Clinical Drug Development

Introduction

After the discovery of a drug candidate, there remain a number of hurdles to overcome before it can be marketed. The ultimate goal is to prove that the drug is safe and efficacious. The watershed between research and development has been reached. Here the overall process of evaluation of the drug candidate changes. The chemistry group and other scientists provide the development group with an opportunity to take to the clinic a chemical with therapeutic utility. The mandate of the development team is to take the chemical entity and change it into a drug that regulatory authorities are prepared to license. In any pharmaceutical company, big or small, transitioning from research to development is probably the largest paradigm shift. The laws of science are supplemented with three additional primarily nonscientific disciplines, adherence to the ethical code of medical research, proof of efficacy and safety, and compliance with regulatory requirements.  Scientific discipline and development discipline are horses of a different color. In research it is a requirement to get the “best possible” entity; in development it is the requirement to choose the potential drug that will be proved to have therapeutic utility in a reasonable development time frame and will be approved by regulatory authorities to be marketed. Research is always looking for the “best”; development is always looking for the “best registrable.” The rules governing the two disciplines are separated by a bureaucratic chasm that requires the research group to be acceptant of a significant up-regulation of bureaucratic process. Development requires much more red tape.

History of Ethical Medical Research

Drug development is wrapped in two interlocking but independent disciplines. On the one hand, there are the regulatory and quasiscientific disciplines, which are dealt with later in this chapter, and on the other hand, there is the moral responsibility for the subject, the ethics of clinical research. Clinical research was being conducted long before there were moves to require proof of safety and efficacy before a drug could be put on the market. In the early days of medical research, ethics were considered to be covered by the medical treatment ethical codes and were not considered as a separate entity. Possibly the best known early medical ethics code was from ancient Greece, the Hippocratic Oath, a modernized version of which is still in use. The American Medical Association’s current Code of Medical Ethics states that the Hippocratic Oath “is an expression of ideal conduct for the physician.” The oath in its original version referred exclusively to the role of the physician in patient management and therefore is not directly relevant to research. However, the oath contained the statement, “I shall keep them from harm and injustice,” a sentiment that encapsulates the essence of the more modern codes of ethics.

There is some controversy over who was the original pioneer of clinical research ethics. One school cites Thomas Percival, an Edinburgh University, Scotland–trained English physician (1740–1804), as the originator of clinical research ethics. He published an ethical code of conduct in 1794, Medical Ethics or a Code of Institutes and Precepts Adapted to the Professional Conduct of Physicians and Surgeons. This code was adapted by the American Medical Association for use by American physicians in 1847. Percival’s detractors point out that the Percivilian code focused on the responsibility of physicians to care for the sick. Although it contained guidance on the use of experimental techniques on patients (“[these] should be scrupulously and conscientiously governed by sound reason”), it did not mention one of the essential modern-day concepts, the consent of the subject. Another school cites William Beaumont, a Connecticut-born physician (1785–1853) and sometime army surgeon who became known as the “father of gastric physiology.” It is said that in 1833 he espoused an ethical research code which included the requirement for voluntary consent by any research subject, cessation of the research if it caused distress to the subject, and the provision that the subject was free to withdraw from the research whenever he or she wanted. Beaumont’s detractors question whether this code ever existed. Whoever has the greater claim to be the father of clinical research ethics, it is apparent that the basic precepts of clinical research ethics were laid down over 100 years before the barbaric deviation from ethical conduct which led to the creation of today’s clinical research ethics.

The modern era in medical research ethics began with the Nuremberg Code (1947). It is no small irony that the clearest pronouncements on the pivotal role of consent were promulgated in Germany at the beginning of the twentieth century. Indeed, in 1931 the German Reichs Minister of the Interior forbad medical experimentation unless the “subject or his legal representative has unambiguously consented to the procedure in the light of relevant information provided in advance.” Just 15 years later, over 20 physicians who worked for the German armed forces stood trial for atrocities committed during World War II. Some were sentenced to death, most because they had conducted human medical experimentation to which no sane person would have consented. Germany did not hold the monopoly of unethical research. The Office of Scientific Research and Development in the United States was accused of using subjects for experimentation without them giving informed consent.

The Nuremberg Code of 1947 defined the voluntary consent of the subject in the following terms; This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice … and should have suffi cient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be known to him the nature, duration and purpose of the experiment; the methods and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. This clear definition of informed consent was supplemented by the following principles:

• Investigators must be scientifically qualified.

• Research must be purposeful and necessary for the benefit of society.

• Appropriate measures should be taken to avoid or protect subjects from injury or unnecessary

physical or mental suffering.

• The risks to the subjects shall not be greater than the humanitarian importance of the

problem.

• Subjects may terminate the experiment at any time.

• Research must be based on animal studies or other rational justification.

The Nuremberg Code encompasses all that has to be adhered to for appropriate clinical research to be conducted without harming the subject who volunteers. The field of clinical research ethics is no more immune from the reinvention of the wheel than any other quasiscientific discipline. The desire for improvement is both laudable and counterproductive. It is fueled by the reality of policy versus practice.

Porton Down in the UK was a biochemical research facility. In the mid-1950s, part of its research activities were concerned with the effects of nerve gases. One young serviceman was asked to participate in an experiment to find a cure for the common cold. It is claimed that he was actually exposed to a nerve toxin, sarin, and subsequently died. As recently as 2002 the British High Court gave the go-ahead for a new inquest into the death. Ethical issues in medical research have a habit of not going away until there is complete resolution.

Some experiments that were on shaky or clearly nonethical grounds at their inception lived on even after the adoption of the Nuremberg Code. Probably the best known is the Tuskegee Syphilis Study. In 1932, three hundred and ninety-nine African Americans who were diagnosed as suffering from syphilis were entered into the study, as were 200 healthy African Americans who acted as controls. There was no informed consent. The purpose of the study was to prove that the antisyphilitic medications available at the time were not just ineffective but were harmful. The requirement to generate data to prove this hypothesis might be considered laudable, but the methods used to populate the study were not ethical. After the study started, the way that the participants were managed raised major ethical concerns. By 1947, penicillin was considered a safe and effective treatment for syphilis. The Tuskegee syphilis patients were not evaluated as to whether they might benefit from this new medication. One justification was that their disease was too advanced for them to be candidates for benefit. The study continued and would no doubt have ended only when all 599 participants had died had its existence not been leaked to the press in 1970. In 1972, an advisory panel determined that the study was medically unjustified. The study was closed and a class action law suit led to a multimillion dollar restitution to the survivors and the surviving family members of this misguided and unethical study. In 1997, President Clinton formally apologized to the Tuskegee study participants.

With human rights abuses such as these, there is more than enough justification to continue to legislate against abuse or at least to try to defi ne what is unethical. The Nuremberg Code formed the basis of the Declaration of Geneva Physician’s Oath (1948). This was adopted by General Assembly of the newly formed World Medical Association (WMA). It was looked on as a modernization of the Hippocratic Oath and was an attempt to focus the individual physician’s attention on medical ethics.

Physician’s oath

At the time of being admitted as a member of the medical profession:

• I solemnly pledge myself to consecrate my life to the service of humanity.

• I will give to my teachers the respect and gratitude which is their due.

• I will practice my profession with conscience and dignity; the health of my patient will be

my first consideration.

• I will maintain by all the means in my power, the honor and noble traditions of the medical

profession; my colleagues will be my brothers.

• I will not permit considerations of religion, nationality, race, party politics or social standing

to intervene between my duty and my patient.

• I will maintain the utmost respect for human life from the time of conception, even under

threat, I will not use my medical knowledge contrary to the laws of humanity.

• I make these promises solemnly, freely and upon my honor.

The WMA went on to adopt an International Code of Medical Ethics (1949). This was an attempt to develop international standards of medical ethics and sought to summarize the most important principles. It did not specifically address clinical research ethics. That topic was brought to the attention of the WMA Medical Ethics Committee in 1953. After several years of discussion and research a draft declaration was finally tabled in 1961. It was adopted at the 18th WMA General Assembly, held in Helsinki in 1964. The main points in the declaration are:

• Clinical research should be based on adequately performed laboratory and animal

experimentation.

• It must be conducted by scientifically qualified persons.

• There must be a protocol which will be reviewed by an ethical committee.

• The risk-benefit ratio must be favorable.

• Informed consent must be obtained.

The Declaration of Helsinki was the first time that medical ethics impinged on the regulation of new drugs. The first item could be said to be the start of the requirement for documentation to establish that sufficient preclinical research has been conducted to allow a drug to be given to a human being. In the United States, this documentation is called the investigational new drug (IND) application. It could be argued that its existence is due largely to the ethical considerations that were behind the Declaration of Helsinki. From this requirement there grew a massive industry dedicated to preclinical research in animals. This has led to additional ethical considerations regarding the use of animals in the development of a drug. At one extreme it is argued that the use of animals in biomedical research is unnecessary because equivalent information can be obtained by alternative methods. The fact is that it may be possible sometime in the future, but is not at present. Some animal studies that were at one time considered essential for an IND, such as the LD50 (the lethal dose of drug required to kill 50% of the animals to which it is given), have been reevaluated and dropped from the preclinical requirements. Nonanimal evaluation can supplement animal testing and can reduce the use of animals in research (e.g., in the UK the number of laboratory animals used annually has almost halved in the past 20 years), but the technology does not exist to supplant animal studies completely. Relevant research requires intact physiological systems, and they cannot be mimicked accurately at present. It is not acceptable ethically to risk the health of a human being on the basis of nonphysiological data alone. The Declaration of Helsinki remained unchanged until 1975 when an extensive revision, conducted on behalf of the WMA, was adopted at the 29th General Assembly in Tokyo. This amendment included an expansion of the basic principles and categories developed to address clinical research combined with therapeutic care and clinical research for purely scientific purposes.

