Clinical Trial Project Management

By Ashok Kumar Peepliwal

Clinical Trial Project Management provides a detailed overview of how to conduct clinical trials, in an international context. The process of conducting clinical studies across nations is based on a set of regulatory regimes developed by respective regulatory agencies. The book focuses on clinical study protocol approval processes, Ethics Committee approval processes, clinical study feasibilities, site selection, site initiation, site monitoring, database lock, sit close-out, clinical data processing and management, SAE reporting and compensation, randomization procedure, pharmacovigilance, statistical tools, BA/BE studies, and clinical study report writing etc. covering entire clinical trial process of conductance. In addition to that the author also incorporated the clinical trial approval process of USFDA, EMA, and JAPAN to conduct the clinical trials.

• Covers how to conduct clinical trials in detail
• Present useful, basic, and advanced statistical tools
• Provides real-time project management methods like Program Evaluation Review Technique (PERT) and Critical Path Method (CPM) to manage complex projects are described in the book

• Language: English
• Publisher: Academic Press
• Release date: Nov 15, 2023
• ISBN: 9780443136283

Ashok Kumar Peepliwal

Dr. Ashok Kumar Peepliwal holds a PhD in Pharmaceutical Sciences, Bachelor of Pharmacy, LLB, MBA (Human Resource Management). He has extensive experience in conducting clinical trials and project management: including regulatory dossier submission, protocol approvals, site selection, site initiation, site monitoring, and site close-out etc. He has more than 19 years of experience in the pharmaceutical industry (clinical research) and academics as well. Currently he is working as an associate professor at the School of Pharmaceutical Management, IIHMR University

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Chapter 1

Historical development of clinical research

Abstract

The history of clinical research dates to 650 BCE, and the ethical rules underwent evolution between CE 1135 and 1204. In the modern scientific era (19th to 20th century) clinical trial were the requisite part of drug development. World War II (1945) witnessed the unethical practices and inhuman treatment to Jews by Nazis. As a result of World War II, Nuremberg Code, created in 1948 to satisfy the moral requirements of human research and human rights, was adopted by the General Assembly of the United Nations to participate in trials. A human disaster occurred in 1960 named THALIDOMIDE DISASTER, and government agencies made yet another significant change, making informed consent mandatory for trial participants. Following the disaster, the DECLARATION OF HELSINKI-1964 outlined the guidelines for trial execution for the investigators. The Indian Council of Medical Research, which was founded in 1911 for the purpose of conducting medical research, also set the rules governing clinical trials in India. In order to conduct clinical trials only in India, Schedule Y of the Drugs and Cosmetic Acts of 1940 entered into force in 1988. Indian Good Clinical Practices were created in 2001 to legalize clinical trials in the nation. Schedule Y of the Drugs and Cosmetic Acts 1940 was replaced by the New Drug Clinical Trial Rules-2019, which must be complied during the human medical research.

Keywords

Clinical research; nuremberg code; thalidomide tragedy; Declaration of Helsinki; NDCTR-2019; health system; drug; pharmacology discipline; therapeutic procedure; research activity; operations management

1.1 Development of clinical trials in world

Clinical trials history is a history before the beginning of civilization. The first time, a person realized cleaning and wrapping a wound to cure or heal the wound is better than keeping the wound open and dirty, was considered a kind of primitive clinical study. As per the old testament bearing references, the first clinical study or trial was conducted in 605 BCE (Grimes, 1995).

As per the documents, the clinical trials were also described and discussed in ancient Greek, Rockman, and Arab Medical Works. It was the time when ethical codes were not in practice but during the 12th to 13th century, ethical codes were drafted and written for human experimentation. There were a few physicians during CE 1135–1204, named Moses Maimonides (Jewish physician, philosopher), and Rabbi of Cairo, who explained the ethical concerns over the trials where a human being was part of trials (Simon & Maimonides, 1999).

They taught the medical fraternity that physicians should help the patients to treat their diseases and should not use them only to learn new facts. An English scientist, philosopher (named Roger Bacon, CE 1214–94), and Franciscan monk mentioned that it is very challenging and difficult to conduct experiments on human beings because of the nobility of the material in which he works; for that body demands that no error be made in operating upon it…. (Sidebottom, 2013).

