Clinical Development 101: General Principles PDF

PROPRIETARY. DO NOT SHARE. Transcript: Clinical Development 101: General Principles Section 1: Introduction Welcome Welcome to the Biotech Primer Course on the General Principles of Clinical Development. This course is broken into 3 sections and will provide an overview of clinical research and con...

PROPRIETARY. DO NOT SHARE. Transcript: Clinical Development 101: General Principles Section 1: Introduction Welcome Welcome to the Biotech Primer Course on the General Principles of Clinical Development. This course is broken into 3 sections and will provide an overview of clinical research and conducting clinical trials. Each of the phases of clinical studies will then be further discussed in a course specific to that phase of clinical development. Section 1: Introduction Objectives At the end of the section, you should be able to: • Define the terms clinical research, clinical study, and clinical trial. • Describe the purposes for which clinical studies are conducted. • Define the terms evidence-based medicine, translational medicine, and patient-centric clinical trials, and describe the key milestones for drug development. What is Clinical Research? What is clinical research? Clinical research is a scientific investigation that involves human subjects, and clinical research typically involves what is referred to as clinical studies. Clinical studies advance scientific and medical knowledge, this is referred to as basic research. Clinical studies also can apply knowledge to benefit human health, this is referred to as applied research. A note here about some terminology. In pharmaceutical and medical device development programs, clinical studies conducted on human subjects are distinguished from non-clinical studies, which are generally animal studies such as toxicology and pharmacology studies. Purposes of Clinical Studies Clinical research studies can serve a variety of specific purposes. For example, the investigation of disease characteristics in natural history studies. Disease characteristics include patterns and variability, a spread in human populations, signs and symptoms of specific diseases, causes, risk factors, and markers such as genetic markers. Clinical research studies can investigate ways to better manage diseases or can investigate improved screening procedures for diseases. Clinical research studies can evaluate ways to better predict diseases. And finally, the safety and 1 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. effectiveness of medications, therapies, medical devices, and surgical procedures are typically evaluated through clinical research studies. Types of Clinical Studies Observational clinical studies are clinical studies where data are gathered on health-related outcomes while the clinical study subjects receive only routine or standard health care. For example, studies of lifestyle factors associated with specific diseases are observational clinical studies. Importantly, observational studies do not include interventions such as experimental treatments. Another type of clinical study is a clinical trial, and in clinical trials, the effects of specific interventions are evaluated. Interventions can include such things as investigational drugs, therapies, medical devices, or surgical procedures, and can include new applications for approved treatments. Clinical trials also investigate, for example, new combinations of drugs and therapies in combating specific diseases. Clinical Research: Some Additional Terms Evidence-based medicine is the use of the most reliable, scientifically generated evidence as the basis of medical decision-making in medical practice. For example, the data from multiple wellcontrolled clinical trials are considered to be highly reliable evidence from which to make medical decisions. Translational medicine, often referred to as bench-top to bedside, refers to the integrated approach to using research knowledge effectively to facilitate public health improvements such as prevention, diagnosis, and treatment of diseases. The goal of translational medicine is to ensure the delivery of the right drug directed against the right target within the disease picture to the right patient at the right dose. We can sum up the goal of translational medicine by saying it is an effort to streamline and coordinate the activity bridging from the research and preclinical development into effective clinical development and medical problemsolving. Patient-centric clinical trials are a move to better engage patients to improve the design and conduct of clinical trials. For example, to ensure that the outcomes being assessed are meaningful for patients. To learn more about patient-centric clinical trials click the Learn More button. Otherwise, click next to continue with the main course. 2 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Learn More: Patient-Centric Clinical Trials Let's talk a little more about what we mean by patient-centric clinical trials. Historically, many clinical trials were designed primarily based on the study team and study conduct considerations without sufficient understanding of patient convenience or patient needs. This could result in a number of issues and has resulted in a number of issues including low recruitment, where patients are not interested in accepting the burdens associated with certain clinical trials, or patients participating in clinical trials, but experiencing excessive burdens as they participate. Study sponsors are increasingly making clinical trials more patient-centric by researching more carefully patients' everyday lives and identifying factors that could impact participation, and surveying patients and their caregivers for input on trial designs before the trials are established. Regulatory agencies are adapting to this trend as well. For example, FDA and the European Medicines Agency have formed a working group, the FDA EMA Patient Engagement Cluster, which