Further revisions occurred in 1983 (Venice amendment), 1989 (Hong Kong amendment), and 1996 (Somerset West, Republic of South Africa, amendment). The last of these revisions caused something of an uproar in the medical research community. What made the balloon go up was the language of paragraph 29: “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods. This does not exclude placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists” [author’s italics]. To put it another way, a placebo-controlled study design could not be used ethically in drug studies unless no other treatment was available. This interpretation effectively excluded the placebo-controlled study from clinical research. Most regulatory authorities considered that the placebo-controlled clinical trial design was vital to the evaluation of drug efficacy and safety in the majority of medical conditions. Here again, as with the advent of the Declaration of Helsinki, medical ethics impinged on clinical research and drug regulatory process. It took four years before that controversy was partially resolved. In 2000 at the General Assembly in Edinburgh, Scotland a note of clarification was attached to the Declaration of Helsinki;

it read:

[A] placebo controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

• Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety….

• Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

This masterpiece of bureaucratic language was meant to blunt the debate, but the controversy

still has not gone away. The Declaration of Helsinki continues to evolve and its presence will ensure that medical ethics and clinical research will forever be intertwined. In the United States it was as a direct result of the revelation of the Tuskegee Syphilis Study that the next U.S. medical ethics initiative emerged. The National Research Act of 1974 was passed (Public Law 93348), which required regulatory protection for human subjects and created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. In 1979 this commission produced the Belmont Report, named after the Smithsonian Institution’s Conference Center, where the discussions were first held in 1976. The report established three ethical principles to allow problems to be solved in the area of ethics in clinical research:

(1) respect for persons, (2) beneficence, and (3) justice.

In general terms, these categories were equivalent to informed consent, risk–benefit assessment, and an appropriate choice of subjects for the research. U.S. federal regulations were developed from the Belmont Report. They were adopted, in 1991 by 17 federal departments and agencies: hence the term “the Common Rule.” This governs research conducted or supported by these departments and agencies. The regulations are called Title 45, Code of Federal Regulations 46 (45 CFR 46): Federal Policy for the Protection of Human Subjects.

There are four parts:

1. Subpart A: Department of Health and Human Services (DHHS) policy for the protection of human research subjects

2. Subpart B: DHHS protections pertaining to research, development, and related activities involving fetuses, pregnant women, and human in vitro fertilization

3. Subpart C: DHHS protections pertaining to biomedical and behavioral research involving prisoners as subjects

4. Subpart D: DHHS protections for children involved as subjects in research

The Food and Drug Administration (FDA) has a different set of regulations governing human research, including:

• 21 CFR 50: Informed Consent

• 21 CFR 56: Institutional Review Boards

• 21 CFR 312: Investigational New Drug Application

All clinical research is subject to these and other FDA regulations. Medical ethical issues are now enshrined in U.S. law. Let the final word on ethics come from the National Bioethics Advisory Commission: “It is essential that the research community come to value the ethics of research as central to the scientific process.”

History of the Regulation of Medical Research

Today, there is general acceptance that clinical testing of proposed therapeutic entities is mandatory. No drug will be approved without compelling clinical evidence of safety and efficacy. Clinical studies cannot be initiated without a clearly defi ned preclinical development

program which forms an integral part of the IND.

At the beginning of the twentieth century, preclinical testing of drugs was not obligatory, and the requirement of clinical trials to demonstrate that a drug was safe, let alone efficacious, had never been seriously considered. In the final years of the nineteenth century, Dr. Harvey W. Wiley was appointed chief chemist at the Department of Agriculture.

He embarked upon a crusade to protect the public from adulterated food and established in 1903 a volunteer “poison squad,” who agreed to eat food that was treated with chemical preservatives to establish whether they were injurious to health. Among the chemicals fed to the poison squad were salicylic acid, formaldehyde, benzoic acid, and borax. After five years it was concluded that chemical preservatives should be used in foods only when necessary, a sentiment with which few would argue. Wiley expanded his interest to drugs, and by persistent lobbying and campaigning was a major force behind the inclusion of provisions to protect the public against “misbranded” or adulterated drugs in the Pure Food and Drug Act signed by President Theodore Roosevelt in 1906. This act was concerned only with violations of the food and drug regulations after they occurred. There were no provisions for testing new drugs. Three decades later the act was still in force. There were no requirements to determine the clinical safety of drugs. It took a major disaster in health care to set in motion the regulatory processes that we consider indispensable today to ensure patients’ safety.

In 1932, Gerhard Domagk demonstrated that a chemical called prontesil protected mice against some bacterial infections. Subsequent evaluation showed that prontesil was metabolized to p-aminobenzenesulfonamide, which was known as sulfanilamide. As prontesil had been discovered in 1908, there were no intellectual property issues. Many pharmaceutical companies, including Merck, Parke-Davis, and Eli Lilly, had obtained the backing of the American Medical Association Council on Pharmacy and Chemistry (AMACPC) to market sulfanilamide in capsules and tablets for streptococcal infections. It should be noted that this AMACPC review was not a legal requirement before a drug could be marketed. In 1937 sulfanilamide was being used extensively in the treatment of a variety of infectious diseases. A small pharmaceutical company, S. E. Massengill of Bristol, Tennessee, became aware that there was an unmet need for a liquid preparation. The company’s head chemist was instructed to develop such a product. The reason that a liquid formulation was not available was that a suitable solvent had not been identified. The formulation that the Massengill Company produced comprised diethylene glycol (better known now for its use as an industrial solvent), water, and flavorings, including raspberry extract. The liquid formulation was called an elixir. This term was reserved exclusively for formulations that contained ethanol. Elixir Sulfanilamide did not, a fact that played an important role in minimizing an iatrogenic catastrophe. The liquid formulation of sulfanilamide was “tested”, but the tests that the company conducted were based on its marketability and included appearance and flavor acceptability. No toxicity testing was conducted; none was required by the Food and Drugs Act of 1906.

In the fall of 1937, Massengill’s Elixir Sulfanilamide was distributed and was used by approximately 350 patients. Nearly one-third of those patients died, due primarily to renal failure. The Massengill Company’s response to this disaster was as forceful as it could be; they sent out over 1000 telegrams requesting the return of Elixir Sulfanilamide from the distributors. As the extent of the tragedy became apparent, a government department, the FDA, moved with commendable alacrity to seize the remainder of the manufactured batch. Without a legal nicety in the act of 1906, the FDA would have been powerless to prevent the distribution of the remainder of the first manufactured batch. However, as Elixir Sulfanilamide did not contain ethanol, it was “misbranded.” A misbranded product could be seized. Such was the fi ne line drawn by bureaucratic language, which prevented a tragedy from becoming a medical catastrophe. It was the medical enforcement equivalent of Al Capone being sent to prison for tax evasion rather than bootlegging, racketeering, and murder. Had the entire batch of Elixir Sulfanilamide been distributed and consumed, the death toll would have reached several thousand. In Massengill’s defense, however, it should be stated that they had contravened no laws other than the issue of misbranding. This medical tragedy produced one positive outcome. The U.S. Congress was galvanized into passing the Federal Food, Drug and Cosmetic Act, which was introduced by Senator Royal S. Copeland and signed by President Franklin Roosevelt in 1938. It replaced the original drug legislation from 1906. This act began regulation of the pharmaceutical industry.

Drug manufacturers were henceforth required to provide scientific proof of safety of new drug products before they were allowed to market them. In addition, proof of fraud was no longer necessary before action could be taken to prevent false claims being made for drugs. Hitherto, wild exaggerations were common. Labeling claims for drugs emblazoned with such names as “Warner’s Safe Cure for Diabetes” could be stopped only if it could be proved that the manufacturer of the medication did not believe the claim was justified. The reversal of this absurd interpretation of freedom of speech was a major step forward in protecting consumers from unsubstantiated claims but fell well short of protecting the public from being exposed to nonefficacious “snake oil” products. Proof of efficacy was the next watershed in the protection of the public from those pharmaceutical manufacturers who were prepared to take the money but not deliver the therapeutic goods.

The legislation that was to be enacted to require proof of efficacy was forced on Congress by a most unusual and tragic set of circumstances. It was recognized by the legislators that additional controls on pharmaceutical products were required, although their concept of what type of controls did not assign efficacy a major role. In 1960, Senator Estes Kefauver initiated hearings to control unfair marketing practices. The main thrust of what became Kefauver’s bill dealt with pricing and intellectual property. It paid lip service to the proof of efficacy. The bill was not popularly received and would probably never have gained sufficient support to be enacted had it not been for another horrendous medical tragedy. Chemie Grunenthal was a German company which manufactured a wide variety of over-the-counter and prescription drugs that were sold by many different companies. One of the drugs that it manufactured was called thalidomide. It was a tranquilizer that was recommended for, among other indications, the treatment of morning sickness in pregnant women. First marketed in the mid-1950s, by 1962 it was on the market in 46 countries. Thalidomide was marketed in West Germany in 1957, and reports started to be released concerning potentially drug-related neural toxicity. In addition, there were reports of congenital malformations in babies born to women who had taken thalidomide. The predominant malformations were limb deformities, including shortening or missing arms, with hands extending from the shoulders, and similar problems with legs. This malformation was not unknown; it had been reported as early as the eighteenth century and was called phocomelia after the Greek word for “seal limbs.” The drug continued to be marketed despite increasing evidence that it was toxic, because preclinical testing of the drug in pregnant rats, mice, hamsters, dogs, and primates had not shown this teratogenic potential.  However, in 1962 the drug was withdrawn voluntarily because of increasingly negative public opinion.

