Keywords

14.1 Introduction

Clinical research is the science of designing, conducting, analyzing, and interpreting the results of clinical trials. The main aim is to understand whether a test article, such as a drug or a device or a procedure, has an effect on selected endpoints. Clinical research provides data or evidence based on a group of study participants rather than a single study participant.

By implementing methodical science and operations together, clinical research provides effective and/or improved therapies for patients. Most of the traditional medicines came into existence based on historical knowledge, personal experiences, and observational evidences, but they were not based on any formal validation. However, evolving times called for more rigorous and robust ways to evaluate the safety and efficacy of potential new therapies.

The main rationale behind clinical research is to find whether an intervention is efficacious and/or safe and that a response is not by chance. Utilization of proper statistics can help reduce bias. Clinical trials and studies need to prespecify endpoints and use sound statistical methods to analyze results. Like in any research, clinical trials may have limitations. For example, the study sample may not be representative of the population or the results are not generalizable.

Broadly, clinical trials are divided into Descriptive and Hypothesis trials. Descriptive trials do not test hypothesis and do not provide relation between the test article and clinical outcome. Most of the Phase I trials are Descriptive type. To evaluate whether a test article improves outcome, hypothesis testing trials are performed. Most of the hypothesis testing uses randomization.

Designing a trial plays a key role in clinical research. Well-designed trials yield interpretable results, whereas poorly designed trials yield uninterpretable results. Some of the questions that need to consider before and during study design and execution planning are as follows:

  1. 1.

    How to reduce bias?

  2. 2.

    What are the aims?

  3. 3.

    Do those aims address the appropriate issues?

  4. 4.

    What procedures are being followed to make sure the patient’s safety and rights are protected?

  5. 5.

    Is this trial feasible and practicable?

  6. 6.

    What is the target population for the study?

  7. 7.

    What kind of trial design is needed to address the study aims?

  8. 8.

    Is this trial ethically correct?

  9. 9.

    Do we have enough trial participants available to enroll?

  10. 10.

    Do we have the correct dose(s) to conduct study?

14.2 Ethical Issues: History of Clinical Research

There are unfortunately, several past experiences where study participants were subjected to unethical treatment and research procedures. As a result, clinical research is now a highly regulated field and regulations continue to evolve to protect human subjects. Before planning or conducting a clinical trial, clinical researchers must carefully consider if the study’s projected value outweighs the projected risks for study participants.

During World War II, German Nazi scientists performed horrific and dangerous experiments on concentration camp prisoners without any scientific rationale. Because of this, Nuremberg code emerged in 1946 with the following outcomes: (1) subject participation in clinical trial is voluntary (2) the researcher has to be qualified and should make every effort to protect the subject (3) the study design should be justifiable and scientifically sound. The Nuremberg code serves as a foundational document in clinical research, however its only focus was on human rights and did not address the questionable practices by investigators.

In 1937, an elixir, Sulfanilamide, which contained diethylene glycol, killed 107 people, many of whom were children. Even though FDA had a presence in the US before 1937, it was the Sulfanilamide case that provided the need to establish drug safety before marketing and made the passing of the 1938 Federal Food, Drug, and Cosmetic Act possible.

In post-World War II era, the use of sleep aids was widespread in the US and Europe. Thalidomide, a non-barbiturate sedative, entered into German market in 1957 and was marketed in 40+ countries by 1960. This was prescribed to pregnant women to reduce morning sickness without any studies supporting this specific use. Several kids were born with phocomelia: shortened, absent, or flipper-like limbs. In the US, FDA inspector Frances Kelsey prevented the Thalidomide’s approval despite pressure from the pharmaceutical company and from FDA supervisors. Kelsey felt the application for thalidomide contained incomplete and insufficient data on its safety and effectiveness. This motivated profound changes in the FDA. By passing the Kefauver-Harris Drug Amendments Act in 1962, legislators tightened restrictions surrounding the surveillance and approval process for drugs to be sold in the US which requires manufacturers to prove the safety and efficacy before they are marketed.

