s), and whether the benefits of the drug outweigh its risks.
• Whether the drug’s proposed labeling is appropriate, and, if not, what the drug’s labeling should contain.
• Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.

The sponsor, upon completion of a sufficient amount of clinical work to demonstrate the safety and effectiveness of the new drug for the use or uses for which it is intended, may then submit a new drug application (NDA) to the FDA. This application must include:
(1) Detailed reports of the preclinical (animal) studies;
(2) Reports of all clinical (human) studies;
(3) Information on the composition and manufacture of the drug and on the controls and facilities used in its manufacture
(4) Samples of the drug and its labeling.

Summaries of the data must be provided, and the full case reports of each person who received the drug are needed only in limited circumstances. Material previously submitted to the FDA in the IND or in periodic reports must be included by reference in the NDA.The information contained therein must be sufficient to justify the claims made in the proposed labeling for the drug as to effectiveness, dosage, and safety, and foreign data can be used. The exact wording that may be used in the labeling of a drug usually is decided by an exchange between the sponsor and the FDA.Once a new drug application is approved, any significant change in the manufacturing, control, packaging, or other physical properties of the drug, or any change in its labeling that may have an effect on safety and effectiveness relative to either the drug itself or the manner in which it is used must be covered by a supplemental new drug application. The requirements of an NDA for prescription and over-the-counter drugs are similar. It is extremely rare, however, that any new chemical entity would be approved by the FDA for over-the-counter sale for reasons of lack of sufficient data to support the safety in use of a totally “new” drug. Since the basic test is the ability to provide on the label adequate direction for use, most applications specifically for over-the-counter drugs would tend to be supplemental applications, mainly on the particular showing that the drug might be safely used without direct medical supervision.

Abbreviated New Drug Application

The ANDA represents a form of new drug application in which certain information is not needed because previously acquired data has been filed with the FDA. FDA’s intent is, in the ANDA procedure, to minimize duplication of effort in preparing applications for drugs about which some of the needed information is already available, while assuring that the new product will be equivalent to established marketed products. Normally, the information allowed to be omitted relates to preclinical and clinical studies pertaining to the safety and effectiveness of the active ingredient(s), which have been on the market for many years. Since many of the items are established generic drugs, it is unnecessary to reverify their efficacy. It may simply be necessary to have assurance that the manufacturing procedures, specifications, and labeling are adequate. In other cases it will be necessary to demonstrate the bioequivalence of the new product relative to currently available standard products or to the original NDA approved product. Unlike the NDA-which requires submission of well-controlled clinical studies to demonstrate effectiveness, data to show safety, and detailed description of the manufacturing and packaging of a drug as well as stability data-the ANDA only requires the following: a description of the components and composition of the dosage form to be marketed; brief statements that identify the place where the drug is to be manufactured; the name of the supplier of the active ingredients; assurance that the drug will comply with appropriate specifications; an outline of the methods and facilities used in the manufacturer and packing; certification that the drug will be manufactured in compliance with current GMP as defined by regulation; labeling; and- when so specified-data adequate to assure the drug’s biological availability.

In selecting drugs suitable for the ANDA, one considers the characteristics of the drug, method of use, method of manufacture and packaging, stability, extent of use, safety and potency, and past history. Difficulties or known problems in any of these areas usually prevent the drug from being included in the abbreviated new-drug procedure category. For example, the limited information included in an abbreviated application would not be sufficient to permit the FDA to conclude that a high-potency drug which requires extremely careful handling during manufacturers is suitable for marketing. The same is true of a drug where the container plays a critical part in its administration, for instance, a metered aerosol. The purpose of the ANDA procedure is thus to eliminate unnecessary and costly animal and human experimentation, to assist the manufacturers in attempting to market duplication drug products, and to make all drug substances not covered by patents readily available to the consumer in a competitive market.8

Generic Drugs

In USA an amendment to the Food, Drug and Cosmetic Act was passed in 1984 and was entitled “Drug Price Competition and Patent Term Restoration Act of 1984”. This revised the Abbreviated New Drug Application (ANDA) procedure and allowed for the approval of post-1982 drugs once the patent of the innovator had expired. This has also become known as the Waxman-Hatch Amendment to the act. The result of this amendment has allowed many generic products to be placed in the market with a minimum amount of clinical effort, but with the establishment of the physical and chemical equivalency of the, marketed materials. These are generic equivalent materials of previously patented drug products. The amount of bioequivalency study necessary will vary with the particular drug product. This act was also tied into the patent restoration act, which allows an extended time to be given to innovator firms for new drug substances. Although this amendment allows numerous individuals to get into generic manufacturing of drugs, the act is specific about the requirements, and only those who can document the ANDA adequately will be permitted to distribute the drugs in the marketplace.8 After the patent expiration of a brand drug product, a generic drug product may be developed. A generic product contains the same amount of the drug in the same type of dosage form (e.g., tablets, liquids, injectables). A generic drug product must be bioequivalent (i.e., have the same rate and extent of drug absorption) to the brand drug product.22 Therefore, a generic drug product is expected to give the same clinical response. These studies are normally performed with healthy human volunteers. The generic drug product may differ from the brand product in physical appearance (i.e., size, color, shape) or in the amount and type of excipients. Before a drug product is marketed, the manufacturer must submit an abbreviated new drug application (ANDA) to the FDA for approval. All generic drugs must be reviewed and approved by FDA.23