In the United States in 1960, Richardson-Merrell sought marketing approval for thalidomide under the brand name Kevadon. It never reached the market because of the resistance of an FDA medical reviewer, Dr. Francis Kelsey. It is said that she was influenced by her previous experience with the antimalarial drug quinidine, which had teratogenic activity. Her misgivings were based on concerns that peripheral neuritis had been observed in adults. This mixture of concern about safety and previous experience combined to overrule the considerable body of preclinical evidence that the drug was safe. Kelsey exercised the bureaucrats’ power to delay the approval process and thereby prevented a major medical disaster in the United States. It is believed that mine babies were born with thalidomide-induced phocomelia in the United States, whereas in the rest of the world the total is conservatively estimated at 10,000. As a result of her actions, Kelsey was given the President’s Distinguished Federal Civilian Service Award by President John F. Kennedy, the highest civilian honor that can be conferred on a government employee. The major change in drug legislation caused by the thalidomide disaster was induced

by an increased public awareness and demand for drug safety. This public need was the motivation for the Kefauver bill to be redrafted. The revised Kefauver–Harris Amendment was signed into law by President Kennedy on October 10, 1962. One of the most significant effects of this legislation was the requirement that drugs were to be proven effective before they could be marketed in the United States. A safety issue was transformed into a requirement for proof of efficacy. It was the second major change in drug legislation and it was enacted almost as an afterthought.

Proof of efficacy was defi ned as the requirement that two adequate and well-controlled studies confirm appropriate activity. This language, crafted in the early 1960s, was to haunt the drug approval process for the next 35 years. The dye was cast for drug development. The Elixir Sulfanilamide disaster led to the requirement for proof of safety, and the thalidomide disaster was the vehicle which ensured that a drug has to be proved effective before it can be marketed. Everything relating to the drug approval process as we know it today relates back to the requirement to prove safety and efficacy. The FDA had been transformed from an agency that responded to negative drug issues to an agency that proactively scrutinized new drug development.

Since the adoption of the Kefauver–Harris Amendment, there have been innumerable modifications, additions, and changes made to the remit and responsibilities of the FDA. For example, clinical research has had to respond to the challenges of the global market. Different countries in the developed world required different data to obtain marketing approvals. This led to slower, more expensive development programs. It was proposed that within reasonable limits, a safe and effective drug should not require vastly different clinical development programs to gain approvals to be marketed in different parts of the world. Europe had pioneered harmonization in the European Community in the 1980s and initiated discussions with Japan and the United States on the harmonization of drug development requirements. These discussions culminated in the birth of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This occurred at a meeting of the European Federation of Pharmaceutical Industries and Associations in April 1990 in Brussels. The ICH comprises representatives of the regulatory bodies and research-based industry from Europe, Japan, and the United States.

The terms of reference for the ICH were agreed on and the topics selected for harmonization were safety, quality, and efficacy. The focus was on harmonizing the technical content of blocks of data where it was apparent that there were significant regional variations in requirements. This resulted in over 60 guidelines and revisions being published in the first 10 years that the ICH existed. This phase of development was deemed complete at the 5^th International Conference on Harmonization (ICH 5) held in San Diego in November 2000. The main focus of the ICH switched to harmonization of the format and content of registration applications. Ultimately, this will result in a common technical document. Other areas targeted for harmonization include new technological advances, new innovative medicines, and postmarketing issues. The U.S. drug regulatory process is now more closely linked to Europe and Japan than ever before. The ICH guidelines are implemented after publication in the Federal Register.  Fundamentally, however, with regards to drugs, the societal mandate in the United States has remained the same: The drug must be proven safe and effective. This led to the development of arguably the most important piece of documentation in drug development in the United States, the new drug application (NDA). If that document passes the FDA approval process, the drug is deemed safe and effective within the scope of the clinical program and may be given to patients. The content and format of the NDA will continue to evolve, but

the basic tenets have endured: Ensure full comprehension of the participant as to the risks of the study and its methods of eliciting usable results, establish safety and efficacy, and going full circle historically, return to the Hippocratic Oath, keep [subjects] from harm and injustice. Ethics and development have come together through tortuous paths.

Preclinical Development

The aim of a clinical development program is to generate sufficient data to satisfy the regulatory requirements for allowing the drug to be marketed. The endpoint of this process is

to prove that the drug is safe and effective in humans. The doorway to testing the drug in humans in the United States is to generate an investigational new drug (IND) application. The initial animal studies to determine pharmacological effects are usually conducted using laboratory-scale drug synthesis. After the initial in vitro and in vivo tests have shown preclinical “proof of principle”, the scale-up process is begun. The initial scale-up is usually between a few hundred grams to a kilogram, depending on the complexity of the synthesis and whether the synthetic route is scalable (i.e., chromatography steps can be accommodated in the scale-up or there are no potentially explosive steps that would preclude scale-up). For drugs that have little or no toxicity, the scale-up will have to be on the order of tens of kilograms, as the IND enabling toxicology evaluations may have to go to 100-fold the expected human dose. The next major event is the manufacture of good manufacturing practice (GMP) material. Good manufacturing practice is a system for ensuring that products are produced consistently and controlled according to quality standards. This system forms an integral part of the manufacturing process. It is considered necessary for the following reasons:

• To assure consistency between and within batches of the investigational product and thus assure the reliability of clinical trials

• To assure consistency between the investigational product and the future commercial product and therefore the relevance of the clinical trial to the efficacy and safety of the marketed product

• To protect subjects of clinical trials from poor-quality products resulting from manufacturing

errors (omission of critical steps such as sterilization, contamination and cross-contamination, mix-ups, wrong labeling, etc.) or from starting materials and components of inadequate quality

• To document all changes in the manufacturing process, in the early clinical trials the dosage form may be different from the commercial product (e.g., capsule instead of tablet), but for the pivotal studies on which registration is based it should be the same as for the commercialized product. It is accepted that validated analytical procedures may not always be available for the early clinical trials, so provisional production parameters and in-process controls should be deduced from experience with analogous products. In short, the GMP system evolves during the clinical development but should be the same as is required by marketed product for the drug that is used in the pivotal trials.

It is not necessary to manufacture material for any of the preclinical studies to GMP. Some companies like to use GMP material for the IND-enabling toxicology studies, but a reasonable compromise is to use material that has a certificate of analysis. The progression in GMP manufacture is usually facilitated if the last non-GMP batch is larger than the GMP batch. The latter faces only the stringency of the in-process controls and intermediate and API release specifications, not the potential problems of those controls applied to a scale that has not previously been manufactured. The aim in the succeeding scale-up is not to produce a drug that is significantly different (API or impurities) from the drug that was used in the IND-enabling in vitro and in vivo studies.

There are two main reasons for conducting preclinical in vitro and in vivo studies:

• To characterize the drug and investigate its utility in models of possible therapeutic targets

• To satisfy the regulatory requirements to allow clinical development of the drug to advance

The characterization and assessment of possible utility are not subject to any stringent controls other than ethical committee approval when animals are used. As an example of such a program, here is a potential feasibility assessment of a topical application of a drug to treat atopic dermatitis. The initial study could be to determine activity: for example, applying the drug topically to prevent an injection of zymosan-inducing paw edema in a mouse model, or topical application to prevent a delayed-type hypersensitivity response to 2,4-dinitrofl urobenzene in a mouse model. The next stage in characterization could be assessing penetration of the drug to the dermis, which is the target site. The mini-pig has skin which is structurally similar to human skin, so that an analysis of a cutaneous punch biopsy after topical application of the drug would determine penetration. The third model in the proof of principle program would be topical application of the drug to a mini-pig model of atopic dermatitis to assess efficacy. In three simple studies, answers are found as to whether the drug delivered topically is active, penetrates to the required site of action, and is effective. It must be accepted that animal models are not necessarily predictive of human efficacy or safety (e.g., the failure of animal models to predict the mutagenic activity of thalidomide), but a positive set of efficacy results in animal studies is usually grounds for advancing the development program. Should the results of the animal studies be negative, there is scant reason to continue the program. These studies are not usually subjected to the preclinical documentation requirement of good laboratory practice (GLP), the equivalent for preclinical testing to GMP for manufacturing. However, these studies, if conducted pre-IND, will be used in the pharmacology/toxicology section of the IND to establish a rationale for exposing the drug to humans and must therefore be adequately documented.

In the same way as the bureaucratic noose tightens the GMP requirement as the development program approaches the pivotal clinical studies, so the bureaucratic requirements for preclinical testing strengthen as the studies become the determinant of whether a drug can be given to humans. Throughout the clinical development, additional nonclinical studies are required, but initially the requirement is for IND enabling studies so that the drug can be given to humans. The standard requirements are:

1. Single- and repeat-dose toxicity studies

2. Pharmacokinetic, toxicokinetic, and absorption, distribution, metabolism, and

excretion (ADME) studies

3. Genotoxicity studies

4. Safety pharmacology studies

It should be noted that all of the studies listed above relate to drug safety, and none to preclinical proof of concept. This is the dividing line between studies that require the bureaucratic vigor of GLP and those that do not. The IND-enabling studies have to be conducted to GLP standards. GLP was developed to promote the quality and validity of the test data used for determining the safety of chemicals and chemical products. The FDA published GLP regulations for nonclinical studies in 1976, and they provided the basis of the Organisation for Economic Co-operation and Development guidelines that made GLP international in 1978. Like the Declaration of Helsinki and the ICH guidelines, the OECD GLP guidelines remain under continuous review and are updated periodically.