Tuskegee experiment: One of the most notorious cases which supported the development of the informed consent process and the Informed Consent Form (ICF) was the Tuskegee experiment. Researchers followed 400 African American men with syphilis for the natural course of disease however, researchers denied those men the available treatment for syphilis during the trial period. In addition, there was no scientific need for including only African Americans. This led the National Institutes of Health requirement for institutions conducting clinical research to have an Institutional review board (IRB) or Ethics committee (EC) to assess and approve clinical trial protocols. The primary purpose of an IRB or EC is to protect study participants.

As a result of all these historical tragedies, Good Clinical Practice (GCP) guidelines came into existence in clinical research. Furthermore, the International Conference on Harmonization (ICH) requirements for registration of pharmaceuticals for human use created standards for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.

The main ethical principles for clinical research are (1) a clinical study’s potential benefits should always outweigh the risks, (2) informed consent from study participants, (3) fairness towards all study participants, and (4) study participant’s rights to keep their information confidential.

Two pioneering regulatory authorities, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have created the Investigational New Drug Application (IND) and the Clinical Trial Application (CTA) process, respectively, before granting the approval to conduct clinical trials in humans. For an IND application, all nonclinical study reports, nonclinical summaries, detailed chemistry, manufacturing, and control (CMC) information, as well as the protocol and Investigator Brochure (IB) (summary of the known nonclinical and clinical safety and efficacy information of the test article) are submitted. FDA has a 30 day review period for an initial IND. For a CTA, the protocol, informed consent form (ICF), IB, and Investigational Medicinal Product Dossier (IMPD) are required for submission. The average timelines for review of a national CTA is ~60 days [1].

14.3 Phases of Clinical Trials

Demarcation of Clinical trial Phases (I, II, III, and IV) are not clearly defined as it depends on therapeutic areas. Clinical development success rates are dependent on several factors and vary from one phase to another phase and from one therapeutic area to another. BIO, which is a trade association of biotechnology companies, has published the success rates of Phase 1 to regulatory approval to be around 10%. This was higher in rare diseases and lower in chronic diseases. With respect to success in different phases, lowest success rates were observed in the transition from Phase 2 to Phase 3 [2].

Phase 1 studies: Phase 1 studies are also addressed as First-in-Human (FIH) studies where adequate scientific justification and well-designed methodology is an essential part to move the test drug to advanced phases. Phase Is in most therapeutic areas (exceptions are Oncology and rare diseases) involve healthy volunteers. Typically, these studies are smaller with around ~20–80 study participants. These studies aim to establish a safe dose. Starting dose selection should be conservative in the approach so that the first dose tested does not produce unmangeable adverse events. Phase I is a very exciting time for drug development where researchers work to understand whether the drug is safe; researchers may also begin to explore whether the drug has direct or indirect efficacy. In addition to the safety and efficacy, Phase Is may also provide information about tolerability and pharmacological effects of the test drug.

The majority of the phase 1 studies are conducted in Phase 1 units where study participants are in an inpatient setting with close monitoring. Starting dose generally determined in first-in-human studies is based on mostly either No Observable Adverse Effect Level (NOAEL) that involves applying appropriate scaling factors to adjust for body surface area among different species or based on minimal anticipated biological effect level (MABEL) approach where all in vitro and in vivo information is taken into consideration. Dose escalation is conducted in different ways in these studies, i.e., single ascending dose (SAD) and multiple ascending dose (MAD) studies (Fig. 14.1). In SAD studies, drug is administered to a small group of study participants. Starting dose of SAD may be multiple orders lower than the expected efficacious dose. After completion of dose limiting toxicity (DLT) period, a new group of study participants will be exposed to the next dose level of drug. Based on route of administration, regulatory authorities may also require drug–drug or drug–food interaction studies. In addition, in order to rule out cardiovascular liabilities, thorough QT studies are also requested by regulators. Some key considerations that sponsors need to concentrate are (1) selection of correct doses, (2) paying attention to any adverse events of special interest that may emerge, (3) any preliminary correlation of biomarkers to safety and/or efficacy, and (4) selection of the countries/sites follow ICH guidelines. From this stage, approximately 70% of test drugs move to the next phase.