allows the agencies to share best practices related to patient involvement within drug development programs. Clinical Trials in Drug Development The purpose of a clinical trial within a drug development program is to measure the effects of an investigation of a new drug in people. This is done in order to answer questions such as, is that measurable effect better than the already available treatment, assuming one exists? Are the side effects manageable? How is the drug metabolized? Does the drug have a measurable effect on the disease it is designed to treat? In other words, what is the true medical benefit? Here is an example of a famous clinical trial, the first effective polio vaccine, which was developed in the 1950s by Jonas Salk and colleagues at the University of Pittsburgh. And as part of this development in one of the largest clinical trials that have ever been conducted, more than 600,000 children were injected with either an experimental vaccine or placebo. In this trial, the polio vaccine was shown to be 80% to 90% effective, and, a version of the Salk polio vaccine, inactivated polio vaccine that is, is still widely in use today. Clinical Trial Phases Clinical trials are typically conducted stepwise in phases. Phases one, two, and three are typically conducted prior to a product being approved and marketed. Phase four, or post-approval studies, are clinical trials that are conducted after a product is approved and available commercially in the 3 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. market. Now, we are referring here to the standard development approach, these successive phases one, two, three, and then following approval phase four. But in some cases, we can see combinations or other streamlining approaches to clinical development, so in certain situations such as rare, orphan diseases. Or in cases of serious unmet medical need, clinical development programs can be customized and streamlined in order to better address those specific needs and accommodate available patient populations, which in the case of rare diseases may be quite limited. Examples are combined phase one, two studies, or phase two, three studies managed within a single protocol. Key Clinical Milestones in Drug Development This screen provides an overview of the key milestones associated with clinical activity within drug development programs. We see here the progression from preclinical through clinical stages, ultimately to registration and launch. And preclinical is where we're assessing the safety and biological activity formulations typically in animals in laboratory studies. If the data from preclinical studies are sufficiently favorable, which means that there is evidence of a favorable risk-benefit relationship, then a decision is made to move to clinical studies in humans. In the phase one study in humans, we will typically be determining the safety of a product and sometimes investigating the dosage. In phase two, we begin to evaluate the effectiveness and continue to monitor safety. In phase three, we are looking to confirm effectiveness, continue to monitor for safety, and ultimately gather the pivotal information required to decide the approvability of a product. If through the clinical phases, the product profile is sufficiently favorable, once again from a riskbenefit standpoint, an application can be made for marketing commercialization of a product through a formal application process to a regulatory agency. That can be referred to as the registration stage. And if the regulatory authorities such as FDA approved the application, our product can then be launched. Following the launch of a product, it is typical that one or more phase four studies will be agreed to. Phase four is referred to as post-marketing studies investigating different questions related to clinical data. Clinical Trial Phases Progress in Complexity As an introduction to clinical trial phases, we can see that as we progress from preclinical through phases one, two, three, and ultimately into phase four, we have increasing numbers of clinical 4 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. trial subjects through the different phases, and the duration of the studies is increasing. Typically, the sophistication of the studies is also increasing, and as we'll see shortly the purposes of studies in the different phases differ from phase to phase. Key Milestones for Drug Development: Some Details So, to look into a bit more detail. In the preclinical development stage, again, we are typically working in laboratory studies and animal studies, and the purpose of these studies is to assess the safety, the biological activity, and some preliminary information regarding formulation development for, for example, an investigational therapy. It is not atypical to have a duration of approximately four-and-a-half to six-and-a-half years required for completion of the preclinical testing. Again, providing that the risk-benefit relationship is suitably favorable, we can then progress to clinical studies in humans, beginning with phase one. In phase one, as we see, the purpose of the study is to focus on the assessment of the safety, and in some cases investigate the dosage of the product. But the principal objective of phase one is safety assessment. Phase one typically involves 20 to 100 healthy subjects. In some cases, it is not ethical to include healthy subjects in phase one studies. For example, in studies of oncology products, we would typically use only cancer patients for ethical reasons, but for the most part, 20 to 100 healthy volunteers are typical for phase one. If data looks favorable after phase one, we can progress to phase two, and in phase two we would typically be evaluating hundreds of patients, and in this, case patients. In many cases, this is the first treatment of patients with investigational therapy. The purpose of phase two is to not only look for safety, which we will continue to assess throughout development but now also to begin to evaluate effectiveness. Once again, if the data are sufficiently favorable at the conclusion of phase two, we can move to phase three where now we are including thousands of subjects, in some cases even 10s of thousands of subjects. And here the purpose of phase three is to confirm effectiveness as well as continue to monitor safety. Phase three studies are often referred to as pivotal studies, these being the most important data often to determine the approvability of an investigational therapy. The clinical development portion of drug development programs, including phase I through III, can typically last anywhere from 7 to 7.5 years on average, some longer, some shorter. And, again, at the end of phase three, if data looks suitably favorable, an application can be made to regulatory authorities, such as the FDA, for approval to market a product. 