Good laboratory practice is a quality system concerned with the organizational process and the conditions under which nonclinical health and environmental safety studies are planned, performed, monitored, archived, and reported. The guidelines examine the requirements for test facility organization and personnel, such as qualifications, training (including training logs of updates), and standard operating procedures. They defi ne the requirements of the quality assurance program, including documentation, inspections, and sign-off of final reports. There are guidelines on facility utilization, apparatus, materials and reagents, test systems, test articles, study performance, report quality, and the storage and retention of records and materials.

1. Toxicity studies. One program in the safety evaluation straddles the requirement for GLP. The toxicology program frequently starts with dose-finding studies to determine the high, middle, and low doses that will be used in the repeat-dose toxicity studies to support phase I clinical studies. These studies can include single-dose escalation and short-duration multiple-dose studies (approximately 5-day dosing). Usually, these studies record gross pathology without histology. They are not subject to GLP but will, of course, be reported in the IND. The IND-enabling repeat-dose toxicity studies should be conducted under GLP. These studies are usually conducted in two mammalian species (one nonrodent) and should be equal or exceed the duration of the human clinical trials proposed. If, in the later stages of development, the duration of the dosing period increases in the human clinical trials, additional toxicity studies must be conducted of sufficient duration to support those trials. For a chronic treatment it is necessary to conduct a six-month study in rodents and at leasta nine-month study in nonrodents.

2. Pharmacokinetic, toxicokinetic, and ADME studies. As a part of the toxicity studies, or in other studies, toxicokinetics should be performed. Toxicokinetics is defi ned as the generation of pharmacokinetic data in order to assess systemic exposure. These data can be used in the interpretation of toxicology fi ndings and their relevance to clinical safety. For meaningful results to be generated, analytical methods must have been developed with the analytes (API, metabolites, etc.) and matrices (plasma, whole blood, tissue, etc.). These methods are under continuous review as additional information is gathered on metabolism and species differences. The drug and metabolite distribution in tissues should be determined. The ICH members are in agreement that single-dose distribution studies should form part of the preclinical evaluation. There are circumstances when it will be necessary to conduct repeat-dose tissue distribution studies. They would be appropriate for compounds that have a long half-life, incomplete elimination, or unanticipated organ toxicity.

3. Genotoxicity. Tests are designed to show whether a drug can induce genetic damage. The ICH guidance on the standard battery for genotoxicity testing of drugs advocates the following as an initial assessment:

• A test for gene mutation in bacteria

• An in vitro test of chromosomal damage

• An in vivo test of chromosomal damage using rodent hematopoietic cells

If these tests are negative, it is usually considered that no additional testing of genotoxic activity is required. Positive tests will require additional evaluations.

4. Safety pharmacology studies. Safety pharmacology studies are those studies that determine undesirable pharmacodynamic effects of a drug on physiological functions. The most important of these are effects of physiological functions that are critical for life, cardiovascular, respiratory, and central nervous systems. However, if a drug is targeted to affect a disease process in another system with a specific effect such inflammatory cell migration in the gastrointestinal tract, closer scrutiny of that system may be necessary.

Hot topic issues will always ensure that this preclinical category remains under consideration.

Recent acknowledgment of enhanced proarrhythmic risk is an example. Much attention is being paid to nonclinical evaluation of the potential for delayed repolarization (QT interval prolongation) by pharmaceuticals. Like the process chemistry modifications and formulation development, the nonclinical evaluation process continues well past the IND enabling phase. Additional preclinical evaluation will be necessary. For example, if human beings of reproductive age will be treated by the drug, reproductive toxicology will be necessary before an NDA can be fi led, and if the drug is to be dosed chronically, carcinogenicity studies will be required. The nonclinical evaluation process continues throughout the clinical development. Once suffi cient preclinical data have been gathered, there is an opportunity to meet with the FDA for a prefi ling IND assessment. This pre-IND meeting allows the sponsor to outline the basic elements that will be in the IND and to seek the FDA’s view as to whether the filing appears to meet the requirements that will allow the IND to be approved and thus allow clinical trials to begin. The structure of the IND is detailed below.

1. Introductory statement. This includes the name of the drug and all active ingredients, the pharmacological class, the structural formula, the method of formulation, the route of administration, and a summary of previous human experience.

2. General investigational plan. This should cover the investigations that will be conducted during the next year and a rationale for this approach.

3. Investigator’s brochure. The most important feature of this document, which is the primer for the investigating physician, is the summary of safety and efficacy and the pharmacokinetics

and biological distribution of the drug in animals.

4. Protocols. These give the details of the types of studies that will be conducted, in which subject population, for how long, with what variables. The protocols also list the qualifications of the investigators and subinvestigators and the name and address of the investigational review board.

5. Chemistry, manufacturing, and control (CMC) information

a. Drug substance [active pharmaceutical ingredient (API)], including the general methods of preparation, the analytical methods used to assure identity, strength, quality, and purity, and data supporting the stability of the drug substance for the duration of the toxicology studies.

b. Drug product, including all components, analytical methods for release, a brief description of the manufacturing and packaging procedures, and sufficient data to assure the product’s stability during the planned clinical studies.

6. Pharmacology and toxicology (pharm/tox) information. This includes data from animal and in vitro studies:

a. Pharmacological effects and mechanisms of action and drug disposition, including effects and mechanisms of action and information on absorption, distribution, metabolism, and excretion. Safety pharmacology data must be available on the effects in animals on vital functions such as cardiovascular, central nervous, and respiratory systems.

b. Integrated summary of toxicological effects of the drug in animals and in vitro. The clinical studies proposed determine the duration of toxicology testing required, whether reproductive toxicology is required, and whether special toxicity tests due to the drug’s route of administration are required. Prior to human exposure, in vitro tests for the evaluation of mutations and chromosomal damage are generally required.  There are a number of other sections that may be required, depending on the drug being evaluated. These include sections on previous human experience and dependence and abuse potential.

The data-driven elements in the IND are the CMC and pharm/tox Sections. The mechanism of drug synthesis has to have been defi ned and analytical methods developed to ensure reproducible quality that is sustainable over time. It is recognized that as manufacturing scale-up occurs, changes will take place in the synthetic pathway, but care has to be taken to ensure that the drug substance and impurity profile remain the same as for the batches of drug substance used in the IND enabling toxicology or safety pharmacology studies. If there is a significant deviation from the analytical release specifications, it could invalidate the results of those studies, which would have to be repeated; bridging studies conducted to show that the current drug is essentially similar in its effects to the original drug; or in the worse-case scenario, a new IND would have to be filed.

The fi ling of an IND takes the development process to the next level. If the IND is accepted by the FDA [i.e., if it conforms to the content and format laid down in the Code of Federal Regulations (21 CFR 312.23)], the FDA has 30 days to comment. At the end of this time, the clinical study may be started whether or not comments have been received. If the FDA determines that there is inadequate information to justify administering the drug to humans, the program is put on clinical hold until such times as adequate data are provided to support giving the drug to humans, once this is achieved, the clinical phase of the development program has begun.

Clinical research design

Clinical research design has two major types that include non-interventional/observational and interventional/experimental studies. The non-interventional studies may have a comparator group (analytical studies like case-control and cohort studies), or without it (descriptive study). The experimental studies may be either randomized or non-randomized. Clinical trial designs are of several types that include parallel design, crossover design, factorial design, randomized withdrawal approach, adaptive design, superiority design, and non-inferiority design. The advantages and disadvantages of clinical trial designs are depicted in Table.

Table - Clinical trial designs, their advantages, and disadvantages

There are different types of clinical trials that include those which are conducted for treatment, prevention, early detection/screening, and diagnosis. These studies address the activities of an investigational drug on a disease and its outcomes. They assess whether the drug is able to prevent the disease/condition, the ability of a device to detect/screen the disease, and the efficacy of a medical test to diagnose the disease/condition. The pictorial representation of a disease diagnosis, treatment, and prevention is depicted in Figure.

 The clinical trial designs could be improvised to make sure that the study's validity is maintained/retained. The adaptive designs facilitate researchers to improvise during the clinical trial without interfering with the integrity and validity of the results. Moreover, it allows flexibility during the conduction of trials and the collection of data. Despite these advantages, adaptive designs have not been universally accepted among clinical researchers. This could be attributed to the low familiarity of such designs in the research community. The adaptive designs have been applied during various phases of clinical trials and for different clinical conditions. The adaptive designs applied during different phases are depicted in Figure.

The Bayesian adaptive trial design has gained popularity, especially during the Coronavirus Disease-19 (COVID-19) pandemic. Such designs could operate under a single master protocol. It operates as a platform trial wherein multiple treatments can be tested on different patient groups suffering from disease.

A clinical trial involves the study of the effect of an investigational drug/any other intervention in a defined population/participant. The clinical research includes a treatment group and a placebo wherein each group is evaluated for the efficacy of the intervention (improved/not improved). Clinical trials are broadly classified into controlled and uncontrolled trials. The uncontrolled trials are potentially biased, and the results of such research are not considered as equally as the controlled studies. Randomized controlled trials (RCTs) are considered the most effective clinical trials wherein the bias is minimized, and the results are considered reliable. There are different types of randomizations and each one has clearly defined functions as elaborated in Table.

Table - Different types of randomizations in clinical trials

Principles of clinical trial/research

Clinical trials or clinical research are conducted to improve the understanding of the unknown, test a hypothesis, and perform public health-related research. This is majorly carried out by collecting the data and analyzing it to derive conclusions. There are various types of clinical trials that are majorly grouped as analytical, observational, and experimental research. Clinical research can also be classified into non-directed data capture, directed data capture, and drug trials. Clinical research could be prospective or retrospective. It may also be a case-control study or a cohort study. Clinical trials may be initiated to find treatment, prevent, observe, and diagnose a disease or a medical condition.

