Clinical Research Past, Present and Future 1 WHY IS CLINICAL RESEARCH IMPORT ANT T O THE SOCIETY Clinical Research involves methodical and systematic study of drugs, devices, biologicals, vaccines used in the diagnosis, prevention or treatment of disease. During the process of clinical research, the physician is treating an individual with an aim to develop an intervention for the patient of tomorrow. Therefore, the broad aims of clinical research are: i . Improve patient outcomes i i . Improve quality of care iii. Enhance efficiency of system i v . Inform health policy. Clinical research is central to translating the promise of biomedical research into improved clinical practicethe neck of scientific bottle through which all advances in biomedicine must flow before they can benefit the public. THE P AST OF CLINICAL RESEARCH Clinical research has come a long way from the times of The Old Testament bearing reference to a trial of water and bread versus bread and wine. Clinical trials are also discussed in ancient Greek, Roman and, Arab Woks, but it was not until the 12th and 13th centuries A.D. that any ethical codes regarding human experimentation were written down. Moses Maimonides (1135-1204), the Jewish Philosopher, Physician and Rabbi of Cairo, expounded that physicians should seek to help individual patients, and should not use them to further their own knowledge.

20 Basic Principles of Clinical Research and Methodology INTRODUCTION The drug development is a scientific endeavor and is highly regulated due to public health concern. The discovery of a new molecule and its development in to a new drug is complex, expensive and time-consuming process. The cost of new drug development is also critically dependent on the proportion of new molecules that fail in clinical testing. Coupled with the extremely high failure rate hundreds and thousands of chemical compounds are made and tested in an effort to find one that can achieve desirable results. Only one in about 10000 compounds can ever reach market. In general, it takes about 8 to 10 years and about $ 900 million to bring the drug to the market. This estimate includes early laboratory and animal testing, as well as later clinical trials using human subjects. This may vary depending on the type of molecule, targeted disease etc. In view of the high cost of the drug development process, the industry has to be very careful and has to look in to the factors that have significant impact on the process and should form basis for allocation of resources. The decision to develop a new drug by a pharmaceutical company depends on the various factors and one of the key factors is to review and find out the unmet medical needs in the specific therapeutic area in which the company is interested due to strategic reasons. Sometimes, scientists like to pursue an interesting or promising line of research. In some cases there may be industry- university or industry government scientific institutes collaboration that may help to develop a new molecule. New and interesting findings may also come from University, Institutes and the lead may be taken over by Pharmaceutical companies for further research. There are a number of research companies, which are comparatively small in their size, but they are contributing a lot in the new drug research. New molecules are being in-licensed by big pharmaceutical Companies to develop them further as they have technical and financial resources.

39 Designing Clinical Trials INTRODUCTION Clinical trial, which is properly planned and executed, is a very powerful experimental technique for assessing the effectiveness of intervention. Careful planning is required before the collection of data begins for conducting successful clinical research projects. Some investigators know the planning process; others must learn how to plan clinical research by observing their mentors and reading books on research designs. It is important that the investigator should recognize the difficulty encountered in studies with human subjects and planning any clinical trial and attempt to estimate the magnitude of participants failure to protocol compliance. Ideal clinical trial is one, which is randomized and double blind. In most of the clinical trials, drawbacks are unavoidable, but these deficiencies can be prevented by adhering to fundamental features of clinical trial design, conduct and proper analysis. HIST O R Y OF CLINICAL TRIAL The earliest evidence of the clinical trial dates back to 20th May 1747, where in his classical study James Lind evaluated six treatments in 12 patients of scurvy. One of the two patients who were given lemons and oranges quickly recovered from signs and symptoms of scurvy and were fit for their duty after 6 days. Earliest experiments involved arbitrary, non-systematic schemes for patients, assigned to various therapeutics as that described by Lind. The concept of process of randomization in clinical trials was first introduced by Fisher. In year 1926, Fisher applied randomized in an agriculture research. The study by Amberson et al in 1931 was the first clinical trial that used a form of random assignment of subject to study group. In this study a flip of coin determined which group of 12 subjects would receive Sanocrysin, a gold compound for pulmonary tuberculosis versus control.

58 Basic Principles of Clinical Research and Methodology Research has been called a good business, a necessity, a gamble, a game. It is none of these; It is a state of the mind. Martin H Fischer. INTRODUCTION Clinical Research is defined as a systematic investigation in human beings designed to discover or contribute to a body of generalisable knowledge. As clinical research involves human participants, researchers and their teams are legally and ethically obligated to protect them. In clinical practice a physician would be expected to use interventions that have a reasonable expectation of success and are designed solely to enhance the well-being of an individual patient. As against this, clinical research is designed to test a hypothesis, permit conclusions to be drawn; and thereby develop or contribute to generalisable knowledge here the participant, therefore may not get the best known treatment and, therefore the obligations on the researcher are more. Thus, the key principle of ethics in Biomedical Research attempts to protect the right of every human subject to understand the nature of research, the risks and benefits involved and then choose to agree or disagree to participate. This chapter reviews some ethical aspects that arise while designing and conducting clinical research. After discussing some historical milestones, I shall cover some of the key issues elaborated in some of the codes, declarations, and other documents that govern the ethical conduct of human subject research; define and discuss the basic principles of ethical research, review the critical elements of informed consent; explore controversial issues relating to clinical research especially in developing countries; and finally review the roles and responsibilities of Ethics Committees. HISTORICAL ASPECTS The Charaka Samhita and the Hippocratic Oath both describe the ethics that govern medical practice. However, they did not cover research. In the 18th century, clinical investigations were exemplified by self-experimentation.