5 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. That review process typically takes between one to two years, and if approved, a product will typically be subjected to additional phase four studies, and these would be to continue to monitor such parameters as safety and effectiveness in, for example, different populations and so on. Section 1: Introduction Summary To summarize this section, we learned that: • Clinical research is defined as a scientific investigation involving human subjects. • Clinical studies are performed to advance scientific and medical knowledge in the form of basic research, as well as to apply knowledge to benefit human health or applied research. • Clinical studies include both non-interventional observational studies and clinical trials involving interventions. • Clinical trials in drug development programs typically proceed through premarket, which is phase one, two, and three stages, and post-market, phase four stages. • In certain situations, such as rare diseases, and unmet medical needs, clinical trial phases can be combined to streamline development. 6 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Section 2: Clinical Trials - Basics Principles Section 2: Clinical Trials: Basics Principles Objectives At the end of this section, you should be able to: • Describe the core principles of Good Clinical Practices • Explain how risk management is approached in designing and managing clinical trials. • Discuss how the scientific method applies to clinical trials. • Define the clinical trial terms control group, bias, blinding, randomization, and endpoints. • List the basic elements of parallel, crossover, and natural history clinical trial designs. Good Clinical Practices (GCP): Introduction Good Clinical Practices are an internationally adopted standard that ensures appropriate ethical principles and scientific quality applied to the design, conduct, and management of clinical trials. GCP, Good Clinical Practice, provides assurance that the rights, well-being, and confidentiality related to clinical trial subjects are protected and maintained, as well as that the data obtained in clinical trials are reliable and of appropriate quality. GCP evolved historically from the Nuremberg Code following the Nuremberg trials at the end of World War II, and also from the Declaration of Helsinki, which is a declaration from the World Medical Association and is considered the cornerstone document that relates to human research ethics. The International Council for Harmonization, or ICH, coordinates international harmonization, including those related to GCP. For example, ICH E6 is a guideline for Good Clinical Practice that represents the practical application of GCP principles and the Declaration of Helsinki. GCP requirements are also codified in various regional and national regulations and laws, including various parts of the Code of Federal Regulations in the United States. Good Clinical Practices: General Principles To summarize the core principles of GCP, clinical trials should be conducted in accordance with ethical principles such as the Declaration of Helsinki, and also with any local regulatory requirements. Risks should be weighed against anticipated benefits for the individual trial subjects 7 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. as well as for society. Trials should be conducted only if anticipated benefits justify the risks. The rights, safety, and well-being of clinical trial subjects are the most important consideration and should prevail over the interest of science and society. Freely informed consent must be obtained from each clinical trial subject prior to their participation. The confidentiality of subject records should be protected. Nonclinical and clinical information, including safety data in animals as well as any previous clinical data, on investigational products should be adequate to support the proposed clinical trial. Again, referring here to knowledge regarding the risk-benefit relationship. General Principles of GCPs In Clinical Trials Clinical trials should be scientifically sound and described in clear, detailed protocols, which are approved by institutional review boards or independent ethics committees. Medical care and medical decisions must be the responsibility of qualified physicians, or dentists in some cases. Finally, GCP contains a number of other requirements, such as those relating to data handling, systems such as computer systems, clinical trial procedures, the quality of investigational products used in clinical studies, and so on. And of course, these relate to data integrity, which is core to Good Clinical Practice. Risk Management in Clinical Trials Ethical conduct of clinical trials requires adequate identification and control of risks to not only trial subjects but also data integrity, and risk management is something that is continuously addressed during development. So, as part of the risk management program, we start with risk identification. What might go wrong? In other words, what are specific risks? How likely is it that those risks will occur, referred to as probability? And finally, what are the consequences if a specific risk is realized, referred to as severity? In a risk management program, specific risk identification is followed by the development of a risk control strategy, and the risk control strategy is typically based on a combination of probability and severity knowledge for each identified risk, often probability times severity is assigned a number within an index. Risk management programs are developed on the basis of risk control measures, and once again, these are subjected to continuous review throughout the course of a clinical trial. 