Fig. 14.1
figure 1

Graphical representation of Single Ascending Dose (SAD) (Left) and Multiple Ascending Dose (MAD) (Right) schema. Each triangle represents dosing and each alphabet represents different cohorts

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14.3.1 Phase I Lessons Learned

  1. (a)

    TeGenero Immuno Therapeutics was developing TGN1412 for B cell lymphoma or rheumatoid arthritis. TGN1412 is a humanized monoclonal antibody which binds and causes agonism to the T cell’s CD28 receptor. In preclinical experiments, TGN1412 did not cause any pro-inflammatory responses, however TGN1412 led to T cell expansion. TeGenero also conducted toxicological studies using rhesus and cynomolgus monkeys because they have similar affinity for TGN1412 because of 100% sequence homology of extracellular domain of CD28 receptor. They also conducted a repeat dose pilot study in cynomolgus and rhesus monkeys with dose range from 5 to 50 mg/kg; however they did not observe any systemic immune system dysregulation or hypersensitive reactions even with the highest dose tested. Based on the animal data, TeGeneroTGN1412’s phase I was initiated in 2006 by PAREXEL in London. Starting dose was selected based on a NOAEL approach. Six volunteers who were administered a subclinical dose of 0.1 mg/kg were within a short span of time admitted to the intensive care unit. Although the dose was 500 times lower than in animal studies, all six volunteers had multi-organ failure from rapid release of cytokines by activated T cells, i.e., cytokine release syndrome (CRS) minutes after infusion. One of the participants experienced a balloon head similar to elephant man. United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) initiated an investigation on the trial procedures and ethics and they did not find any flaws with procedures associated with preclinical to clinical study transition; however there were several deficiencies in trial conduct, such as inadequate maintenance of medical records, improper qualification of trial staff, inadequacy in ensuring insurance protection of the sponsor, and failure in arranging early medical coverage.

    An important reason for the lack of CRS in animal models compared to humans was laboratory animals may not have the similar density of memory T cells when compared to humans and that these memory cells could have been activated by the TGN1412 in the trial. Some lessons learned from the TGN1412 trial are (1) prior to clinical trials, more in vitro human tissue experiments are needed, such as immobilized mAb-based assay or endothelial cell co-culture assays which may predict pro-inflammatory response in humans, (2) NOAEL alone may not be enough for starting dose selection, (3) all the volunteers of same dose cohort should not be dosed at the same time, and (4) prepare for unexpected adverse events based on preclinical data and the mechanism of action of the drug.

  2. (b)

    In 2016, BialPortela, a Portuguese pharmaceutical company, had started a Phase I with BIA 10–2474, a fatty acid amide hydroxylase (FAAH) inhibitor which led to one death of a subject and caused serious neurological damage in few other healthy volunteers. This trial was done by a contract research organization, Biotrial in France on behalf of the BialPortela. The trial was approved by the French National Agency for Medicines and Health Products Safety (ANSM) and a local institutional review board. Endpoints for the study were safety, tolerability, pharmacokinetic, and pharmacodynamic profile of BIA 10–2474 with single-ascending dose (SAD) and multiple-ascending doses (MAD) in healthy volunteers. A few other companies had taken similar molecules through phase I and II trials without any incidents. Based on NOAEL data in the rat, the human equivalent dose was determined to be 100 mg. Planned starting dose in SAD was 0.25 mg/day. After 0.25 mg/kg, other dosing cohorts were planned with 1.25 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 40 mg, and 100 mg/day. A total of 90 subjects completed treatment without incident in the SAD and in the first four MAD cohorts. One subject became ill after the fifth dose in the fifth MAD cohort, and was admitted to the hospital with symptoms similar to stroke. Despite this, remaining subjects in the cohort continued to be dosed until the study was suspended later that day. Four of the five subjects who were dosed were eventually hospitalized, and the first subject incurred brain injury that resulted in death. Hemorrhagic and necrotic lesions were seen on brain magnetic resonance imaging (MRI) of the subjects. One probable reason for this serious adverse event was BIA-102474-101’s non-selectivity to FAAH at the higher doses and can bind other molecular targets. Doses administered in the affected cohort of the BIA-102474-101 study were several-fold higher than required to fully inhibit FAAH. Following this incident, some companies had voluntarily suspended the development of FAAH inhibitors. Some of those were even in Phase II stage, such as JNJ-42165279.