73 ICH-GCP Guidelines INTRODUCTION A paradigm shift has occurred in the way clinical research is being conducted today. Times are changing fast and research has become more prevalent globally. There is a more intense search for expanding research sites beyond US/Europe to countries that are called emerging countries. Thus, an increasing number of trials are being conducted in multicultural and multinational environments. Various trends facilitate this, including increasing industry pressures on clinical development and improved infrastructure and medical expertise in these emerging countries. India is such an emerging market and the various opportunities that lie here are by now well acknowledged worldwide. 1 In the same breath, it is important to realize the challenges that clinical researchers face here before, during and after conducting clinical studies most (if not all) would be prevalent in various degrees in other (more developed) countries, too. 2 Amongst all the challenges that have been described in various publications, it is somewhat ironical that, while the concept of globalization of clinical trials is gaining momentum, the main challenge across all countries worldwide still appears to be protecting human subjects and ensuring that trials are conducted according to good clinical practices ([GCP], Fig. 5.1). Certainly, we have many universal standards and ethical principles or codes guiding clinical trials the Nuremberg Code, Council for International Organizations of Medical Services (CIOMS), the Declaration of Helsinki, National Institutes of Health (NIH) Policy, the National Research Act, the Belmont Report and the International Conference on Harmonization (ICH) GCP Guidelines. However, a major issue remains the training of all clinical researchers in GCP. It is very important to ensure, not only the satisfactory knowledge of GCP, but also the willingness to comply with the above-mentioned principles/ codes.

93 Informed Consent Process: Protecting Subjects Rights INTRODUCTION The oath that the physicians have been taking for more than two thousand years clearly articulates that the physician knows what is best for his or her patient. For over two millennia, the culture has put the physician in an almost God like position in terms of his or her wisdom to practice in the patients best interest. However, the last fifty years have been different than the past history. The concept that the physicians should prefer to protect their patients from information about their diseases or treatment options has totally changed and we have seen a trend towards patient rights. That has included the right to know what the physician intends to do and why. This is the essence of informed consent. Ensuring that study subjects are engaging voluntarily, without coercion and in the knowledge they can withdraw at any time, is a fundamental ethical principle of research. With the current changing research environment and the various regulations governing biomedical research, the informed consent process should also assure subjects that the information they give will be securely stored with complete confidentiality and used responsibly by the various parties involved in the research. THE HISTO R Y OF INFORMED CONSENT AND THE SYSTEM OF SUBJECT PROTECTION The last fifty years have seen the international and US medical communities taking various steps to protect people who take part in clinical research. A comprehensive movement towards informed consent began after World War II with the 1947 Nuremberg trials. In these war trials, physicians conducted medical experiments on concentration camp prisoners. This research included human experimentation with germ warfare, freezing individuals to learn what temperature can kill individuals most effectively, and similar other horrifying research trials.

105 Role of CRC and CRA in Clinical Trials INTRODUCTION Over the years, it has become more and more necessary to have a multidisciplinary specialist approach in planning and conducting clinical trials. The team conducting the clinical trial usually consists of the principal investigators, the co-investigators, the Clinical Research Associates (CRAs), the Clinical Research Coordinators (CRCs), the data management team and the statisticians. Each person in the research team has a key role to play in the smooth and accurate conduct of the clinical trial. In this chapter, we shall discuss about the key roles and responsibilities of the CRAs and the CRCs. Several guidelines like the FDA regulations and the international guidelines for Good Clinical Practice (GCP) have very clearly defined the roles and responsibilities of the investigators, sponsors and monitors. Very little formal description is, however, available about the importance of CRAs and CRCs and their roles and responsibilities. The CRC and the CRA are like the two pillars of any clinical trial and they are the key members who ensure that the data is obtained faster and is clean. THE CLINICAL RESEARCH COORDINA T OR (CRC) The clinical research coordinator (CRC) is a vital link between the trial subjects and their family, the investigator and other team members at the site, central laboratory personnel, the courier service personnel, the contract research organization (CRO), the site management organization (SMO), the sponsor and other players involved in the trial. The concept of a CRC is a relatively new addition to the trial team at the site. No matter what these individuals are called or designated, they act like the Central Hub of the wheel of clinical trial at a site. The CRC is a specialized research professional who works with and under the guidance of the clinical investigator at the trial site. It is seen that many sponsor companies do not place a trial at a site that does not have a CRC working alongside the investigator.