8 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Clinical Trials and The Scientific Method Clinical trials are science experiments, and as such the standard scientific method applies to clinical trials, so the standard scientific method includes observation, question, followed by hypothesis, experimental design, experiment, data collection, analysis, and conclusions. That's the typical scientific method flow. As applied to clinical trials, for observation and question, based on available knowledge a research question is identified. For example, will new drug X benefit patients with disease Y? Next, a hypothesis is derived. A clinical trial hypothesis is established, and this is the research question placed in a form that can be clinically tested. For example, new drug X will be better than a placebo in treating disease Y. That's an example of a hypothesis. For experimental design, a clinical trial design is developed that will objectively test the hypothesis. A detailed, written protocol is prepared to serve as the study plan. The experiment is conducted, in this case, the clinical trial is conducted, so subjects are enrolled, interventions are administered, tests, observations, et cetera, are carried out according to the details in the clinical protocol. Data are next collected and stored for analysis, and of course, data integrity is key, and we saw that in Good Clinical Practices. Nes in the analysis step, the results of the trial are analyzed in accordance with predetermined statistical criteria, which again are included in the protocol. And finally, conclusions. Conclusions are reached on the basis of the original hypothesis. Control Groups Control groups are study groups within clinical studies and are often referred to as arms within the clinical study. A control group, or control arm, is a group of subjects who do not receive the experimental drug or treatment that is the subject of the investigation. We use control groups to minimize the risk of observing imagined or random effects of treatment. Depending on the trial, the control group subjects may receive, for example, no treatment, they may receive standard of care treatment, they may receive placebo treatment. Placebos are so-called dummy treatments that resemble active medication or therapy. Examples are sugar pills, saline injections, and so on. And this allows for the detection of any placebo effect. To learn more about the placebo effect and some examples of studies that demonstrate the need for a placebo control group, click the learn more button. Otherwise, click next to continue with the main course. 9 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Learn More: The Placebo Effect Let’s discuss some examples of the placebo effect in clinical trials. The first example is a review in the Journal of Psychiatric Research published in 2008. In a metaanalysis of eight depression studies, 79% of placebo responders were observed to remain free from relapse during the 12-week evaluation period within the study. That compares to 93% relapse-free in the group taking an actual antidepressant, which is an active substance. So, although the placebo responders were a lower percentage, it was still a relatively high percentage of 79% who responded favorably during that 12-week evaluation. This demonstrates that the placebo effect can certainly affect study results and should be considered. Another example of the placebo effect has been demonstrated in Parkinson's disease trials. In a review study published in Nature Communications in 2018 which examined data from 11 clinical trials, it was found that 16% of subjects with Parkinson's disease that were assigned to a placebo group not only showed significant improvement, but some showed significant improvement for up to six months, and this is based on a unified disease rating scale that's used to assess the progress of Parkinson's disease. Another very interesting example of the placebo effect was published in general hospital psychiatry in 2007, in this case, there was an apparent placebo, quote-unquote, overdose. The details of this case are as follows. A 26-year-old man attempted suicide by swallowing 29 capsules of a clinical trial drug that he thought was an experimental antidepressant formulation. That patient was taken to the hospital and discovered to have a number of significant vital signs and symptoms, including extremely low blood pressure, 80 over 40, and a very rapid pulse, pulse of 110. Doctors stabilized this patient's blood pressure by administering intravenous fluids to maintain adequate blood pressure. His pulse remained high, nevertheless. Shortly after a doctor who was associated with the clinical trial arrived at the hospital and revealed the fact that that specific patient had been assigned to the control arm of the trial and had received only a placebo. Upon learning that information, the patient's blood pressure quickly stabilized at 126 over 80, and his heart rate dropped to a normal 80 beats per minute. These examples demonstrate that the placebo effect can affect clinical trial results and the use of placebo should always be considered to separate the true effect of the drug being tested from any placebo effect that may be demonstrated. 