Some lessons learned from this trial are (1) incorporate detailed stopping rules at the subject, cohort, and study levels, (2) ensure integration of the pharmacokinetic/pharmacodynamic data and modeling to determine the appropriate doses and schedule, (3) screen the off-target effects of test drugs with higher dose ranges as MADs can be higher than SADs, and (4) NOAEL may not be suitable for all test drugs in selecting the starting dose.

Phase II studies: The purpose of this phase is to understand efficacy and side effects of test article. In general, Phase II studies enroll patients (n = 100–300) and generate early efficacy and additional safety data. This phase can be divided into IIa and IIb. Phase IIa is the first trial in patients with several doses and phase IIb is to find the efficacy with the selected dose of IIa. After Phase II, the sponsor can meet with FDA to obtain guidance on Phase III design and studies (aka “end of Phase II meeting”). Consulting FDA can be informative however, an end of Phase II meeting will not guarantee regulatory approval. From Phase II, approximately 33% of test drugs move to the Phase III.

14.3.2 Phase II Lessons Learned

  1. (a)

    Olmutinib, by Hanmi Pharmaceuticals, is a third-generation epidermal growth factor receptor (EGFR)-targeted therapy for EGFR mutation-positive lung cancer and was approved in Korea. FDA had granted breakthrough therapy designation for Olmutinib’s development in the US; however, South Korea’s Board of Audit and Inspection found significant deviations in Hanmi’s monitoring and reporting of the Phase II study where patients had developed toxic Stevens-Johnson syndrome, one of which was fatal. Hanmi was cited by regulators for not reporting the death until 14 months later.

Some lessons learned from Olmutinib’s clinical development are (1) transparency with regulatory authorities is critical in development and (2) timely reporting of any adverse events and deaths is required.

Fraud in clinical research is rare but sometimes occurs with individual clinical investigators at the site of clinical trial. Fraud can tarnish science, an institution’s reputation, and patients beliefs. Any fraud found should be reported to the IRB/EC and regulatory authorities immediately. Several countries have legal protection for whistle-blowers. Some examples of investigator fraud are as follows:

  1. 1.

    Professor Werner Bezwoda of the University of the Witwatersrand, Johannesburg, South Africa, reported in conferences in the 1990s the beneficial effect of autologous stem cell transplantation with chemotherapy in solid tumors. He showed a striking benefit of high-dose chemotherapy for both lymph node-positive and metastatic breast cancer. As there were striking differences with the results from other investigators, NCI physician auditors conducted an on-site audit and found fraud. It is known that high-dose chemotherapy is toxic and autologous stem cell transplantation is very expensive, but Bezwoda’s study required patients to be exposed unnecessarily. In addition, inspectors were not able to find all patients’ consent forms and not all the patients were eligible for the study. Bezwoda only provided data from the high-dose chemotherapy patients of the trial and did not share the control group data. He later admitted to falsifying the data.

  2. 2.

    Dr. Robert Fiddes was the director of the Southern California Research Institute in the 1990s and was the lead clinical investigator for a large number of clinical trials conducted for various sponsors. Dr. Fiddes was famous for rapid recruitment of patients into clinical trials with a low dropout rate. A whistle-blower contacted the FDA about the enrollment of ineligible patients and fictitious patients. Several laboratory data were altered and fabricated. For example, in order to obtain proteinuria urine samples, he allegedly paid an employee who was proteinuric for urine sample. After thorough investigation, Dr. Fiddes pled guilty to fraud in 1997 and was sentenced to 15 months in prison.

Phase III studies: Phase III trials are generally large global trials with many study participants (n = 300–20,000 or more) and are very expensive to conduct. At the end of these Phase IIIs, marketing approval will typically be submitted and reviewed by regulatory authorities. There is no specific rule however, at least one successful Phase III trial is needed to demonstrate a drug’s safety and efficacy, in order to obtain full marketing approval from regulatory agencies such as FDA or the EMA. Most of the time, FDA requires large, confirmatory or registrational, phase 3 studies to ensure the safety and efficacy of test drugs. One research from 359 studies showed the main reasons for Phase III suspensions are ranked in order of efficacy>commercial>safety [3]. Some efficacy reasons for Phase III failures are (1) high placebo response, (2) biomarker-based efficacy prediction failures, and (3) different mechanism of action. From Phase III, approximately 25–30% of test drugs move to the next phase.