Among the various types of clinical research, observational research using a cross-sectional study design is the most frequently performed clinical research. This type of research is undertaken to analyze the presence or absence of a disease/condition, potential risk factors, and prevalence and incidence rates in a defined population. Clinical trials may be therapeutic or non-therapeutic type depending on the type of intervention. The therapeutic type of clinical trial uses a drug that may be beneficial to the patient. Whereas in a non-therapeutic clinical trial, the participant does not benefit from the drug. The non-therapeutic trials provide additional knowledge of the drug for future improvements. Different terminologies of clinical trials are delineated in Table.

Table - Clinical trial methods and terminologies

In view of the increased cost of the drug discovery process, developing, and low-income countries depend on the production of generic drugs. The generic drugs are similar in composition to the patented/branded drug. Once the patent period is expired generic drugs can be manufactured which have a similar quality, strength, and safety as the patented drug. The regulatory requirements and the drug production process are almost the same for the branded and the generic drug according to the Food and Drug Administration (FDA), United States of America (USA).

The bioequivalence (BE) studies review the absorption, distribution, metabolism, and excretion (ADME) of the generic drug. These studies compare the concentration of the drug at the desired location in the human body, called the peak concentration of the drug (Cmax). The extent of absorption of the drug is measured using the area under the receiver operating characteristic curve (AUC), wherein the generic drug is supposed to demonstrate similar ADME activities as the branded drug. The BE studies may be undertaken in vitro (fasting, non-fasting, sprinkled fasting) or in vivo studies (clinical, bioanalytical, and statistical).

Planning clinical trial/research

The clinical trial process involves protocol development, designing a case record/report form (CRF), and functioning of institutional review boards (IRBs). It also includes data management and the monitoring of clinical trial site activities. The CRF is the most significant document in a clinical study. It contains the information collected by the investigator about each subject participating in a clinical study/trial. According to the International Council for Harmonisation (ICH), the CRF can be printed, optical, or an electronic document that is used to record the safety and efficacy of the pharmaceutical drug/product in the test subjects. This information is intended for the sponsor who initiates the clinical study.

The CRF is designed as per the protocol and later it is thoroughly reviewed for its correctness (appropriate and structured questions) and finalized. The CRF then proceeds toward the print taking the language of the participating subjects into consideration. Once the CRF is printed, it is distributed to the investigation sites where it is filled with the details of the participating subjects by the investigator/nurse/subject/guardian of the subject/technician/consultant/ monitors/pharmacist/pharmacokinetics/contract house staff. The filled CRFs are checked for their completeness and transported to the sponsor.

Effective planning and implementation of a clinical study/trial will influence its success. The clinical study majorly includes the collection and distribution of the trial data, which is done by the clinical data management section. The project manager is crucial to effectively plan, organize, and use the best processes to control and monitor the clinical study.  The clinical study is conducted by a sponsor or a clinical research organization (CRO). A perfect protocol, time limits, and regulatory requirements assume significance while planning a clinical trial. What, when, how, and who are clearly planned before the initiation of a study trial. Regular review of the project using the bar and Gantt charts, and maintaining the timelines assume increased significance for success with the product (study report, statistical report, database).

The steps critical to planning a clinical trial include the idea, review of the available literature, identifying a problem, formulating the hypothesis, writing a synopsis, identifying the investigators, writing a protocol, finding a source of funding, designing a patient consent form, forming ethics boards, identifying an organization, preparing manuals for procedures, quality assurance, investigator training and initiation of the trial by recruiting the participants. The two most important points to consider before the initiation of the clinical trial include whether there is a need for a clinical trial, if there is a need, then one must make sure that the study design and methodology are strong for the results to be reliable to the people.

For clinical research to envisage high-quality results, the study design, implementation of the study, quality assurance in data collection, and alleviation of bias and confounding factors must be robust. Another important aspect of conducting a clinical trial is improved management of various elements of clinical research that include human and financial resources. The role of a trial manager to make a successful clinical trial was previously reported. The trial manager could play a key role in planning, coordinating, and successfully executing the trial. Some qualities of a trial manager include better communication and motivation, leadership, and strategic, tactical, and operational skills.

Practical aspects of a clinical trial operations

There are different types of clinical research. Research in the development of a novel drug could be initiated by nationally funded research, industry-sponsored research, and clinical research initiated by individuals/investigators. According to the documents 21 code of federal regulations (CFR) 312.3 and ICH E-6 Good Clinical Practice (GCP) 1.54, an investigator is an individual who initiates and conducts clinical research. The investigator plan, design, conduct, monitor, manage data, compile reports, and supervise research-related regulatory and ethical issues. To manage a successful clinical trial project, it is essential for an investigator to give the letter of intent, write a proposal, set a timeline, develop a protocol and related documents like the case record forms, define the budget, and identify the funding sources.

Other major steps of clinical research include the approval of IRBs, conduction and supervision of the research, data review, and analysis. Successful clinical research includes various essential elements like a letter of intent which is the evidence that supports the interest of the researcher to conduct drug research, timeline, funding source, supplier, and participant characters. Quality assurance, according to the ICH and GCP guidelines, is necessary to be implemented during clinical research to generate quality and accurate data. Each element of the clinical research must have been carried out according to the standard operating procedure (SOP), which is written/determined before the initiation of the study and during the preparation of the protocol.

The audit team (quality assurance group) is instrumental in determining the authenticity of the clinical research. The audit, according to the ICH and GCP, is an independent and external team that examines the process (recording the CRF, analysis of data, and interpretation of data) of clinical research. The quality assurance personnel are adequately trained, become trainers if needed, should be good communicators, and must handle any kind of situation. The audits can be at the investigator sites evaluating the CRF data, the protocol, and the personnel involved in clinical research (source data verification, monitors).Clinical trial operations are governed by legal and regulatory requirements, based on GCPs, and the application of science, technology, and interpersonal skills. Clinical trial operations are complex, time and resource-specific that requires extensive planning and coordination, especially for the research which is conducted at multiple trial centers.

Recruiting the clinical trial participants/subjects is the most significant aspect of clinical trial operations. Previous research had noted that most clinical trials do not meet the participant numbers as decided in the protocol. Therefore, it is important to identify the potential barriers to patient recruitment.  Most clinical trials demand huge costs, increased timelines, and resources. Randomized clinical trial studies from Switzerland were analyzed for their costs which revealed approximately 72000 USD for a clinical trial to be completed. This study emphasized the need for increased transparency with respect to the costs associated with the clinical trial and improved collaboration between collaborators and stakeholders.

Clinical trial applications, monitoring, and audit

Among the most significant aspects of a clinical trial is the audit. An audit is a systematic process of evaluating the clinical trial operations at the site. The audit ensures that the clinical trial process is conducted according to the protocol, and predefined quality system procedures, following GCP guidelines, and according to the requirements of regulatory authorities. The auditors are supposed to be independent and work without the involvement of the sponsors, CROs, or personnel at the trial site. The auditors ensure that the trial is conducted by designated professionally qualified, adequately trained personnel, with predefined responsibilities. The auditors also ensure the validity of the investigational drug, and the composition, and functioning of institutional review/ethics committees. The availability and correctness of the documents like the investigational broacher, informed consent forms, CRFs, approval letters of the regulatory authorities, and accreditation of the trial labs/sites.

The data management systems, the data collection software, data backup, recovery, and contingency plans, alternative data recording methods, security of the data, personnel training in data entry, and the statistical methods used to analyze the results of the trial are other important responsibilities of the auditor.   According to the ICH-GCP Sec 1.29 guidelines the inspection may be described as an act by the regulatory authorities to conduct an official review of the clinical trial-related documents, personnel (sponsor, investigator), and the trial site. The summary report of the observations of the inspectors is performed using various forms as listed in Table.

Table - The FDA regulatory forms for the submission of inspection results

FDA: Food and Drug Administration; IND: investigational new drug; NDA: new drug application; IRB: institutional review board; CFR: code of federal regulations

Because protecting data integrity, the rights, safety, and well-being of the study participants are more significant while conducting a clinical trial, regular monitoring and audit of the process appear crucial. Also, the quality of the clinical trial greatly depends on the approach of the trial personnel which includes the sponsors and investigators.  The responsibility of monitoring lies in different hands, and it depends on the clinical trial site. When the trial is initiated by a pharmaceutical industry, the responsibility of trial monitoring depends on the company or the sponsor, and when the trial is conducted by an academic organization, the responsibility lies with the principal investigator.

An audit is a process conducted by an independent body to ensure the quality of the study. Basically, an audit is a quality assurance process that determines if a study is carried out by following the SPOs, in compliance with the GCPs recommended by regulatory bodies like the ICH, FDA, and other local bodies.  An audit is performed to review all the available documents related to the IRB approval, investigational drug, and the documents related to the patient care/case record forms. Other documents that are audited include the protocol (date, sign, treatment, compliance), informed consent form, treatment response/outcome, toxic response/adverse event recording, and the accuracy of data entry.

Clinical trial data analysis, regulatory audits, and project management

The essential elements of clinical trial management systems (CDMS) include the management of the study, the site, staff, subject, contracts, data, and document management, patient diary integration, medical coding, monitoring, adverse event reporting, supplier management, lab data, external interfaces, and randomization. The CDMS involves setting a defined start and finishing time, defining study objectives, setting enrolment and termination criteria, commenting, and managing the study design.  Among the various key application areas of clinical trial systems, the data analysis assumes increased significance. The clinical trial data collected at the site in the form of case record form is stored in the CDMS ensuring the errors with respect to the double data entry are minimized.