A brief summary of the Drug Approval Process

1. Preclinical (animal) testing.
2. An investigational new drug application (IND) outlines what the sponsor of a new drug proposes for human testing in clinical trials.
3. Phase 1 studies (typically involve 20 to 80 people).
4. Phase 2 studies (typically involve a few dozen to about 300 people).
5. Phase 3 studies (typically involve several hundred to about 3,000 people).
6. The pre-NDA period, just before a new drug application (NDA) is submitted. A common time for the FDA and drug sponsors to meet.
7. Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval.
8. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed.
9. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor’s research on the drug’s safety and effectiveness.
10. The FDA reviews information that goes on a drug’s professional labeling (information on how to use the drug).
11. The FDA inspects the facilities where the drug will be manufactured as part of the approval process.
12. FDA reviewers will approve the application or find it either “approval” or “not approval”. [17]

Review of NDAs at FDA

Once a new drug application is filed, an FDA review team comprising of medical doctors, chemists, statisticians, microbiologists, phrmacologists, and other experts evaluate whether the studies the sponsor submitted show that the drug is safe and effective for its proposed use. No drug is absolutely safe; all drugs have side effects. “Safe” in this sense means that the benefits of the drug appear to outweigh the risks.
The review team analyzes study results and looks for possible issues with the application, such as weakness of the study design or analyses. Reviewers determine whether they agree with the sponsor’s results and conclusions, or whether they need any additional information to make a decision. [17]
While scrutinizing the New Drug Applications the FDA officials specifically give considerations to the following factors:
1. Validity of pivotal/key studies.
2. Consistency of the studies that is replicability.
3. Generalization of the studies across various population groups geographical reasons etc.
4. Establishment of safe dosage and dose regimens along with supporting documents.
5. Clinical significant of the efficacy results.
6. Safety profiles with respect to the seriousness of the condition /disease being treated.
7. Over all usefulness of drug to the patients (risk/benefit ratio). [18]

The sooner the drug can reach its intended market, the sooner can its therapeutic promise be realized in the prevention and treatment of disease.24

Hurdles in the Road to Approval

A designation of approval means that the drug can probably be approved, provided that some issues are resolved first. This might involve the sponsor and the FDA coming to a final agreement on what should go on the drug’s labeling, for example. It could also involve more difficult issues, such as the adequacy of information on how people respond to various dosages of the drug.

A designation of “not approval” describes deficiencies significant enough that it is not clear that approval can be obtained in the future, at least not without substantial additional data.

Common problems include unexpected safety issues that crop up or failure to demonstrate a drug’s effectiveness. A sponsor may need to conduct additional studies--perhaps studies of more people, different types of people, or for a longer period of time.
Manufacturing issues are also among the reasons that approval may b delayed or denied.

Drugs must be manufactured in accordance with standards called good manufacturing practices, and the FDA inspects manufacturing facilities before a dug can be approved. If a facility isn’t ready for inspection, approval can be delayed. Any manufacturing deficiencies found would need to be corrected before approval.
The FDA outlines the justification for its decision in an action letter to the drug sponsor. [17]

Conclusion

In addition to specialists in biology and therapeutic chemistry, the discovery of a new drug involves the collaboration of pharmaceutical R&D specialists and clinical research teams, composed of doctors, pharmacists, nurses, chemists and other health specialists. For the rational design of new pharmaceuticals, chemical synthesis involving modern instrumental techniques for purification and characterization are used while statistical methods are employed to improve the efficiency of analogue development process. Computer –aided drug designs are used to elucidate the three-dimensional structure of a particular biological target and to design a molecule that interacts specifically with the target. Computer libraries have an important role in drug discovery process.
To ascertain the safety of a new drug pharmacokinetic and toxicological examinations are carried out. The detailed analysis of bioconversions that a new drug candidate undergoes is performed and the final selection can be performed only after proper toxicological evaluation in animal models. Transgenic technology facilitates drug discovery into development by providing models designed to alert researchers early to potential problems with drug metabolism and activity as well as providing better models for human diseases.
At various stages of drug development, regulatory agencies like USFDA are involved and approve a new pharmaceutical for sale only after a drug manufacturer follows a set procedure of filing of drug applications and submits all the relevant data to the regulatory body. It can take over ten years from the time a drug is discovered to complete all the mandatory clinical phases and obtain regulatory approval for the new medicine.
A collaborative and inter-disciplinary approach to this process can speed up this process and cut down the huge volume of expenditure involved.

Authors

1). SAURABH DAHIYA (Main Corresponding Author)
Research Scholar, Faculty of Pharmacy, Jamia Hamdard University, New Delhi- 110062, India.
Email: saurabhdahiya@gmail.com

2).Prof.Roop K. Khar, Professor of Pharmaceutics,
Faculty of Pharmacy, Jamia Hamdard University, New Delhi- 110062, India.

3).Dr.Anil K. Mishra, Scientist F, Institute of Nuclear Medicine & Allied Sciences, Timar Pur, Delhi-110054, India.

4).Dr. Aruna Chhikkara, Reader (Chemistry)
Dayal Singh College(University of Delhi)
Lodhi Road, New Delhi-110001, India

The corresponding authors mailing address:

SAURABH DAHIYA (M.Pharm.)
A-132, Majlis Park,
Delhi-110033.
India

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First Published June 2007

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