14.3.3 Phase III Lessons Learned

  1. (a)

    Most Phase III studies utilize global multicenter randomized study designs. Randomization is considered the gold standard of clinical trials, however it is important to note that not all regions perform the studies with the same quality standards. NIH initiated the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial to determine whether treatment with spironolactone would improve clinical outcomes in patients with symptomatic heart failure and a relatively preserved ejection fraction. There was a benefit with the treatment in South and North America, however no change in Russia and Georgia. To assess adherence in different regions as post hoc analysis, the spironolactone metabolite canrenone was measured in that study. Canrenone levels were undetectable in 30% of participants from Russia, as compared with only 3% from the United States and Canada. One important lesson learned from TOPCAT is even though global clinical development is less expensive in certain countries, differences in the level of quality should be carefully considered.

  2. (b)

    Phase IV studies: Phase IV trials focus the side effects caused over time by an approved marketed drug. These studies specifically look for adverse effects that were not seen in earlier trials and may also study how well a new treatment works over a long period of time. Phase IV clinical trials may include thousands of people. Sometimes these are also called as post-marketing surveillance trials.

    Most of the time, Phase IV drugs are withdrawn from the market because of either any safety finding or commercial viability.

14.3.4 Investigator-Initiated Studies (IISs)

Investigator-Initiated Studies are research studies typically sponosored by investigators with support from pharmaceutical companies. IISs generate additional efficacy data and often aim to address clinical questions observed in everyday practice. Most pharmaceutical companies who establish IIS programs require Investigators to submit a proposal that must be reviewed and accepted by supporting company prior to conducting the trial. Some advantages of IIS are (1) reduced cost and complexity compared to larger multi-center trials, (2) reduce off-label use of drugs, and (3) generate data which may lead to supplemental approvals.

14.4 Clinical Trial Protocol Contents

The clinical trial protocol is a key document that describes how a clinical trial will be conducted and ensures the safety of the trial subjects and integrity of the data collected. Below are some of the sections included in a clinical trial protocol (not all protocols have the same sections or same order).

14.4.1 Trial Synopsis

This section provides brief summary of the whole protocol with rationale, objectives, endpoints, trial design, etc.

14.4.1.1 Visit Assessment Schedule or Schedule of Activities or Time and Events Table

This is an important section where information on various study procedures and timing of study assessments are outlined.

14.4.1.2 Introduction

This section provides information on the disease(s) that the protocol is evaluating and also information about the investigational agent. In addition, a summary of preclinical and clinical studies (both efficacy and safety) will also be present. This section will include key information about rationale and benefit-risk assessment of the study.

14.4.1.3 Objectives and Endpoints

This section outlines the aims of the protocol. The endpoints (outcomes) are divided mainly into primary, secondary, and exploratory categories and assess efficacy, safety, pharmacokinetic, and pharmacodynamic measurements. Endpoints should be reliable and robust. Endpoints will differ based on the phase of the study, objectives, and the indication that is being evaluated. In some cases where clinical outcome endpoints are not feasible or practical, surrogate endpoints can be used.

14.4.1.4 Trial Design

In this section, the type of design used for the study will be described. The designs can be either a traditional design or flexible design. Traditional design has no flexibility, i.e., they are rigid to changes. Flexible designs can be altered based on safety and efficacy. Even though flexible designs need more time and effort, they can move faster than traditional designs.

14.4.1.5 Trial Population

Type of trial population needed for the study is described in this section. The criteria should be described properly without any confusion or openness. In this section, both inclusion and exclusion criteria will be described. These criteria need to have practically feasible requirements, to avoid slow or limited recruitment. In addition to study entry, information on rescreening will be elaborated here for screen failure subjects.

14.4.1.6 Treatment

In this section, the manner in which treatment is assigned to the study subjects will be described. The type of design plays an important role here because treatment assignment can be either open or blinded. The protocol describes how the subjects are numbered and how subjects get their test article assignment. This section has more information related with Interactive Response Technology (IRT). IRT system can be either Interactive Voice Response or Interactive Web Response systems or both.

The other section in treatment includes information on the preparation and administration of the test drug. This may be included in a document called pharmacy manual. In some studies, premedication and supportive care administration are also needed and those will be described here as well. Permitted and prohibitive concomitant medication information are also added in this section.