10 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Bias Subconscious influences that can prejudice investigators and-or clinical trial subjects are referred to as bias. Bias can lead to invalid conclusions, including conclusions regarding treatment effects. Bias in clinical research can be introduced through, for example, any systematic differences in the baseline characteristics of study groups being compared, the level and nature of treatment received, how outcomes are assessed, and how outcomes are reported and or not reported. Control of bias is essential in clinical trials, and that is achieved through measures such as blinding, randomization, and transparency in reporting and publishing results. Blinding Blinding refers to the withholding of knowledge of treatment assignment. In other words, is a subject assigned to the experimental group or the control group? Withholding of treatment knowledge from one or more parties is done in order to control bias. Some examples of blinding approaches by trial design include open-label trials, sometimes referred to as unblinded trials, in which both the trial subjects as well as the study staff are aware of assignments. In other words, the trial subjects and the study staff are aware of whether the subject is in the experimental group or the control group, for example. Another example is a single-blind study, in this case, trial subjects are not aware of the assignment, but the study staff are aware of the specific assignment per trial subject. In a doubleblind study, neither the trial subjects nor the study staff are aware of assignments in either experimental or control groups. Randomization Variables such as sex, age, et cetera, and factors related to health status, may influence outcomes in clinical trials, therefore these variables must be considered and addressed. We address those factors through what's called randomization. In randomized clinical trials, subjects are randomly assigned to either treatment or control groups in order to minimize differences between groups. Randomization methods can be as simple as a coin toss or the drawing of sealed envelopes, but more often we see a bit more sophistication, for example through computer-program-generated randomization assignments. Different randomization schemes are possible; for example, simple randomization could involve placing an individual 11 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. randomly into a group as they enter the clinical trial, or block randomization in which several subjects at a time are assigned randomly to a group. Endpoints: What Clinical Trials Measure Endpoints are what we measure in clinical trials. Endpoints are outcome measurements such as disease occurrence, symptoms, signs, laboratory findings, et cetera. Clinical endpoints are observations and measurements for such parameters as survival, disease-free survival, relapse, specific symptoms, functioning, quality of life, et cetera. Surrogate endpoints are biomarkers that are expected to be predictive of a targeted clinical benefit. Some examples are cardiovascular disease using blood pressure and cholesterol levels as surrogate endpoints, or the study of glucose control using A1C blood analysis measurements as a surrogate endpoint. A primary endpoint is the principal outcome that the trial is designed to address, and typically this is the principal outcome the trial is statistically designed to answer. So, for example, the overall efficacy associated with the treatment is an example of a typical primary endpoint. A secondary endpoint is an outcome often analyzed post hoc to provide additional information. The trial may not be statistically powered nor randomized for secondary endpoints. Introduction To Clinical Trial Designs: Parallel and Crossover In a parallel study, there are two treatment groups. One receives a placebo, for example. The other receives an investigational drug. These groups are followed through time separately in one group or the other, and patients do not change groups. In a crossover study, subjects receive a sequence of different treatments, and in a crossover study we have initial randomization where subjects are placed into either placebo or drug groups, for example, and after a sufficient period elapses, the so-called washout period, the assignments of the subjects are reversed, where for example the drug treatment subjects then go to placebo treatment, and the placebo treatment subjects are changes to drug treatment. The benefit of a crossover study is that each subject represents their control, and therefore the number of study subjects required for such a study can be significantly lessened. Introduction To Clinical Trial Designs: Natural History Natural history studies are studies that compare clinical trial results to what occurs with the natural course of a disease progression. Trial arms, usually without a placebo, compared to natural history studies. Sometimes these studies make use of external or synthetic controls, which are 12 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. controlled data taken from sources outside the study population such as electronic health records, insurance data, or historical clinical trial data. Natural history studies apply to some ultra-orphan diseases where it's not possible or practical to have multiple study arms, or for example to include a separate control arm. Section 2: Clinical Trials: Basic Principles Summary To summarize this section, we learned that: • Good Clinical Practices are internationally adopted standards that ensure appropriate ethical principles and scientific quality in the design, conduct, and management of clinical trials. • Risk management is essential to clinical trial design and conduct. • Clinical trials follow the steps and principles of the scientific method. • A control group is a group of subjects who do not receive an experimental drug or treatment, included to minimize the risk of observing imagined or random treatment effects. • Bias refers to subconscious influences that can influence investigators or trial subjects leading to invalid conclusions. • Blinding, randomization, and transparency in reporting and publishing results are all measures that help control clinical trial bias. • Endpoints are outcome measures such as disease occurrence, symptoms, signs, or laboratory findings that are measured or observed in clinical trials. • Parallel, crossover, and natural history studies are some examples of clinical trial design strategies. 