Protocol Designing 8 Anish Desai, Manish Garg INTRODUCTION This chapter outlines the main steps in designing a protocol for a research project. It is not our intention to be prescriptive in the outline; we are simply providing guidelines for the potential researcher who hopes to carry out a research project. The ideas in this chapter are a condensation of our experiences and those derived from several readily available sources. This chapter has been written to ensure that researchers have the necessary information to be able to write a protocol according to ICH Guidelines for Good Clinical Practice (ICH-GCP) standards for clinical trials. PROTOCOL A protocol is a document that explicitly states the reasoning behind and structure of a research project. Every well-designed clinical trial requires a protocol, which is the written mechanism that describes how the clinical trial design will be implemented. The study protocol can be viewed as a written agreement between the investigator, the participant and the scientific community. Protocol is also defined as a document that describes the background, rationale, objective(s), design, methodology, statistical considerations and organization of a trial. It also serves as a reference document that describes; why the trial is being conducted How should it be executed and what is to be done in any eventuality Though there is no single approach in designing clinical trial protocols, there are a number of principles that are usually adhered to. A general approach is often followed although many variations are possible. One may begin to write a clinical protocol after many discussions with several experts. The initial draft/synopsis of a study protocol in the early stage of planning a trial may be a rather basic/incomplete document, which outlines the general scheme without detailed specifications.

Sponsors and Investigators Responsibilities 9 Zinobia Madan, Anil Kukreja SPONSOR A sponsor in literal terms is defined a s an individual or a company or an institution that takes the responsibility for the initiation, management and/or financing of a clinical study. In case an investigator independently initiates and takes full responsibility for a trial, he/she automatically assumes the role of a sponsor. The clinical trials conducted are broadly divided in two classes those conducted for regulatory purpose and those conducted as academic projects. For the trials conducted for regulatory purpose, the sponsor is generally the pharmaceutical company interested in evaluating a product for potential use in specific therapeutic indication/s. The sponsor as a pharmaceutical company conducts the clinical trial with a primary aim to ultimately seek manufacturing and/or marketing permission for the product evaluated for commercial purposes. For the clinical trials conducted as academic projects, the sponsor is the individual or institution interested in such a project for academic reasons, e.g. epidemiological studies, research projects conducted by students, professors , etc. S ponsor s Responsibilities Enlisted below are the sponsors responsibilities in the management of a clinical trial: Selection of Investigator and Clinical T rial Site The sponsor is responsible for selecting the investigator(s)/clinical trial site(s) after ensuring the appropriateness and availability of the study site and facilities. The sponsor must assure itself of the investigators qualifications and availability for the entire duration of the study. In the event of a need of a coordinating committee/ coordinating investigator, sponsor is also responsible for organization of the same in case of multicentric studie s .

154 Basic Principles of Clinical Research and Methodology Patient Recruitment and Retention in Clinical Trials 10 Suhasini Sharma, Rashna Cama INTRODUCTION The process of new drug development is extremely time consuming and expensive. It is estimated that for a new molecule that is discovered it would take approximately 10-15 years to reach the market at an approximate cost of $ 500 800 million. Of these 10-15 years, it is estimated that recruitment of subjects takes up 30 percent of clinical timelines. 1 Therefore, recruiting of appropriate subjects is an issue that must be considered before the study and throughout the duration of the study and investigators must be realistic when determining feasibility of recruiting patients into a particular study. For a long time patient recruitment was neglected as studies were conducted at large hospitals where it was presumed that a large patient database already existed. However, soon realization set in that these studies were taking an enormous length of time and pharmaceuticals began looking for novel and faster ways of patient recruitment. Thus began the advent of professionalizing recruitment activities. Internationally, recruitment and retention of clinical trial patients are a big challenge. More than 80 percent of global trials fail to enroll on time, with 52 percent delayed by 1-6 months. Failure to recruit patients on time leads to loss of over 85-95 percent of days in a clinical trial. 2 Patient recruitment today is considered the key bottle-neck of clinical trials. It is the leading cause of missed clinical trial deadlines and it costs more and consumes more time than any other aspect of clinical trials. Due to this reason patient recruitment is being focused upon by pharmaceuticals as reducing the time for recruitment would eventually reduce total costs of drug development and make treatments available to the consumer at an earlier date and at more affordable prices. BACKGROUND Over the years the number of patients required to undergo clinical trials on a new drug is steadily increasing.