If there is any issue with the preparation of test article, such as presence of particles in prepared product and discolorations, site staff must notify the sponsor.

14.4.1.7 Dose Modifications and Safety Management Guidelines

In this section, safety management information from preclinical studies and previous clinical studies are summarized. Dose limiting toxicity periods are discussed and also the type of adverse events which can lead to study discontinuation are described here. For some adverse events, the dose can be reduced with proposed reductions or the dose can be delayed. To prevent some specific adverse events, mitigation plans can be described in this section.

14.4.1.8 Discontinuation, Follow-up, and Completion

This section provides information on the reasons behind discontinuation of the treatment and trial. It also has information on follow-up of safety evaluations. In addition, the protocol describes how follow-up is conducted and with what frequency. The protocol also provides information on lost to follow-up subjects.

14.4.1.9 Trial Assessments

In this section, the protocol describes the parameters to be collected from participants, such as Demography, Baseline Assessments, Medical History, Concomitant Medication, Physical Examination, Body Measurements, Vital Signs, Electrocardiograms (ECG) and Prior Therapy and Surgery. This section also describes the methods that will be used to measure Efficacy Assessments, Pharmacokinetics, and Biomarkers.

14.4.1.10 Safety Monitoring and Adverse Event Reporting

This section has several safety aspects of protocol, including method to report adverse events. If there are any adverse events of special interest including special scenarios, such as pregnancy of a trial participant, they are described here. This section also has information about intensities and relatedness of the adverse events. Some studies utilize Data Monitoring Board (DMB) to get unbiased view of safety data. If study uses DMB, this section delineates as to when they investigate that data.

14.4.1.11 Statistics

This is a crucial section for any study. This section describes how analysis will be conducted and what sets of data (safety, efficacy, pharmacokinetic, biomarker, vital signs, laboratory abnormalities, and ECGs) will be used. Sample size selection details are also described. Missing values are very common in clinical trials and this section describes the information on using missing values here.

14.4.1.12 Data Handling and Record Keeping

This section provides the information associated with data entry, recording, and retention policies. It also has information related to Investigator Responsibilities, EC or IRBs, Informed Consent, and Privacy of Personal Data.

14.4.1.13 Administrative Procedures

This section has all administrative procedures, such as Contractual and Financial Details and Insurance, Indemnity and Compensation.

14.5 Clinical Trial Designs

As not all clinical trials are the same, clinical design selection depends on aspects, such as randomization (process of assigning the treatment to subjects in a random manner may be by a permutation of a sequence) and stratification, blinding (concealment of treatment group allocation from one or more individuals involved), placebos, sample size, selection of a control group, target population, and endpoints. The main objective of a clinical trial is to demonstrate the effect of test article.

14.5.1 Parallel Design

There are two types of parallel designs: (a) single arm and (b) multiple arm. In single-arm design, there are no placebo or comparison interventions. Even though technically single-arm design is not parallel design, it is still considered as parallel design. One of the issues with single-arm design is determining whether the change is due to other factors or the intervention. Even though this design is not the same level of rigor as a randomized study, single-arm designs are easier and less costly to conduct. These designs are appropriate when the efficacy will not occur by itself generally, when the efficacy is obvious, and when the patients are rare and homogenous. Multiple arm parallel design is the common clinical study design where it has less complex underlying assumptions when compared to other designs. In multiple arms, each group receives one type of treatment and this design has least risk for bias. Compared to other clinical designs, these design studies do not take long time to complete. One main issue with this design is variability in groups may have an impact. To reduce this variability, within-patient or between-patient designs can be used.

14.5.2 Within-Patient Designs

Each patient receives both treatments, i.e., one treatment in one period, and different treatment in another period. This switch can also be with placebo to active treatment. This comparison in each subject with themselves minimizes the variability among different subjects. Because of the same subjects’ utilization for different treatments, this design needs fewer subjects than other designs; hence it may not be as expensive to run as parallel designs. Some disadvantages with this design are temporal effects (disease improvement or worsening in one direction), carryover effects, in between dropouts of subjects, and longer time to complete the studies.

Common within patient designs are crossover trial design and Latin square design (Fig. 14.2). Crossover trials are commonly used in Bioequivalence studies, pharmacokinetic studies, and drug–food interaction studies. Latin square designs are common with orphan diseases where the subject availability is difficult.