Table -Types of clinical trial audits

CRF: case report form; CSR: clinical study report; IC: informed consent; PV: pharmacovigilance; SAE: serious adverse event

Clinical trial data management uses medical coding, which uses terminologies with respect to the medications and adverse events/serious adverse events that need to be entered into the CDMS. The project undertaken to conduct the clinical trial must be predetermined with timelines and milestones. Timelines are usually set for the preparation of protocol, designing the CRF, planning the project, identifying the first subject, and timelines for recording the patient’s data for the first visit. The timelines also are set for the last subject to be recruited in the study, the CRF of the last subject, and the locked period after the last subject entry. The planning of the project also includes the modes of collection of the data, the methods of the transport of the CRFs, patient diaries, and records of severe adverse events, to the central data management sites (fax, scan, courier, etc.).

The preparation of SOPs and the type and timing of the quality control (QC) procedures are also included in the project planning before the start of a clinical study. Review (budget, resources, quality of process, assessment), measure (turnaround times, training issues), and control (CRF collection and delivery, incentives, revising the process) are the three important aspects of the implementation of a clinical research project.  In view of the increasing complexity related to the conduct of clinical trials, it is important to perform a clinical quality assurance (CQA) audit. The CQA audit process consists of a detailed plan for conducting audits, points of improvement, generating meaningful audit results, verifying SOP, and regulatory compliance, and promoting improvement in clinical trial research. All the components of a CQA audit are delineated in Table.

Clinical trial operations at the investigator's site

The selection of an investigation site is important before starting a clinical trial. It is essential that the individuals recruited for the study meet the inclusion criteria of the trial, and the investigator's and patient's willingness to accept the protocol design and the timelines set by the regulatory authorities including the IRBs.  Before conducting clinical research, it is important for an investigator to agree to the terms and conditions of the agreement and maintain the confidentiality of the protocol. Evaluation of the protocol for the feasibility of its practices with respect to the resources, infrastructure, qualified and trained personnel available, availability of the study subjects, and benefit to the institution and the investigator is done by the sponsor during the site selection visit. The standards of a clinical research trial are ensured by the Council for International Organizations of Medical Sciences (CIOMS), National Bioethics Advisory Commission (NBAC), United Nations Programme on Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) (UNAIDS), and World Medical Association (WMA).

Recommendations for conducting clinical research based on the WMA support the slogan that says, “The health of my patient will be my first consideration.” According to the International Code of Medical Ethics (ICME), no human should be physically or mentally harmed during the clinical trial, and the study should be conducted in the best interest of the person. Basic principles recommended by the Helsinki declaration include the conduction of clinical research only after the prior proof of the safety of the drug in animal and lab experiments. The clinical trials must be performed by scientifically, and medically qualified and well-trained personnel. Also, it is important to analyze the benefit of research over harm to the participants before initiating the drug trials.

The doctors may prescribe a drug to alleviate the suffering of the patient, save the patient from death, and gain additional knowledge of the drug only after obtaining informed consent. Under the equipoise principle, the investigators must be able to justify the treatment provided as a part of the clinical trial, wherein the patient in the placebo arm may be harmed due to the unavailability of the therapeutic/trial drug.

Clinical trial operations greatly depend on the environmental conditions and geographical attributes of the trial site. It may influence the costs and targets defined by the project before the initiation. It was noted that one-fourth of the clinical trial project proposals/applications submit critical data on the investigational drug from outside the country. Also, it was noted that almost 35% of delays in clinical trials owing to patient recruitment with one-third of studies enrolling only 5% of the participants.  It was suggested that clinical trial feasibility assessment in a defined geographical region may be undertaken for improved chances of success. Points to be considered under the feasibility assessment program include if the disease under the study is related to the population of the geographical region, appropriateness of the study design, patient, and comparator group, visit intervals, potential regulatory and ethical challenges, and commitments of the study partners, CROs in respective countries (multi-centric studies).

Feasibility assessments may be undertaken at the program level (ethics, regulatory, and medical preparedness), study level (clinical, regulatory, technical, and operational aspects), and at the investigation site (investigational drug, competency of personnel, participant recruitment, and retention, quality systems, and infrastructural aspects).

Clinical trials: true experiments

In accordance with the revised schedule "Y" of the Drugs and Cosmetics Act (DCA) (2005), a drug trial may be defined as a systematic study of a novel drug component. The clinical trials aim to evaluate the pharmacodynamic, and pharmacokinetic properties including ADME, efficacy, and safety of new drugs.  According to the drug and cosmetic rules (DCR), 1945, a new chemical entity (NCE) may be defined as a novel drug approved for a disease/condition, in a specified route, and at a particular dosage. It also may be a new drug combination, of previously approved drugs.  A clinical trial may be performed in three types; one that is done to find the efficacy of an NCE, a comparison study of two drugs against a medical condition, and the clinical research of approved drugs on a disease/condition. Also, studies of the bioavailability and BE studies of the generic drugs, and the drugs already approved in other countries are done to establish the efficacy of new drugs.

Apart from the discovery of a novel drug, clinical trials are also conducted to approve novel medical devices for public use. A medical device is defined as any instrument, apparatus, appliance, software, and any other material used for diagnostic/therapeutic purposes. The medical devices may be divided into three classes wherein class I uses general controls; class II uses general and special controls, and class III uses general, special controls, and premarket approvals.  The premarket approval applications ensure the safety and effectiveness, and confirmation of the activities from bench to animal to human clinical studies. The FDA approval for investigational device exemption (IDE) for a device not approved for a new indication/disease/condition. There are two types of IDE studies that include the feasibility study (basic safety and potential effectiveness) and the pivotal study (trial endpoints, randomization, monitoring, and statistical analysis plan).

As evidenced by the available literature, there are two types of research that include observational and experimental research. Experimental research is alternatively known as the true type of research wherein the research is conducted by the intervention of a new drug/device/method (educational research). Most true experiments use randomized control trials that remove bias and neutralize the confounding variables that may interfere with the results of research.  The variables that may interfere with the study results are independent variables also called prediction variables (the intervention), dependent variables (the outcome), and extraneous variables (other confounding factors that could influence the outside). True experiments have three basic elements that include manipulation (that influence independent variables), control (over extraneous influencers), and randomization (unbiased grouping).

Experiments can also be grouped as true, quasi-experimental, and non-experimental studies depending on the presence of specific characteristic features. True experiments have all three elements of study design (manipulation, control, randomization), and prospective, and have great scientific validity. Quasi-experiments generally have two elements of design (manipulation and control), are prospective, and have moderate scientific validity. The non-experimental studies lack manipulation, control, and randomization, are generally retrospective, and have low scientific validity.

Clinical trials: epidemiological and human genetics study

Epidemiological studies are intended to control health issues by understanding the distribution, determinants, incidence, prevalence, and impact on health among a defined population. Such studies are attempted to perceive the status of infectious diseases as well as non-communicable diseases.  Experimental studies are of two types that include observational (cross-sectional studies (surveys), case-control studies, and cohort studies) and experimental studies (randomized control studies). Such research may pose challenges related to ethics in relation to the social and cultural milieu.

Biomedical research related to human genetics and transplantation research poses an increased threat to ethical concerns, especially after the success of the human genome project (HGP) in the year 2000. The benefits of human genetic studies are innumerable that include the identification of genetic diseases, in vitro fertilization, and regeneration therapy. Research related to human genetics poses ethical, legal, and social issues (ELSI) that need to be appropriately addressed. Most importantly, these genetic research studies use advanced technologies which should be equally available to both economically well-placed and financially deprived people. Gene therapy and genetic manipulations may potentially precipitate conflict of interest among the family members. The research on genetics may be of various types that include pedigree studies (identifying abnormal gene carriers), genetic screening (for diseases that may be heritable by the children), gene therapeutics (gene replacement therapy, gene construct administration), HGP (sequencing the whole human genome/deoxyribonucleic acid (DNA) fingerprinting), and DNA, cell-line banking/repository. The biobanks are established to collect and store human tissue samples like umbilical tissue, cord blood, and others.

Epidemiological studies on genetics are attempts to understand the prevalence of diseases that may be transmitted among families. The classical epidemiological studies may include single case observations (one individual), case series (< 10 individuals), ecological studies (population/large group of people), cross-sectional studies (defined number of individuals), case-control studies (defined number of individuals), cohort (defined number of individuals), and interventional studies (defined number of individuals).

Genetic studies are of different types that include familial aggregation (case-parent, case-parent-grandparent), heritability (study of twins), segregation (pedigree study), linkage study (case-control), association, linkage, disequilibrium, cohort case-only studies (related case-control, unrelated case-control, exposure, non-exposure group, case group), cross-sectional studies, association cohort (related case-control, familial cohort), and experimental retrospective cohort (clinical trial, exposure, and non-exposure group).

Ethics and concerns in clinical trial/research

Because clinical research involves animals and human participants, adhering to ethics and ethical practices assumes increased significance. In view of the unethical research conducted on war soldiers after the Second World War, the Nuremberg code was introduced in 1947, which promulgated rules for permissible medical experiments on humans. The Nuremberg code suggests that informed consent is mandatory for all the participants in a clinical trial, and the study subjects must be made aware of the nature, duration, and purpose of the study, and potential health hazards (foreseen and unforeseen). The study subjects should have the liberty to withdraw at any time during the trial and to choose a physician upon medical emergency. The other essential principles of clinical research involving human subjects as suggested by the Nuremberg code included benefit to the society, justification of study as noted by the results of the drug experiments on animals, avoiding even minimal suffering to the study participants, and making sure that the participants don’t have life risk, humanity first, improved medical facilities for participants, and suitably qualified investigators.