168 Basic Principles of Clinical Research and Methodology Project Management in Clinical Trials 11 Arun Bhatt INTRODUCTION The discovery and development of a new drug costs $800-1000 million and takes longer than 10 years. Clinical development, the most important step prior to a drug entering the market, takes over five years. Each days delay in completing the drug development and launching the product in the market means a revenue loss of $1.5 million. With the increasing cost and time pressures, the clinical trials are an important area where project management techniques are applied. The pharmaceutical companies use project management techniques and tools to plan for a timely and successful entry of a new product in the market. This chapter reviews the current concepts of project management. EVOLUTION OF PROJECT MANAGEMENT The concept of project management traces its origins to development of planning techniques such as Gantt chart, Program Evaluation and Review Technique (PERT) and Critical Path Method (CPM). The Gantt chart is named after Henry L Gantt, who was awarded a US presidential citation for his application of this type of chart to ship building during World War I. The PERT was developed by the United States Department of Defense. The department, faced with the sputnik crisis, needed to speed up the military project process. In 1958, they invented the PERT, as part of the Polaris missile submarine program. This was a massive project involving over 3000 contractors. As most of activities had never been done before, there was an uncertainty about the time estimates. The PERT was developed to handle these uncertainties. Around the same time, the DuPont Corporation created a new project management tool called Critical Path Method (CPM) for scheduling maintenance shutdowns at their chemical processing plants. Over the years, the features that distinguished CPM and PERT have diminished. These concepts, because of their inherent utility in the product development, were quickly adopted by the industry.

Pharmacovigilance in Clinical Research 177 INTRODUCTION PharmacovigilanceInternational Scenario Pharmacovigilance has always been considered a critical activity by almost all the key stake holders, associated with drugs, and its high place in organizational priorities has never been questioned. From time to time, episodes like thalidomide tragedy (1962) and cardiovascular risks posed by COX 2 inhibitors (2005), only add emphasis to this ever evolving medico-regulatory discipline. Traditionally speaking, the science of pharmacovigilance has been a discipline more focused on the post marketing or post authorization period. As a part of Risk Management Tool it has not only an important role to play in patients safety, but it has also assumed astronomical significance, to safeguard pharma industry against possible loss of revenue through damaging litigations and declining share value. However, as biological sciences have evolved, pharmacovigilance has also become an integral part of new drug development process. The new regulations require that the would be marketing authorization holders submit in the application dossier, a comprehensive review of the safety profile of the new drug, and how the potential risks will be further investigated and/or minimized during life cycle of medicines. Most of the regulations that describe safety reporting from clinical trials (CTs) focus on the expedited reporting of the individual case safety reports (ICSRs). ICH guidelines E2A which is generally considered the standard for the information to be sent, stipulates that sponsors should submit suspected adverse drug reactions that are both serious and unexpected to the regulators within 7 (if fatal or life threatening) or 15 calendar days in an appropriate format. 1 Expedited single case reports from clinical trials (CTs) are accepted by majority of the Regulatory Authorities (RAs) on the CIOMS I or similar form.

Role of Contract Research Organizations in Clinical Research Management 199 INTRODUCTION The pace of drug discovery in recent years has resulted in an enormous pressure on the drug development process. The inability of the conventional development pathways to deliver on the demands has for the first time ever transformed the industry from discovery constrained to development constrained. Outsourcing or contracting of clinical research to third parties is being increasingly viewed as an effective option to partially overcome the development related constraint. In fact this option has been around for a long time now, in various forms, since the late seventies to be precise. That was a time when outsourcing was not a very common term, contracting was; thats how the name stuckContract Research Organization (CRO). Contract research is a very broad term comprising of any type of research outsourced, including discovery related or other market related research apart from clinical research. To provide for this specificity in identification, the term clinical research organization came in to vogue. However, the abbreviation CRO remains the same so the confusion continues. For the purpose of this chapter we use CRO as an abbreviation for contract clinical research organization. CROs conduct clinical research on behalf of the pharmaceutical, biotechnology, and medical device industries (sponsors). Clinical trials are a CROs core competency just as a pharmaceutical companys core competency is usually developing drug pipelines and marketing. CRO professionals bring their scientific, regulatory and information management expertise to bear for the completion of timely, accurate, cost-effective trials. By outsourcing, the drug and device companies gain the benefits of CRO experience, even while controlling costs and reducing the research and development timeline. In the Code of Federal Regulations (CFR), the US Food and Drug Administration regulations state that a CRO is a person [i.e.

218 Basic Principles of Clinical Research and Methodology WHA T IS OUTSOURCING Outsourcing is the act of transferring some of an organizations recurring internal activities and decision rights to outside providers, as set forth in a contract. WHA T CAN BE OUTSOURCED IN CLINICAL RESEARCH In a nutshell every aspect of clinical research! Organizations outsource complete clinical development program. Depending on need of the organization it is possible to outsource a study or its parts viz. protocol design and development, case report form design, regulatory activities, safety reporting, study report writing, investigator qualifications and recruitment, investigator grant administration, meeting management, site selection, clinical monitoring, data processing and data management, laboratory sample processing or statistical analysis of study results. This is by no means an exhaustive list. There are a number of other areas in conduct of clinical research, which involves interaction with service providers and have an element of outsourcing. These may include data management, central laboratories, translation services, CRF printing, site supplies, couriers, drug distribution and IT resources including EDC vendors, hardware requirements, and software requirements. WHY OUTSOURCE There are many surveys floating around that give you the Top five or Top Ten reasons to outsource any activity in your organization. Not surprisingly the results vary. Just as the probability of another persons shoe fitting you is remote so is the probability of another organizations reasons to outsource fitting yours equally remote. What is important is to understand the reasons for considering outsourcing and the benefits your organization seeks.