13 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Section 3 Conducting Clinical Trials Section 3 Conducting Clinical Trials Objectives At the end of this section, you should be able to: • Describe the basic steps in conducting a clinical trial. • List the various clinical trial participants and their roles. • Discuss the purpose of clinical protocol and the basic elements of a clinical protocol. • Explain the purpose and composition of ethics committees in institutional review boards. • Describe the purpose and elements of the informed consent process. • Discuss the purpose of defined inclusion, and exclusion criteria in clinical trials. • List the basic steps in clinical trial data management and reporting; and finally • Review clinical trial transparency measures. Clinical Trial: Sequence of Steps Clinical trials typically proceed in a defined sequence of steps. As we discussed earlier, based on the scientific method, a study is designed, and a clinical protocol is developed. That protocol is reviewed by an IRB or an ethics committee that oversees the ethics of the investigation. Following review and approval of the ethics committee, a plan for a clinical study with associated information, as required, is submitted to a regulatory agency, such as FDA, seeking authorization to proceed with the study. If the regulatory authorities and the IRB ethics committee are in agreement that a clinical study can be conducted, the study begins through recruitment, enrollment, and randomization followed by treatment, follow-up, and ultimately analysis and reporting of data. All through the clinical trial process, data collection is ongoing, as well as safety analysis and safety reporting. Safety information, for example, is reported to ethics committees as well as to regulatory authorities. Clinical Trial Participants and Roles Clinical trials have a number of participants, each with their role in the trial. Subjects are select populations of either patients or healthy individuals. Healthy individuals, for example, are typically subjects in phase one trials. The clinical trial sponsor is the individual, 14 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. company, or organization that is responsible for trial management and-or financing. Typically, the sponsor of a clinical trial for an investigational drug is a pharmaceutical company. The investigator is the individual responsible for the conduct of a trial, typically a physician, and often a specialist. In cases where a clinical trial is carried out by a team of investigators, one of the investigators is designated the principal investigator and they are the responsible leader of the investigation team. The ethics committee, or institutional review board, are independent panels that oversee the ethics of a clinical trial as well as the rights and welfare of clinical trial subjects. Contract research organizations, or CROs, are organizations that provide support activities on a contract basis for many clinical trials. The Clinical Protocol As mentioned previously, a clinical protocol is a document that provides a detailed, written plan for a clinical study, including objectives, design, methodology, statistical considerations, as well as the organization of the trial. There are standard elements for clinical protocols, and the standard format includes a synopsis, a rationale for the conduct of the study, and specific inclusion and exclusion criteria, which detail what subjects should be included, and which subjects should not be included in the trial. What are the study procedures? What measurements will be taken? What efficacy and safety outcomes will be assessed? How will data be analyzed statistically, and finally a number of administrative sections, including records of GCP, informed consent, ethics committee approvals, and so on? Ethics Committees and Institutional Review Boards (IRBs) Ethics committees or IRBs are independent committees that oversee the ethical conduct of clinical trials. That entails protecting the rights and safety of clinical trial subjects, as well as an ongoing look at the risk-benefit relationship. The ethics committees and IRBs should be composed of at least five members that reflect the diversity of scientific and nonscientific backgrounds and cultural interests. They should include both sexes and have at least one member not affiliated with the institution. IRBs and ethics committees review such documents as a clinical protocol, an investigator's brochure, which is a summary of known information regarding an investigational product, informed consent documentation, subject recruitment materials, investigator qualifications, and so on. 15 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. The Informed Consent Process Informed consent ensures that prospective subjects in your clinical trial can make well-informed decisions regarding their participation based on an understanding of a number of factors, including what will be involved specifically in the study, and what will happen to the subjects. Subjects must be informed of all treatments, procedures, samples, visits, et cetera. What risks or discomforts may be experienced? What benefits might be realized? In this case, we use the word might because it is important to stress that typically at the clinical trial stage, relatively little information is known regarding the benefits of the investigational therapy. Finally, potential clinical trial subjects should understand that their participation is voluntary. For an individual to give