During the 18th to 19th century, human experimentation or clinical trials became very common to investigate the new treatments for diseases. Initially, physicians start to test the new medicines on themselves, relatives, close friends, or some volunteers who wish to participate in the experiments. A very much popular invention was the smallpox vaccine innovation in 1789. It was researched, innovated, and developed by an English physician Edward Jenner. Edward Jenner attempted the vaccine first time on his own son and inoculated it to his son when he was only one year old. He was expecting that it will protect children from the milder form of disease observed in pigs and safeguard the children from developing a more serious disease. As a result of it, Jennifer’s son developed smallpox anyway. After a few months, Jenner inoculated a cowpox injection to a neighbor’s son, followed by an injection of smallpox. The child did not develop any disease and he concluded that the vaccination worked. A physician Louis Pasteur (French, 1822–95) also focused on the ethical implications of clinical work and favored the clinical trials on humans. In his animal experimentation, he developed an antidote for rabies in 1884 and found that it would be very effective, but he was not sure of its effectiveness in humans. He was not sure when and whether to plan the experimentation on a human being to assess its safety and efficacy. A mother of a nine-year-old boy approached Pasteur and begged for a rabies antidote for his son who had been bitten by a rabid dog. After consulting with his two colleagues who assured him that the child would lose his life without treatment, and there was no treatment for rabies, in such case he was persuaded to try the antidote. Pasteur was so anxious, but he has inoculated 12 doses of antidote. It was a miracle to get a positive result from it and the boy lived. In this way, vaccines for rabies have been discovered and the world is the eyewitness to saving the life of billions across the globe from rabies (Riedel, 2005).

Clinical trials became more and more organized, planned, and meticulously executed during the 19th century. Ethical principles during the research on humans are considered important and played a greater role to improve the patient’s willingness to participate in the trials. It has given a new dimension to clinical trials and legitimized the researcher which distinguishes between science and quack medicine. Then it became part of Anglo-American common law. An American physician Walter Reed (1851–1902) recruited many volunteers among the American Soldiers during his experimentation on yellow fever in Panama. In this experimentation, the soldiers were asked to be bitten by mosquitoes, which Reed believed that it is the source of infection. Against such volunteer enrollment, he offered a princely sum of $100 in gold, and in addition to that, he gave $100 in gold to the patients who contracted yellow fever (Kendall, 2012; Pierce, 2003).

Before World War II, regarding the vulnerable populations George Sternberg, the Surgeon General of the United States emphasized that clinical trials could be done on such populations with prior approvals or intimations to concerned authorities. Many times, it has been observed that condemned prisoners, infants, and people who stayed in the mental asylum were the prime victim of clinical studies and were frequently used in human experimentations including the studies that were not designed for a meaningful therapeutic purpose (Iyalomhe & Imomoh, 2008).

The clinical trials are transformed after World War II as described by David J. Rothman and it is considered a transforming period in clinical trial development, because the odious experiments are conducted by Nazis on concentration-camp inmates and these experiments got more attention worldwide. There were painful experiments on Jews and the only ones who are prosecuted postwar. It is always remembered in the history of clinical trials that medical experiments conducted after World War II were regarded as the most unethical practice in medical research. Nazi experiments are extremely horrible to explain, describe, or acknowledge. Camp inmates are forced to keep in decompression chambers to investigate the extremely high-temperature effects. Even they are thrown into icy water to evaluate how long they can survive in such cold environments. They were administered harmful toxins, dirty liquids, and other infectious agents like Salmonella Typhi to assess antigen’s impact on the human body. They deliberately provided mutilating wounds on the body and assessed the agony of inmates (Stern & Lifton, 1986).

Most of the time, subjects exposed to such experiments died in course of medical research. It is also true that most clinical studies are without any lawful meaning or without any scientific merits. As a result of such horror episodes of human trials, ethical principles evolved to conduct clinical trials on a human being. Post World War II, Nuremberg Tribunal developed certain ethical principles in 1946, called as Nuremberg Code. This code emphasized ethical issues and developed 10 ethical principles for clinical trials. The first and foremost important criteria in ethical principles are Voluntary participation of human subjects is absolutely important. Moreover, such consent must be obtained from the participants without any fraud, duress, deceit, force, overreaching, or means which affect the decision of the patient/volunteer. This code ensures the researchers that the trials must be well designed, conducted by qualified and experienced medical professionals, based on preclinical study results, and consider the risks to humans. In a simple sense, the code directs that an experiment with potentially dangerous adverse effects can be attempted to lie a cancer disease but not if we are trying to cure a body ache or common cold (Ghooi, 2011).