233 Biostatistics in Clinical Trials Biostatistics in Clinical Trials 15 Suresh Bowalekar INTRODUCTION New drug discovery process is an information intensive, very tedious, long, yet inevitable process. It consists of series of activities like identifying diseases, target compounds and planning and conducting investigations and experiments. Target compounds go through a series of tests, investigations or experiments in animals before they are tested in human beings. Experiments carried out in human beings with the target compounds are called as Clinical Trials. Clinical trials are conducted in a specific order and categorized into phases. Usually the first stage of experiments in humans is carried out to generate preliminary information on the chemical action, safe dose level and safety of the indicated drug. All such experiments are termed as Phase I trials. Different phases of clinical trials are explained below (Table 15.1). Each phase of trial consists of experiments designed to test a specific aspect/ objective. Data generated in each phase are analyzed statistically using statistically valid methods, techniques or tests to draw a meaningful conclusion. Conclusion/s derived in any phase are used as guideline to decide whether or not to move over to next phase. Very often a problem or some novel finding is encountered by a scientist (chemists or pharmacist) in the pharmaceutical or chemical laboratory or by a practicing medical professional in the clinic during clinical practice. The problem or novel finding is expressed in simple language, and then gets articulated as clinical question. To obtain solution to problem or to support or refute the newer finding experiment is planned to collect data. Statistician before setting up experiment converts the clinical question in to a statistical question. Thereafter, entire process of clearly defining objective, designing study, collecting and summarizing relevant data, analysis of data and arriving at statistical solution gets completed.

253 Bioequivalence S tudies in Drug Development Bioequivalence Studies in Drug Development 16 Satish Bhatia INTRODUCTION With mounting international pressure to cut down healthcare costs, the generic drug industry came into prominence in the early 1990s. Notwithstanding the GMP-controlled manufacture of the active ingredient and the formulation, a key determinant of a generic products quality lies in a GCP-controlled bioequivalence study in healthy human volunteers to assess the products performance vis-à-vis the innovator product. It is imperative for the generic product to be equivalent and not inferior or superior to the original product. Bioequivalence studies are a series of comparative tests designed to establish equivalence between the test and reference (innovator) products. If a test and reference products are found to be bioequivalent then it is reasonable to expect that the test product will also be therapeutically effective i.e., the test and reference are therapeutically equivalent. The majority of bioequivalence studies are pharmacokinetic studies carried out using healthy volunteers. The underlying rationale is that if two products have the same active ingredient, in the same dosage form and in the same strength, then they are likely to produce similar systemic exposure and hence similar therapeutic effect. Pharmacodynamic studies are only considered appropriate when a pharmacokinetic approach is not possible and a suitably validated pharmacodynamic model is available. Clinical studies are considered an unethical and expensive approach to demonstrating bioequivalence since the products safety and efficacy have been demonstrated in protracted trials before launch by the innovator. In vitro dissolution studies are complementary to a bioequivalence study and are usually the first studies performed. The concept of pharmacokinetic bioequivalence and the logistics involved in its testing would be the subject of this chapter.

272 Basic Principles of Clinical Research and Methodology INTRODUCTION With escalating pressures on research and development (R and D) cost-containment across the global pharmaceutical industry, there is increased focus on reducing the costs of clinical development, which comprises two-thirds of development costs. The additional problem of delayed development times is also affecting new drug introductions, losing incremental revenues. One of the major factors for this delay is an unsatisfactory patient recruitment rate. This dual challenge of accelerating clinical development and reducing costs has forced major pharma companies to look at alternative destinations for sourcing patients for their global studies. Exploration on these lines would then take you to selected countries in Latin America, Eastern Europe, Commonwealth of Independent States (CIS) countries and Asia. Amongst the Asian countries, India stands out prominently due to its huge patient population, English-speaking doctors (many of whom are educated in Western countries) and a large pharmaceutical presence that has dominated the world markets due to cheap generics. TYPES OF COSTS IN MEDICINAL DEVELOPMENT Apart from the cost incurred in new medicine development i.e. Phases 1, 2 and 3 clinical developments, there are numerous other types of costs that are incurred during the process. Non-clinical studies: These are the cost which are including the toxicology programme. Administrative and patent costs: These are costs, which are substantial in the pursuit of NDA (New Drug Application). Patent costs: Patent costs can be considered as a part of the administrative costs. Most patents require periodic fees to maintain their viability. Marketing costs: Cost incurred for promotion and advertizing.