valid, informed consent, three components must be present, disclosure, capacity, and voluntariness. So, there must be full disclosure of the relevant information, the subject or the subject's guardian must have the appropriate capacity to make an informed decision, and finally, all decisions to participate in a clinical trial need to be voluntary. Inclusion/Exclusion Criteria In clinical trials, it's important to limit variables that could complicate the ability to observe and detect potential effects, as well as important to protect subjects and patients from being exposed to unnecessary risks. The establishment of strict inclusion and exclusion criteria addresses these needs. Inclusion criteria are defined as characteristics or factors that make a subject eligible for participation in the trial, whereas exclusion criteria are characteristics or factors that prevent subject participation in a given trial. Examples of criteria are the presence or absence of specific disease conditions, age, gender, other medical conditions, complications that could confound measurements, known sensitivity to medications, and so on. Female subjects who are pregnant, nursing, or planning to become pregnant have often been excluded from clinical trial participation, and this has severely limited the availability of treatment knowledge in pregnant populations for many products. To learn more about the inclusion of pregnant women in clinical trials click the learn more button. Otherwise, click next to continue with the main course. Learn More: Including Pregnant Women in Clinical Trials Historically pregnant women and women of childbearing potential have often been excluded from clinical trials to protect them and/or their fetuses from risks. However, this leads to a lack of clinical 16 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. data regarding the use of certain medications. This can lead to some unfortunate consequences. For example, pregnant women are prescribed and using medically needed drugs without the benefit of a full scientific understanding of the risks and benefits to themselves or their fetuses. As an example of the issues this can create decades after ACE inhibitors were approved for use, it was realized that first-trimester fetal exposure led to an increased risk of major congenital malformations. Another issue that stems from a lack of clinical data on pregnant women is that in some cases there's a reluctance to treat pregnant patients with established medications, fearing they could be potentially harmful to the woman and/or the fetus and that this harm might outweigh the positive effects of the given treatment. Physiological changes associated with pregnancy may have significant effects on the way that a drug is absorbed, distributed, metabolized, or excreted, and therefore clinical data obtained in non-pregnant populations may not adequately predict performance in pregnant patients. Given that pregnant women require drugs to manage diseases or treat medical problems just like any other segment of the population, in recent years a policy evolution is underway. Statutes, policies, and guidelines dealing with scientific and ethical considerations for the inclusion of pregnant women and women of childbearing potential in clinical studies have been addressing the overall gap in information. For example, the 21st Century Cures Act in the US provides for the inclusion of women as well as minorities in clinical research so that these groups have adequate representation. The Health and Human Services Task Force on research specific to pregnant women and lactating women has been established. The National Institutes of Health has established an Office of Research on Women's Health. Finally, the FDA itself has established an Office of Women's Health. These groups are working in concert to ensure that policies and guidelines related to the inclusion of pregnant women and women of childbearing potential are adequately addressed, and therefore the needs of these populations are adequately addressed in clinical studies moving forward. Inclusion/Exclusion Criteria Example This screen shows examples of inclusion, and exclusion criteria for the clinical trial, the efficacy of a single dose of aspirin versus acetaminophen in tension-type headaches. Some inclusion criteria, for example, are subjects must be healthy, ambulatory male or female volunteers between the ages of 18 and 65, have a history of tension headaches, have a history of responding to over17 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. the-counter analgesic products, understand the pain rating scales, and present with at least a moderate headache on a numeric rating scale. In that same trial, some examples of exclusion criteria are the history of hypersensitivity to analgesic products, history of gastrointestinal bleeding or ulcer, or current use of blood-thinning anticoagulant medications. Clinical Trial Documentation Clinical trial documentation must be carefully managed and is typically managed in the form of what's referred to as a trial master file. The trial master file is a collection of essential documents that a sponsor needs to manage to record how they've fulfilled the obligations for the clinical trial. A trial master file ensures the study documentation is adequately managed and contains essential documents. For example, found in a trial master file are such things as protocols, informed consent forms, ethics committee approvals, and so on. A trial master file is a regulatory requirement for the conduct of clinical trials. Clinical Trial Data Management Ensuring that clinical trial data are reliable and of high quality is essential to accurate assessments and valid conclusions, and certainly essential to justify the risks incurred by trial subjects. Data management processes within clinical trials ensure data integrity. Data management procedures are detailed in the clinical protocol. Data collected during clinical trials are