The code exclusively gives the rights to participants for participating in the trial. It is the participant’s own discretion to stay, continue, or discontinue clinical studies. Despite having clear language, more clarity on ethics, and gold standards for the trials, it does have many lacunae. It also protects the mental incompetent and children who do not have the legal capacity to give consent. The code does not mention any specific criteria regarding the consent of parents or legal guardians. The biggest issue with this code was that it was not the force of law in the United States and its provisions were ignored for 20 years. However, the code mainly focused everything on Nazis because most unethical practices were done during Nazi experimentation. The doctors who obeyed Hitler were not said to be doctors, considered as Hitler’s henchmen (Haque et al., 2012).

It gave hope to American physicians to conduct the trials freely and in accordance with own conscience with regulations. After World War II, the American Medical Association developed a code for research involving human participants and the World Medical Association issued the Declaration of Helsinki in 1964 comprising exhaustive rules for clinical experimentations. These documents are more relevant and deal of discussion for the medical fraternity but have not had more impact on clinical trial conductance (Goodyear et al., 2007).

A turning point was there in 1966 when an anesthesiologist Henry K. Beecher at Harvard Medical School researched and published an article on Ethics and Clinical Research in the journal of New England Journal of Medicine. This article was very popular in then times because he described more than 22 clinical trials that were conducted completely unethically, and researchers practiced their experimentation to increase the risk to the patient lives without prior consent and information to them. He revealed in his investigations that researchers fed live hepatitis virus to mentally ill patients of Willowbrook, a state institution in New York (Beecher, 1966).

While in another experimentation, researchers injected live cancer cells in patients at Brooklyn Jewish Chronic Disease hospital to assess immunological responses of cancer cells. In either of the cases, participants were not priorly informed or not explained about the safety of the patients if anything goes wrong. It was very pathetic to know that research was not objective for patient benefit and not had any therapeutic value (Lerner, 2004)

The longest trial of the world came into the picture in 1970, when the revelation came about the Tuskegee experiment. This experimentation started long back in 1930 and continued for at least four decades, researchers were examining only and not treating more than 400 African American men who contracted syphilis. The researcher only focused on the natural course of the disease as it developed. The justification behind not treating human was that the treatment for syphilis was too complex and not effective but it is not acceptable because penicillin became available in 1945 widely and it is highly effective to treat syphilis. In such cases, if the patients were left untreated was completely an unethical concern and this scandal was in the dark until it was discovered in 1970 (Alsan & Wanamaker, 2018). The progressive clinical trial development from ancient time onward depicted in Table 1.1.

Table 1.1

The ancient Hippocratic oath protects humans on ethical grounds and it is the moral duty of an investigator to save the patients/volunteers in the research. However, this oath was not much accepted, popular, or respected by the physicians/researchers to conduct the experiments on human beings. The World War II was the most curse and panic episode for many people where inhuman treatment had been given by the Germany Dictator Hitler to seized prisoners.

1.2 Nuremberg code, Germany, and ethical concerns

Post–World War II (1939–45), the first international guidance, named NUREMBERG CODE was formulated in 1947. At the end of war, an International Military Tribunal was constituted on November 19, 1945, by the Victorious Allied Powers. Many trials were held under the tribunal against the prisoners and Nazis were most supporters of such trials because they lead the political, economic, and military areas. Such atrocities of trials were conducted at Auschwitz concentration camp by 23 Nazi Party’s physicians from Germany. Later these 23 defendants in Doctors Trial (known as the United States of America v. Karl Brandt, et al.) found guilty. Out of which seven were received the death sentence and nine were sent behind the bars for minimums of 10 years to life imprisonment, rest other seven defendants were found innocent and left them freed from the charges. The trial was conducted at the Palace of Justice in Nuremberg, Bavaria, Germany. The decision also resulted as evolution of new ethical principles named as the Nuremberg Code which included the 10 ethical principles for the experimentation on humans. This code is considered as an importance influential document and described the essentiality of voluntary consent prior to participation in research. This code safeguards the human subjects and allows the voluntary participation in the clinical study. These 10 principles are given below:

1. The participation of the subjects must be completely voluntary.

2. The outcomes of the human study must be for the benefits of humans and good cause of society.

3. Prior to expose on humans, it must be experimented on animals.

4. The experiments are conducted in such way that there should not be any kind of mental and physical injury during the period.