Clinical Data Management 285 INTRODUCTION All clinical trials are performed to answer certain questions about the efficacy and safety of a drug or device. The answers solely depend upon the quality of data, which are collected during the trial and submitted after the trial. The study data is an immense asset for the pharma and biotech companies. Probability of getting a drug or device being approved for marketing increases if the study data is in good shape. Hence data management plays a crucial role in ensuring the success of a trial. Adopting proper methods to manage the trial data helps in increasing the quality of data. Learning, practicing and improving upon these methods has lead to the creation of clinical data management as a subject. Drug development encompasses stages such as formulation, toxicology and clinical trials. Clinical trial or a study in turn has various stages as depicted in Figure 18.1. Clinical Data Management 18 Babu S Nema, Shwetha Ramakrishnan Fig. 18.

Clinical Trials for Herbal Drugs and Traditional Medicines 309 Clinical Trials for Herbal Drugs and Traditional Medicines 19 CK Katiyar , SP Y adav INTRODUCTI O N The World Health Organization (WHO) estimates that 4 billion people (i.e. Approx. 80 % of the world population) use herbal medicine for some aspect of primary health care (Farnsworth et al., 1985). Herbal medicine is a major component in all indigenous traditional medicine and is a common element in Ayurvedic, homeopathic, naturopathic, traditional oriental, and Native American Indian medicine and herbal medicine is the most common form of alternative/traditional medicine (Brody 1998). Worldwide, the botanical pharmacopoeia contains tens of thousands of plants used for medicinal purposes. Hundreds, perhaps thousands, of definitive texts, monographs, and tomes on herbal remedies exist. But most of this information is outside current databases and remains unavailable to physicians, researchers, and consumers. During the last decade, use of traditional herbal medicine has expanded globally and has gained popularity. Traditional herbal medicine has not only been continuously in use for primary health care by the poor in developing countries, but has also been used in countries where conventional medicine is predominant in the national health care system. With the tremendous expansion in the use of traditional medicine worldwide, safety and efficacy as well as quality control of herbal and traditional medicines have become important concerns for both health authorities and the public and the medicines with insufficient evidence of safety are not justifiable because such products carry serious health hazards. This has necessitated a move from traditionally followed qualitative observations to the current concepts of quantitative research (Katiyar CK, 2006). Globally, herbal remedies have been researched under rigorous controls and have been approved by the governments of technologically advanced nations.

347 Investigational New Drug Applications INTRODUCTION Regulations of drugs were originally concerned with their quality. The quality of a drug is primarily determined by its identity and purity. Current regulations are however, an integral part of every aspect of discovery, development, manufacturing, presentation, marketing, distribution and use of drugs, and are country specific. The present chapter deals more with the regulations in the US, on which model the regulations of other countries are based. Since regulations regarding the introduction of new drugs are country specific, organizations developing new drugs are put to often unnecessary efforts and expenses when they attempted to register their products in different countries. This leads to an overall increase drug prices, since the innovators had to recoup the expenses incurred. Recognizing this problem extensive efforts were made to achieve global harmonization in terms of policies, standards, monograph specifications, analytical methods and acceptance criteria. These activities spearheaded by USA, Europe and Japan led to the establishment of Good Clinical Practices, which specified requirements for testing of drugs. Though originally meant to insure mutual recognition of new drugs among the member countries, these guidelines have gained acceptance world wide because of their clarity. Additionally economic compulsions make these guidelines acceptable all over the world since all countries would like to market their products in these member countries, which constitute the worlds largest pharmaceutical markets. The safety and efficacy of new drugs have to be demonstrated and confirmed before they can be introduced into clinical practice. In Europe, the principal document guiding the clinical development plan is ICH Harmonized Tripartite Guideline for Good Clinical Practice (GCP). GCP incorporates a series of requirements imposed by the USFDA during 1970s, and those introduced in Europe and Japan.

364 Basic Principles of Clinical Research and Methodology INTRODUCTION Case Report Form (CRF) is a trial document for collecting and recording patient- related information in a standardized and uniform manner. This is important for the clinical trial team because the analysis and reporting of trial outcome is largely based on the completeness and accuracy of data recorded from each patient recruited in the trial. The CRF can be paper-based or in the electronic format allowing direct data entry into the database. CRF must be distinguished from protocol which provides detailed methodology of all aspects of trials whereas, CRF enables to collect subjects information enrolled in the study as per the protocol. The CRF should be designed in a manner that aids the investigator, monitor and data manager to record and review patient information, which is vital for outcome of a trial. A good CRF should have the following characteristics: i . It should be clear, systematic and unambiguous. ii. It should provide comprehensive instructions to be followed by investigator to obtain complete information as per approved protocol and regulatory requirements. iii. It should provide guidance on eligibility criteria for the patient to continue in the trial. i v . The design should minimize uncertainties and facilitate entry verification (e.g., cross-check between related data) by monitor. v . It should facilitate in designing and creating clean database requiring minimum query resolution between the investigator, monitor and data manager. Ideally, the CRF should be critically reviewed by designer, quality assurance department, monitor, investigator, data manager and statistician meeting the objectives of a trial.