During the 18th world medical assembly meeting in the year 1964, in Helsinki, Finland, ethical principles for doctors practicing research were proposed. Declaration of Helsinki, as it is known made sure that the interests and concerns of the human participants will always prevail over the interests of the society. Later in 1974, the National Research Act was proposed which made sure that the research proposals are thoroughly screened by the Institutional ethics/Review Board. In 1979, the April 18th Belmont report was proposed by the national commission for the protection of human rights during biomedical and behavioral research. The Belmont report proposed three core principles during research involving human participants that include respect for persons, beneficence, and justice. The ICH laid down GCP guidelines. These guidelines are universally followed throughout the world during the conduction of clinical research involving human participants.

ICH was first founded in 1991, in Brussels, under the umbrella of the USA, Japan, and European countries. The ICH conference is conducted once every two years with the participation from the member countries, observers from the regulatory agencies, like the World Health Organization (WHO), European Free Trade Association (EFTA), and the Canadian Health Protection Branch, and other interested stakeholders from the academia and the industry. The expert working groups of the ICH ensure the quality, efficacy, and safety of the medicinal product (drug/device). Despite the availability of the Nuremberg code, the Belmont Report, and the ICH-GCP guidelines, in the year 1982, International Ethical Guidelines for Biomedical Research Involving Human Subjects was proposed by the CIOMS in association with WHO. The CIOMS protects the rights of the vulnerable population, and ensures ethical practices during clinical research, especially in underdeveloped countries. In India, the ethical principles for biomedical research involving human subjects were introduced by the Indian Council of Medical Research (ICMR) in the year 2000 and were later amended in the year 2006. Clinical trial approvals can only be done by the IRB approved by the Drug Controller General of India (DGCI) as proposed in the year 2013.

Current perspectives and future implications

A recent study attempted to evaluate the efficacy of adaptive clinical trials in predicting the success of a clinical trial drug that entered phase 3 and minimizing the time and cost of drug development. This study highlighted the drawbacks of such clinical trial designs that include the possibility of type 1 (false positive) and type 2 (false negative) errors.  The usefulness of animal studies during the preclinical phases of a clinical trial was evaluated in a previous study which concluded that animal studies may not completely guarantee the safety of the investigational drug. This is noted by the fact that many drugs which passed toxicity tests in animals produced adverse reactions in humans.  The significance of BE studies to compare branded and generic drugs was reported previously. The pharmacokinetic BE studies of Amoxycillin comparing branded and generic drugs were carried out among a group of healthy participants. The study results have demonstrated that the generic drug had lower Cmax as compared to the branded drug.

To establish the BE of the generic drugs, randomized crossover trials are carried out to assess the Cmax and the AUC. The ratio of each pharmacokinetic characteristic must match the ratio of AUC and/or Cmax, 1:1=1 for a generic drug to be considered as a bioequivalent to a branded drug.  Although the generic drug development is comparatively more beneficial than the branded drugs, synthesis of extended-release formulations of the generic drug appears to be complex. Since the extended-release formulations remain for longer periods in the stomach, they may be influenced by gastric acidity and interact with the food. A recent study suggested the use of bio-relevant dissolution tests to increase the successful production of generic extended-release drug formulations.

Although RCTs are considered the best designs, which rule out bias and the data/results obtained from such clinical research are the most reliable, RCTs may be plagued by miscalculation of the treatment outcomes/bias, problems of cointerventions, and contaminations.  The perception of healthcare providers regarding branded drugs and their view about the generic equivalents was recently analyzed and reported. It was noted that such a perception may be attributed to the flexible regulatory requirements for the approval of a generic drug as compared to a branded drug. Also, could be because a switch from a branded drug to a generic drug in patients may precipitate adverse events as evidenced by previous reports.  Because the vulnerable population like drug/alcohol addicts, mentally challenged people, children, geriatric age people, military persons, ethnic minorities, people suffering from incurable diseases, students, employees, and pregnant women cannot make decisions with respect to participating in a clinical trial, ethical concerns, and legal issues may prop up, that may be appropriately addressed before drug trials which include such groups.

Clinical Development

The IND is a living document that remains open for as long as the drug remains under investigation. As each new study is designed, the sponsor must submit to the FDA a protocol amendment containing the protocol for the next study. Safety reports must be made to the FDA within 15 calendar days of the sponsor being made aware of either a serious and unexpected adverse experience or any fi nding from nonclinical studies which suggests a significant risk to human subjects, such as reports of mutagenicity, teratogenicity, or carcinogenicity. The sponsor must submit annual reports that contain individual study information and summary information which comprises all information obtained during the previous year’s clinical and nonclinical investigations, including a summary of all safety reports generated during the year. Information amendments are made to the IND when essential information is not contained in any protocol amendment, safety report, or annual report. An example of the content of an information amendment would be new chemistry or other technical information. The clinical phase of the development program is the most complex and costly. The overriding concern is for the safety of the clinical trial subjects. Like the manufacturing code of practice (GMP), and the preclinical evaluation code of practice (GLP), there is a code of practice for the human investigation phase of the development program, good clinical practice (GCP). Unlike GMP and GLP, where there are development stages that do not need to adhere to these regulations, all clinical trials must conform to GCP. The ICH GCP guidance is broadly in line with the Declaration of Helsinki. The main sections deal with:

• The Institutional Review Board

• The responsibilities of the sponsor of the clinical trial and the investigator who will conduct the trial

• The clinical trial protocol

• The investigator’s brochure

• The essential documents for the conduct of a clinical trial

This aim of GCP guidance is to minimize the potential for harm to befall a clinical trial subject. This governs the entire structure of the clinical development program. For example, the numbers of patients entered into studies would form an inverted pyramid. The earliest evaluations will be conducted in less than 100 subjects, while the last studies in the clinical development program may include hundreds or even thousands of subjects. This is an attempt to minimize exposure to the drug at a stage when the least is known about its possible toxicity and maximize it to determine safety and efficacy in advance of applying for approval to market the drug. The goal of the clinical development program is to generate sufficient clinical data of

acceptable quality to fi le a new drug application (NDA) with the FDA so that they may determine whether the drug can be approved for marketing. Probably the single most important

document in an NDA is the label text, also called the package insert, a summary of the drug that is made available to prescribers and patients. The information that is contained in the label text summarizes what the FDA has approved to be marketed. Any other use is called off-label and is not sanctioned by the FDA. If something goes wrong, the physician has no defense to the accusation that he misused the drug. The marketing company is also bound completely by the label text. There can be no advertising using information outside the label text. The power of the document dictates that it should be constructed before clinical development is started so that the clinical research efforts are focused on that endpoint. When marketing, medical, and regulatory departments first develop the label text there is often a tendency to craft language that looks like: “tastes like chocolate, cures cancer, and costs a buck.” As long as there is some justification based on the nonclinical data for aiming at these best possible goals, they must be considered feasible endpoints.

Of course, it must be accepted that this exercise will require continual modification as hard data become available, but ultimately, by focusing the clinical development program on the maximum potential of the drug, the end result should be the best that the drug can deliver for the patients who take it. If the preclinically devised label text is the esoteric goal of the clinical development program, the operational aspect of the program is dictated by need for clinical trial subject safety. The traditional terminology divides the program into four temporally related phases. There are well-established definitions of these phases:

Phase I

This phase starts with the first administration of the drug to human subjects. The initial study in phase I (called phase Ia) is directed at an evaluation of safety. As it often consists of single ascending doses, there may be no opportunity to evaluate therapeutic efficacy endpoints. As the subjects that are most often used in these studies are healthy volunteers, no disease-related efficacy endpoint is possible. The subjects are usually male, due to the requirement for reproduction toxicology data before women of childbearing potential can be entered into clinical trials and there being no necessity to submit such studies in the IND. The subjects in the majority of phase I studies are admitted to hospital or a specialized phase I unit and monitored continuously. The initial trial will use an open design; in other words, both the investigator and the subject know that all doses will be test articles and the doses of the test articles will be administered using an ascending-dose regimen. A safety evaluation will be made after each dose is administered before the next dose is given. The assessment of pharmacokinetics and initial data on the characterization of the drug’s absorption, distribution, metabolism, and excretion will be sought. There are too many exceptions to this standard phase I evaluation of drugs to allow a comprehensive account of all types of phase I programs. The following are common variants:

• The subjects are patients because the inherent toxicity of the drug under evaluation precludes it from being given to volunteers; such a situation may arise in the early evaluation of an anticancer drug.

• The subjects are patients because the disease process makes it irrelevant what happens in volunteers; topically applied dermatological drugs for the management of skin conditions are usually evaluated for safety in patients that have a disrupted skin surface, as the healthy skin is a natural barrier.

• A surrogate endpoint exists (e.g., a marker that shows activity but is not predictive of therapeutic activity) so that pharmacodynamic data can be generated. For example, a drug for asthma that exerted its effect by reducing inflammatory mediator release from white cells had a pharmacodynamic evaluation conducted in the initial phase I single-ascending-dose study. Peripheral white cells were harvested and the release of the inflammatory mediator leukotreine B4 (LTB4) was monitored after inflammatory mediator release was stimulated by calcium ionophore. The less LTB4 released after the stimulation, the better the dose of the drug was working.