Fig. 14.2
figure 2

(a) Crossover study design. (b) Latin square design. (c) Factorial design (e.g., GOG240 2 × 2 design)

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14.5.3 Factorial Designs

Factorial design contains two or more interventions with two or more quantities of the interventions; hence 2 × 2 design has two levels and two factors (Fig. 14.2).This design is widely used for very large mortality studies. Greco-Latin square Factorial design is with a Latin square and it is uncommonly used in clinical studies. Some drawbacks of this design are (1) possibility for interaction among different interventions and (2) this design is incomplete if it misses any possible combination.

14.5.4 Group Sequential Designs

Group sequential design is a type of adaptive design where the number of patients is not set in advance. Stopping rules specify when and why a trial might be halted. This design facilitates interim analysis and positive data allows to continue the study and negative data makes the study to stop. Patients are divided into an equal number of groups and data is analyzed at predetermined points in the trial. Basic requirements for this design are (1) intervention’s effects occur rapidly and (2) modification of trial is possible. Oncology trials often use this type of trials where they have preset arbitrary efficacy bars with a different bar in each stage of the sequential trial.

Precision Medicine Trials: Based on precision medicine premise, biomarker-positive patients get treatment benefit and negative patients may not get benefit. Two types of trials where biomarker-positive patients are specifically enrolled to test the efficacy especially in oncology and they are

  1. 1.

    Basket trials: If the plan is to find the effect of a specific treatment within a biomarker-positive subgroup, a basket trial will be good way to find out the effect in different subtypes of disease. Example: In BRAF V600 mutation biomarker patients were tested in different cancers (5 baskets = 5 subtypes of cancers) by the drug Vemurafenib [3].

  2. 2.

    Umbrella trials: In contrast to basket trials, the umbrella trial evaluates many treatments within a single histology. Trial participants are assigned to a specific treatment arm of the trial based on their specific molecular makeup of their cancer. Example: In Lung-MAP, patients get a genomic profile to determine the genomic alterations, or mutations, which may drive the growth of their cancer and are treated based on the results [4].

14.6 Key Staff at Investigative Sites (at Clinic)

14.6.1 Principal Investigator (PI)

The PI is the lead individual at the site that is responsible for leading the clinical trial. This individual is often a medically qualified doctor. The PI’s job is to protect the rights, safety of study participants. PIs typically have several Sub-Investigators (Sub-I) who are also medically qualified doctors. The PIs and Sub-Is, ensure the protocol is executed exactly as written, oversee the activities of the research team, and oversee all protocol amendments, regulatory compliance paperwork, and reviewing adverse events. PIs also supervise data collection, analysis, interpretation, and presentation.

14.6.2 Research Nurse/Site Coordinator

Research nurses hold an active registered nurse (RN) license and handling some of the medical duties, such as administering drugs or performing exams. They communicate regularly with the principal investigator and train staff and educate patients about the trial. They play a crucial role in study monitoring, quality assurance, and data entry management.

Site coordinators who do not have RN license or medically qualified degree will not perform any medical duties, however these individuals handle the daily conduct of study such as screening participants, obtaining informed consent, checking eligibility, collecting, and entering data.

14.6.3 Data Manager (DM)

Data managers manage the entry of data and provide data output to the required parties throughout the course of a clinical trial. DMs also prepare summaries for interim and final data analysis.

14.7 Key Staff at Sponsor or CRO

Safety Physician*, Safety Scientist*, Data programmer*, Stats programmer*, Pharmacometrician*, Medical writer*, CRA*, CMC lead*, Project manager*, Translational medicine lead*. (*—Description for these roles are not provided here).

14.7.1 Medical Monitor (MM)

Medical monitors are mostly physicians. MMs provide medical expertise and oversight for the entire clinical trial and provide guidance of the medical aspects of the protocol. MMs closely work with other team members in designing the clinical trial design. They ensure the clinical integrity of the trial subjects and provide safety accountability across the duration of the study with great knowledge on good clinical practice (GCP). MMs may also present and discuss data findings at advisory committee meetings. They also provide medical input to relevant pharmacovigilance activities throughout the trial.