382 Basic Principles of Clinical Research and Methodology 22 Ravindra Ghooi, Sachin Manocha INTRODUCTION Managing clinical tri als and studies is no different from managing materials, machines and people. Successful trial site borrow heavily from management methods used in large industrial projects. Careful record keeping serves as an important back up source of information if questions arise about study related dates or events. Logs and lists are important tools in meticulous execution of complex activities, such as clinical trials. The likelihood of forgetting a particular item of activity increases in proportion to the number of items that need to be done. Using lists and logs ensures that every item, however, minor is not overlooked, but given equal importance. Most regulatory authorities recognize the importance of logs and demand that they be maintained and produced during audits as evidence of good clinical practice. TYPES OF LOGS AND L ISTS Various logs and lists are recommended for use during clinical trials, each log covering one aspect of the trial.

390 Basic Principles of Clinical Research and Methodology Standard Operating Procedures Ravindra Ghooi 23 INTRODUCTION ICH defines SOPs as Detailed, written instructions to achieve uniformity of the performance of a specific function. (ICH E6 1.55) Quite simply, a standard operating procedure specifies in writing what should be done, when, where and by whom. The pharmaceutical industry, and by default the New Drug Discovery process, is highly regulated, probably only next to the aeronautical industry. To regulate the new drug development process the International Conference on Harmonization (ICH) introduced the Good Clinical Practice (E6) as an ethical and scientific standard for designing, conducting, recording and reporting data that is accurate, credible and acceptable to regulatory authorities. In order to achieve this, quality and consistency is required in all its component processes. For controlling the quality of the end products organizations set up standards for both raw materials and processes. Standardized inputs and processes reduce cost by preventing product failures in the long run. These are generally defined as Raw Material Standards (RMS), Standard Test Procedures (STPs) and Standard Operating Procedures (SOPs). SOPs find application in areas even other than manufacturing and have become the gold standards even for service industries. Similarly raw materials and processes in the pharmaceutical industry, including new drug development must be consistent so that the end product stands the stringent scrutiny of regulatory authorities. This is controlled by Good Manufacturing Practices (ICH Quality Guidelines, Schedule M, Drugs and Cosmetics Act 1940). Prior to 1996, every country had its own guidelines for conducting new drug development process. Registration of the drug in another country usually meant repetition of parts or whole studies as per the requirements of the target country. ICH Guidelines were formed to avoid this duplication of research leading to saving of time, money and efforts.

Audits and Inspections in Clinical T rials 403 Audits and Inspections in Clinical Trials 24 Kavita Singh INTRODUCTION Enormous importance has been directe d in the International Conference of Harmonization (ICH) efficacy guidelines (E6) towards maintaining quality and reliability of the data generated from a clinical trial. The pertinent question remains who is/are responsible for the same and who will ensure it The ICH- Good Clinical Practice (GCP) guidelines indicate that the sponsor is responsible for implementing and maintaining Quality Assurance (QA) and Quality Control (QC) systems. QC systems are the operational techniques and activities undertaken to verify the requirements for the quality of trial related activities. Without QC system in place, deficiencies in the trial procedures cannot be readily detected and rectified. QA is the planned and systematic action that ensures that the trial is performed and the data is generated, documented (recorded), analyzed and reported in compliance with GCP and the applicable regulatory requirements. QC activities in a clinical trial are undertaken by the trial team members themselves; therefore carry an inherent potential for bias. Since the purpose is to have an unbiased appraisal of the quality and completeness of the trial, a person independent of the trial team should conduct it. Audit and inspection refer to such independent QA activities, which examine both the systems and the specific study. Hence, QA activities always form an integral part of a clinical trial. The best method to ensure quality at the end of a clinical trial is to build it right from its outset. Audit refers to an independent examination of trial related activities and documents so as to determine whether or not the trial related activities are conducted in accordance with the study protocol, relevant SOPs, GCP and applicable regulatory requirements. The ultimate purpose is to ensure the quality, integrity and validity of investigational data.

Fraud and Misconduct in Clinical Research 423 Fraud and Misconduct in Clinical Research 25 JK Joshi INTRODUCTION Fraud and misconduct in clinical research has received intense attention in medical literature and the media in recent years. 1-6 This is partly due to the large increase in published clinical research in the last few decades; and partly due to the exposure of several high-profile fraudulent reports in medical literature, commercial newsletters, and the lay press. Several cases of fraud have been detected by high index of suspicion, biostatistical incongruity, 7-9 good monitoring, and whistle-blowing. 2,10 Numerous clinical researchers, often persons of excellent repute and academic standing, as well as pharmaceutical medicine specialists committing scientific fraud have been detected, investigated, found guilty, and punished by due process of the law. Others have gone scot-free because their misconduct could not be proven beyond doubt or by a preponderance of evidence; or because they were genuinely unaware of the situation. It is important for the clinical researcher to be aware of the definitions and the reasons of fraud and misconduct, so that they can more critically analyze published clinical research reports, and avoid accusations of misconduct and fraud in their own research programs due to ignorance of the exact definitions and scope of the terms fraud and misconduct. In view of the large number of clinical trials being planned in India, the subject assumes special importance for clinical researchers in India, so that their research methodology and reports are not tainted by inadvertent or designed fraud and/or misconduct. The terms fraud and misconduct in clinical research, are difficult to define without attaching significant extra terminology, which would help define the degree of seriousness of the occurrence, and the penalties, which should be applied in cases of proven fraud or misconduct. By their very nature these episodes would pass off as genuine research, unless detected, and investigated either formally or informally.