highly structured, and data structure and terminology are standardized according to international standards, for example, CDISC. The Clinical Data Interchange Standards Consortium defines the standard format and terminology for use as applied to clinical trials. Case report forms are either paper or electronic documents that serve as tools for the collection of clinical trial data from individual trial subjects. Clinical trials typically have associated with them a secured database, which is a relational database that stores the data from the case report forms as well as data that are derived from raw data in case report forms. Of course, quality control and quality assurance are key for maintaining the integrity of data and are checked at each stage of data handling to ensure data integrity. Final Study Analysis Occurs When the Database is Locked When all data for a clinical trial is collected, when the final subject has been included in the final follow-up, and all this information has been captured, the database goes through a series of steps to ultimately become locked. 18 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Before this locking can occur, in the course of collecting data within the clinical trial, it's typical to have any number of inconsistencies or small errors or missing data elements, et cetera, so a step called database cleaning typically occurs, and this is where such deviations are followed up on and resolved prior to the database being locked. Once database cleaning is complete, the database is formally locked, and only after database lock is a blinded study unblinded so that the treatment assignments by individual subjects are known. In other words, were the subjects assigned to the control group, or were they assigned to the experimental group? Finally, the data are analyzed, and the output of the analysis is typically tables, listings, and figures presenting the key information provided by the data. These are statistical report elements, which capture the data and the analysis of the data, ultimately to be reported. Typically, the tables, listings, and figures are focused on the primary endpoint and tested for statistical significance. In other words, are any comparisons being made within the clinical trial leading to statistically valid conclusions? Clinical Trial Reporting Following the database lock and completion of the analysis, comprehensive information from the clinical trial is compiled and presented in the form of a clinical study report, sometimes referred to as a CSR. Clinical study reports are prepared in a globally harmonized format, which includes the elements of a synopsis, ethics committee review and approvals, investigational team, and administrative structure, study population, treatments, observations, measurements, analysis, and safety and efficacy evaluation. In other words, the endpoints, conclusions, and a number of appendices. Clinical Trial Transparency In order to address concerns related to transparency of clinical trial information, for example, the finding that historically clinical data that were favorable to an investigational product's future were more often reported than those that were unfavorable, initiatives through various government agencies have resulted in a requirement for clinical trial transparency. So, for example, in the United States, the website clinicaltrials.gov is a website sponsored by the National Library of Medicine and contains a database of clinical trial information that provides patients, health care professionals, and the public access to information on a wide range of clinical studies. 19 Copyright 2023 Biotech Primer, Inc. PROPRIETARY. DO NOT SHARE. Clinicaltrials.gov mandates the publication of registration data as a clinical trial is being planned and conducted, as well as results summaries once the clinical trial data are available. From any publicly or privately funded clinical trial in the US or involving US subjects, results summaries must be posted to clinicaltrials.gov within 12 months of the final subject being included in the trial. A similar system is in place in Europe through the EU Clinical Trials Registry, and this is very similar to what occurs with clinicaltrials.gov in the US. This mandates the publication of registration status and results information for clinical trials conducted in the European Union, and these are good sources of information for any ongoing or historical clinical study. Section 3: Conducting Clinical Trails Summary To summarize this section, we learned that: • Clinical trial enrollment, treatment, and follow-up are initiated after approval by ethics committees or institutional review boards, as well as agreement by regulatory agencies. • Participants in clinical trials include subjects, sponsors, investigators, sometimes principal investigator, ethics committee, institutional review board, and sometimes contract research organizations, or CROs. • A clinical protocol is a detailed, written plan for a clinical study. • Ethics committees and institutional review boards are independent committees that oversee the ethical conduct of clinical trials. • Informed consent is the process by which a subject voluntarily agrees to participate in a clinical trial after having been informed of all aspects of the trial, for example, planned trial procedures and any knowledge related to riskbenefit. • Inclusion criteria are characteristics or factors that make a subject eligible for inclusion in a clinical trial, whereas exclusion criteria are characteristics or factors that prevent subject participation in a trial. • Data integrity is essential in clinical trials and ensured through sound data management practices. • Clinical trial design procedures, data, and conclusions are compiled in a clinical study report. And finally • Publication of clinical trial registration and results summary information are required, for example, clinicaltrials.gov in the US. 20 Copyright 2023 Biotech Primer, Inc.