14.7.2 Clinical Research Scientist (CRS or CS)

CRSs are mostly qualified scientifically or clinical trianed professionals with degrees ranging from BS, MSN, to MD/PhD. An important aspect is that CRSs need to have knowledge about disease(s) included in the protocol, the test article, GCP, and organizational management skills. CRSs work very closely with MMs and Clinical Operations Lead. Some of the activities that CRSs spearhead are:

  1. 1.

    Develops relationships with appropriate KOLs to obtain feedback on protocol design and strategy.

  2. 2.

    Provide input on study design and author protocols. Provides protocol training to internal/external team members.

  3. 3.

    Ongoing medical review of data (issuing/closing queries as applicable).

  4. 4.

    Assist in the review of clinical data for key deliverables.

  5. 5.

    Tracks, review, and/or summarizes safety and efficacy data for ongoing studies (as needed).

  6. 6.

    Reviews and summarizes safety data for safety calls (Phase 1 studies) or safety review meetings.

  7. 7.

    Respond to questions about the protocol by health authority, ethics committees, and investigational sites.

  8. 8.

    Assists in the development and review of abstracts, posters/presentations, and manuscripts.

14.7.3 Clinical Operations Lead or Clinical Management Team (CMT) Lead

The Clinical Operations Lead plans, directs, and coordinates operational activities of clinical studies. The CMT lead works very closely with the sites, CRAs, and other functional area team members. Some of the activities of CMT lead, but not limited to, are

  1. 1.

    Drive vendor selection and vendor management.

  2. 2.

    Day-to-Day management of the trial operational activities.

  3. 3.

    Work closely with MM, CSR, Data Manager, and Biomarker operations management team.

  4. 4.

    Master service agreement (MSA) and Clinical Trial Agreements setup.

  5. 5.

    Responsible for developing recruitment plans.

  6. 6.

    Perform Sponsor oversight/Booster visits.

  7. 7.

    Work closely with project manager that study is progressing according to agreed to timelines and budget.

  8. 8.

    CMT lead provides oversight on CRO management, if there is a CRO involvement.

14.7.4 Clinical Data Manager (CDM) or Data management Lead (DML)

CDMs are responsible for collecting data from various sources (both internal systems and external systems) in the clinical study. They work collaboratively with data programmers and statisticians to make sure data is collected, managed, and reported clearly, accurately, and securely. Clinical data managers have a variety of educational backgrounds and professional experience. Most have degree in life sciences, computer science, or information technology. Some may have graduate certifications in areas such as clinical data management, health informatics, or biometrics. Some of the activities of CDM, but not limited to, are

  1. 1.

    Electronic case report form (Where the trial participant’s data is entered) (eCRF)development.

  2. 2.

    Data quality review.

  3. 3.

    Data delivery for documents and presentations.

14.7.5 Clinical Study Statistician

Statisticians can work on study design, randomization, sample size estimation, statistical methodology, and analysis and reporting. Their main role is to ensure that study’s questions will be answered while satisfying regulatory requirements. Statisticians work very closely with statistics programmers who uses programming software such as SAS® to deliver quality data. Statisticians have Masters or a PhD in Statistics or Mathematics. Some of the activities of statisticians, but not limited to, are:

  1. 1.

    Contribution to trial design.

  2. 2.

    Contributor to development of protocol.

  3. 3.

    Perform vendor oversight related to key deliverables, e.g., SAP, Statistical QC plan, interim analysis.

  4. 4.

    Perform exploratory analysis, ad hoc analyses, and modeling of data.

  5. 5.

    Review and approve the tables, figures, and listings of clinical study.

  6. 6.

    Presenting study data in presentations and publications.

14.8 Summary

Clinical research is highly regulated field as it supports the evaluation of experimental therapeutics in human subjects. Ethical principles and historical lessons led to the development of guidance documents that serve to protect human subjects from wrong doing and establish standards that must be adhered to when conducting clinical research. A brief history of clinical research lessons, trial phases, clinical protocol contents, trial designs, and clinical research team compositions has been shared to support your quest to learn more about this exciting field. To increase the success rate from Phase I to marketing approvals, the drug development industry is working on novel study designs and biomarker-driven approaches. As Science and Regulations around clinical research are evolving rapidly, current and prospective researchers should keep abreast of current regulations mainly through the FDA, EMEA, and ICH websites.