An Introduction to Medical W riting 437 An Introduction to Medical Writing 26 Natasha Das INTRODUCTION Broadly speaking, medical writing is about communicating medical and other health related data and information to a range of audience in many different formats using both the print and the electronic media. It has evolved from being a rather underappreciated field to an important career choice today. Over the last few years, the market for medical writers has been growing at a steady rate of about 15% per year. 1 The demand for medical writers is thus ever increasing. In the United States, the American Medical Writers Association (AMWA), an organization that sets industry standards for medical writers, has been around since the 1940s. Even in India, medical writers have been around for more than 50 years now. 2 However, it is only recently, with the advent of global clinical trials into the country, that the critical role played by the medical writer, is being appreciated well. A good quality medical writing can often cut short the delays encountered in drug submission and approval by the regulatory authorities. TYPES OF MEDICAL WRITERS There are basically two types of medical writers: 3 Scientific Medical Writers Marketing Medical Writers. Scientific medical writers are those who may have a degree in medicine, pharmacy or science. A marketing medical writer does not necessarily need to have a strong science background. An English degree or a degree in journalism may suffice for such medical writers. The type of work that the scientific medical writer and the marketing medical writer undertake may differ.

444 Basic Principles of Clinical Research and Methodology Communication Skills 27 Rajani Mathur DEFINING COMMUNICA TION Communication is defined as the process through which two or more people exchange ideas and improve the understanding between them. Communication is the exchange of facts, ideas, opinions or emotions by two or more people. Alternatively, business communication may be defined as a process that involves transmission and accurate replication of ideas for the purpose of eliciting actions that will accomplish organizational goals. Communication takes many forms such as oral or written. Effective communication skills such as writing and speaking well, displaying proper etiquette and listening attentively have gained tremendous importance with time, to the extent that they often determine career success. Communication shortcomings of individuals and the importance of communication at professional front explain why one should improve communication skills. Basically, there are four aspects to communication, namely, something has to be communicated; there must be at least one receiver; ensure that the communication is understood and lastly, feedback of the communication. Communication is a multi-step process involving a sender, message, encoding of the message, channel of transmission of the encoded message, receiver, decoding of the message by the receiver and feedback. GOALS OF COMMUNICA TION Effective communication helps to achieve the following goals: 1. Planning 2. Effective operations 3. Decision-making 4. Controlling and coordinating 5.

454 Basic Principles of Clinical Research and Methodology CLINICAL TRIAL Definition of Clinical trial Clinical trial means a systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and/or adverse effects with the objective of determining safety and/or efficacy of the new drug. . APPROV AL FOR CLINICAL TRIAL ( i ) Clinical trial on a new drug shall be initiated only after the permission has been granted by the Licensing Authority under rule 21 (b), and the approval obtained from the respective Ethics Committee(s). The Licensing Authority as defined shall be informed of the approval of the respective institutional Ethics Comittee(s) as prescribed in Appendix VIII, and the trial initiated at each respective site only after obtaining such an approval for that site. The trial site(s) may accept the approval granted to the protocol by the Ethics Committee of another trial site or the approval granted by an independent Ethics committee (constituted as per Appendix VIII), provided that the approving ethics Committee(s) is/are willing to accept their responsibilities for the study at such trial site(s) and the trial site(s) is/are willing to accept such an arrangement and that the protocol version is same at all trial sites. ( i i ) All trial investigator(s) should possess appropriate qualifications, training and experience and should have access to such investigational and treatment facilities as are relevant to the proposed trial protocol. A qualified physician (or dentist, when appropriate) who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions. Laboratories used for generating data for clinical trials should be compliant with Good Laboratory Practices.

1 . Introduction A brief description of the drug and the therapeutic class to which it belongs. 2 . Chemical and pharmaceutical information 2.1. Information on active ingredients Drug information (Generic Name, Chemical Name or INN) 2.2. Physicochemical data a. Chemical name and structure Empirical formula Molecular weight b . Physical properties Description Solubility Rotation Partition coefficient Dissociation constant 2.3. Analytical data Elemental analysis Mass spectrum NMR spectra IR spectra UV spectra Polymorphic identification 2.4.