After the initial single-ascending-dose safety study is completed, the next step is to conduct a multiple-dose safety study (phase Ib). The aim in these studies is to get to steady state plasma concentrations (i.e., the highest concentrations that will ever be achieved form a particular dosage regimen). The same potential variations in populations and endpoint exist in this late phase I design as did in the first administration to human subjects in the single-ascending-dose study. The multiple-dose study is often conducted using an ascending-dose protocol where the lowest dose is given first and a safety evaluation is conducted before administering the next-highest dose. In cases where the nonclinical and phase Ia safety profiles are benign, it may be possible to run the different doses in parallel, thereby saving a considerable amount of development time. The total population required for the phase I studies is on the order of 20 to 100. The industry norm for the duration of phase I is less than one year. Of the drugs that enter phase I studies, approximately 70% are progressed to the next phase.

Phase II

Once the drug has been shown to be safe, it will be tested for efficacy. The population to be tested will be patients. Care is still taken to minimize the risk to the study population. The inclusion and exclusion criteria which defi ne patients that are eligible for the study usually exclude signifi cant concomitant disease other than the disease or condition that the drug is intended to prevent, diagnose, or treat. There are also usually restrictions on the use of concomitant therapy. Considerable emphasis is still laid of safety evaluation, but the patients may be treated as outpatients unless the disease requires hospitalization. One of the most important endpoints of the phase II is the definition of the dose or dose range to be taken into Phase III. The objectives will include an assessment of the minimum dose that is maximally or sufficiently effective and free of significant toxicity. An evaluation of the primary endpoint to be used to determine efficacy in phase III is usually a major objective.

For example, the results in nonclinical studies may suggest that an investigational drug will accelerate the healing of a chronically painful skin lesion and will be assessed in phase II/ with that endpoint. The proposed label text will have language related to speed of healing. If, during phase II it becomes apparent that healing is not accelerated but chronic pain is controlled, the option will exist to advance to phase III, with the primary variable being speed of healing in the hope that the phase II results were anomalous, or switch to pain relief as the primary variable understanding that the proposed label text will have to be changed to reflect the change in study endpoint. The FDA describes phase II trials as follows: “Phase II includes controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common or short term side effects and risks associated with the drug. Phase II studies are typically well-controlled, closely monitored, and conducted in a relatively small number of patients.” Whereas the phase I studies were usually conducted with an open design, the phase II studies are randomized. One or more groups of patients, depending on the number of doses being studied, will receive the study drug while another group, the control group, will receive a placebo with or without standard therapy. These studies are usually double-blind; neither the patient nor the investigator knows who is getting test drug, what dose of test drug is being administered and who is getting placebo. This increases the complexity of the operational aspects of drug packaging and allocation of treatments. The investigational drug must be packaged in an identical manner to the placebo and which must be given to the patients in accordance with a pre-determined randomization code.

The overall aim of the phase II studies is to defi ne the type of studies that will be conducted in phase III, including dose, duration of dosing, frequency of dosing, patient population, and primary variable. When this evaluation is poorly conducted, the phase III outcome becomes much more of a guessing game than is necessary. Additional time spent in phase II to establish the best design for phase III is likely to be returned by a shorter successful phase III. Companies that truncate phase II so that they can start pivotal phase III studies as early as possible do so at their own peril. The end result is often a case of more haste, less speed. Once phase II is completed, the option exists to meet with the FDA before starting phase III. The FDA regulations state that the purpose of the end-of-phase II meeting is:

• To determine the safety of proceeding to phase III

• To evaluate the phase III plan and protocols

• To identify any additional information necessary to support a marketing application for the uses under investigation.

As the third bullet point suggests, this meeting is not confined to evaluating only the phase III program. The FDA defi nition of the end-of-phase II meeting states that the focus should be “directed primarily at establishing agreements between FDA and the sponsor of the overall plan for phase III and the objectives and design of particular studies. The adequacy of technical information to support phase III studies and/or a marketing application may also be discussed.” Phase II is usually conducted in a few hundred patients. Of the seven out of 10 drugs that complete phase I successfully, only four will complete phase II and advance to phase III.

Phase III

The studies conducted in phase III are the NDA-enabling studies. In the Federal Food, Drug and Cosmetic Act of 1938 (FFDCA), Drug Amendments of 1962, language regarding clinical study approval requirements read: “…adequate and well controlled investigations…,” which was interpreted by the FDA as a minimum of two such phase III studies. In the mid-1990s Carl Peck, M.D., the ex-director of the FDA Center for Drug Evaluation Research, who had left the FDA to start the Center for Drug Development Science, at Georgetown University in Washington, DC, questioned the validity and utility of this interpretation. Over the next few years this evolved into the concept of single clinical trial submissions, where only one adequate and well-controlled phase III study may be required in certain circumstances.

In 1997, President William Jefferson Clinton signed the Food and Drug Administration Modernization Act. The language in Section 115a related to the evidence of effectiveness required to approve a new drug. It was substantially different from the FFDCA with Drug Amendment of 1962: “…data from one adequate and well-controlled investigation and confirmatory evidence.” The implication is clear; it is no longer mandatory that two adequate and well-controlled studies (i.e., two phase III studies) are necessary for proof of effectiveness required to approve a new drug. A debate still rages over what constitutes “confirmatory evidence.”

One option for the basis of regulatory approval is a single phase III clinical study plus causal confirmation. Causal confirmation has been described by Peck et al. as proof that “the drug, through its pharmacological action, favorably alters the clinical condition of those who are treated with it.” In other words, proof of pathophysiologic and pharmacologic mechanisms is sufficient to be considered confirmatory.  Simplistically, approval to market a drug could be based on one positive, adequate, and well-controlled phase III study supported by a phase II study where the endpoint was a surrogate endpoint marker. For example, if it is accepted that chest x-ray fi ndings may be indicative of pulmonary function deterioration and the claim for the drug will be preservation of pulmonary function, one adequate and well-controlled phase III study with a pulmonary function endpoint supported by one phase II chest x-ray positive finding adequately fulfills the requirements of the act.  There are a number of additional questions that should be addressed in the phase III program program. The primary requirement is to confirm the findings of safety and efficacy in the phase II program. Inclusion and exclusion criteria to defi ne the study patient population tend to be less rigorous in the phase III program, so the patients more closely resemble the population who will be administered the drug when it is marketed. For chronic treatments there is a requirement to dose for longer periods than are normally considered in phase II. The ICH in its efficacy guideline E1 has determined that the exposure to assess clinical safety for drug intended for chronic administration in non-life-threatening conditions should be at lease 500 patients for six months and 100 patients for one year.

Different drugs require different programs to develop sufficient evidence to gain marketing approval. Special population clinical study requirements are important (e.g., the elderly or children). Ultimately, the aim of this gargantuan clinical development program is to establish sufficient cause, safety, and efficacy to allow a new drug to be added to the physician’s therapeutic armamentarium for the benefit of patients. The total patient population required to complete phase III is highly variable. The ICH states that a minimum of 1500 patients should be exposed to the drug before a marketing application should be assessed, but that may be wholly inadequate in terms of the number of patients who might be required in clinical trials to satisfy the statistical considerations for proof of efficacy. Alternatively, in rare conditions, dealt with in 21 CFR 360.20, Orphan Drug Regulations, significantly fewer patients may be required to satisfy the phase III commitment. (Orphan drug status in the United States can be sought for a drug intended for diseases or conditions affecting less than 200,000 patients per year. In Europe the patient population should not exceed 185,000 patients per year, and in Japan, 50,000 patients per year.) Approximately 70 to 90% of drugs that enter phase III eventually make it to the market.

Phase IV

There is one additional phase of drug development which is unrelated to providing documentation for the initial NDA. This is called phase IV. These studies are run to generate additional data on the drug that are not necessary for the approval process but might be used to modify the label text. In phase IV the following information may be sought:

• Relative efficacy compared to different drugs used to treat the same disease

• Cost-effectiveness of the drug

• Assessment of the improvement in the patient’s quality of life

• Safety assessment in an unselected patient population

• Opportunities for additional indications

The clinical development of drugs is usually defi ned as sequential testing through phases I to III for approval and phase IV for additional definition. The process, however, should not be thought of as strictly sequential development. In ICH guideline E8, General Considerations for Clinical Trials, an alternative nomenclature is proposed which more appropriately reflects the development process. Whereas it is usually correct to say that phase II does not start until an adequate phase I is conducted and phase III will not begin until an appropriate phase II has been completed, just because the drug is being evaluated in phase III does not mean that assessments usually associated with phases I and II are not continuing to be developed.

E8 defines the development process as follows:

• Human pharmacology (roughly equivalent to phase I)

• Assess tolerance.

• Defi ne pharmacokinetics and pharmacodynamics.

• Estimate activity.

• Therapeutic exploratory (roughly equivalent to phase II)

• Explore use for targeted indication.

• Defi ne dose range for subsequent studies.

• Generate data to determine study designs.

• Therapeutic confi rmatory (roughly equivalent to phase III)

• Confi rm efficacy.

• Demonstrate safety as well as can be defi ned within the limited exposure of a

clinical program.

• Establish a dose–response relationship.

• Therapeutic use (roughly equivalent to phase IV)

• Refi ne risk–benefit relationship.

• Identify less common adverse reactions.

• Refi ne dosing recommendations.

The concept of a logical serial development of a drug has much to commend it, but frequently there are misunderstanding as to the actual stage of development by misinterpreting the underlying basis of the four temporal phases. Frequently, in the more sophisticated development programs there may be as much or more human pharmacology assessment during phase III as there was during phase I.

When a hypothesis has been developed, when a chemical synthesis program has been developed, when an exploratory preclinical program has been completed, and when the clinical study evaluation all contribute to the data that generates an approved NDA, all the disciplines of research and development come together to provide a tool to the physician to improve the life of his or her patients.