5. No experimentation should be performed if there is a chance of death or permanent disability to the participants.

6. The risks and inconveniences are weighed against he benefits of the trials.

7. Adequate resources and facilities are maintained through the trial to protect the study participants.

8. It is the responsibility of qualified physicians to conduct the experimentation.

9. The subject has the sole power to participate, continue, or discontinue the experimentation at any point of trial period.

10. The in-charge of the trial or principal investigator must terminate the experimentation when death, injury, or any disability occurs.

The Nuremberg Code is the foundation of various fundamental documents who became the part of the regulatory across the globe. It is the backbone of Declaration of Helsinki, ICH-GCP, the Common Rule, and the Belmont Report. Although the new guidance is updated in the ICH-GCP like the digital technology–enabled processes (electronic signatures), the core values of protecting the humans are the part of Nuremberg Code (Ghooi, 2011).

In 1948, for the first time, the rights of human beings are adopted as an important aspect of the trial, and it was expressed by the Universal Declaration of Human Rights (adopted by the General Assembly of the United Nations).

1.3 Thalidomide disaster

It is the disaster of human errors and thousand of people suffered across the western world during the launch of Thalidomide in 1957. Thalidomide was marketed as a sedative to sleepless post World War II. Someone accidently found the additional use of the drug and it can be used for nausea. Therefore, medical practitioners started to prescribe this drug to pregnant women all over the world for morning sickness. The babies were born with congenital deformities like no limbs, no feet, or shortened of limbs too. It was a tragedy of human errors and children were affected badly because the manufactures were unable to detect harmful effects of drug at higher doses on rates or mice stating that the drug is safe and did not have any deleterious effect on humans. It was marketed as a racemic mixture and the impact harmful effect was completely unknown by the scientists. One of the Japan Scientist deciphered the cause of the deformity is disrupting the growth of human embryo (teratogenicity) during developing stage. Scientist stated that thalidomide binds with a protein (Cereblon, CRBN) which triggers an enzyme (E3 ubiquitin ligase) responsible for fetus limb formation. Researcher Hiroshi Handa described in the paper that it is because of the teratogenicity as they repeated the experimentation of thalidomide on chick embryo and got the same kind of results.

After the THALIDOMIDE DISASTER, the United States passed amendments known as 1962 Kefauver-Harris amendments which strengthened the federal agencies’ to conduct the human research with the utmost requirement of informed consent (Kim & Scialli, 2011).

1.4 Declaration of Helsinki-1964

In 1964, the World Medical Association came together in Helsinki, Finland, and articulated certain principles for investigators to conduct the research on humans, named DECLARATION OF HELSINKI-1964 there were several amendments to the Declaration of Helsinki, Brazil since 2013. The declaration included different parts: Preamble; General Principles; Risk, Burden, and Benefits; Vulnerable Group and Individuals; Scientific Requirements and Research Protocols; Research Ethics Committees; Privacy and Confidentiality; Informed Consent; Use of Placebo; Post Trial Provisions; Research Registration and Publication and Dissemination of results; and Unproven Interventions in Clinical Practice (Goodyear et al., 2007).

The Declaration of Helsinki provisions for ethical conduct of the trials are depicted in Table 1.2.

Table 1.2

It was stated by International Covenant on Civil and Political Rights in 1966 that No one will be forced to enroll, or torture or treat in-humanly for purpose of any scientific outcomes. It has been concluded strongly that no participants will be recruited or enrolled in the research without prior consent of participants. Dr. Henry Beecher deciphered and reported in his publications in 1966 about the most inhuman treatment and exploitation that occurred during the Tuskegee experimentation (1930–70). It revealed the darker side of the medical research on humans where thousands of the people suffered and it has been appealed to governments to develop tighter regulations for the experimentation on humans. The revolutionary changes in human research came when the US National Research Act of 1974, Belmont Report of 1979, and International Conference on Harmonization published Good Clinical Practice (ICH-GCP) guidance in 1996 came into force. These three guidelines for human research became popular and the world accepted as a uniform standard for ethical consideration to initiate clinical trials and ensured the public to protect their right, safety, and well-being (Arun & Bhatt,