Clinical Trial: Protocol Designs and Future Considerations

What is a clinical trial?

A carefully and ethically designed experiment with the aim of answering some precisely framed question

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What is a protocol?

A formal document which describes all aspects of a clinical trial including design. Protocol design is critical to the outcome of clinical trials. Summary of reason for drug, establish questions to explore

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State features of poorly designed trials

Unsafe, unethical, unscientific. Lead to erroneous conclusions. Potentially may harm study participants and general public

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Describe features of study protocol background (1)

Summary information (reason for study e.g. development of new drug). Pathology of disease, rationale for development of novel compound (first in class/improvement on existing therapies). Information (pre-clinical/clinical available to date)

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Describe features of study protocol background (2)

Appropriate to stage of development. Rationale of study. Primum non nocere (first do no harm), risk/benefit assessment

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Describe features of study protocol objectives (1)

Derived from hypothesis being tested e.g. is drug A more efficacious than drug B. Usually only one single primary objective (efficacy, safety, bioequivalence), endpoints should be clearly stated (e.g. topical antibiotic - eradication of infection)

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Describe features of study protocol objectives (2)

E.g. anti-epileptic drug for reduction in seizure frequency. SMART (specific, measurable, achievable, realistic, timely). • Endpoints must be practical and realistic (use of human volunteers in clinical trial). Can have secondary objectives

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Describe features of study protocol objectives (3)

PK profiles, oncology - reduction in tumour volume. Tertiary objectives e.g. looking at new biomarkers for an indication

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Describe features of study designs (1)

Number study designs. Vary according to objectives of the protocol. Pilot exploratory (typical in first human studies). Pivotal (phase II/III studies)

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Describe features of study designs (2)

Open - typical in phase I oncology studies, no placebo included in study design, looking at drug for the first time in oncology patients – those who have advanced diseases/failed in other treatments/metastasis developed

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Describe features of study designs (3)

Don’t want to expose patients to placebo

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Give examples of study designs (1)

Open/single blind/double blind. Randomised/controlled/uncontrolled. Placebo/active. Parallel/crossover/matched pairs/add on. Integrated. Each aspect of design can be used in collaboration with any of the others. Scientific, practical and realistic

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Give examples of study designs (2)

Study designs depend on objectives

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Describe features of pilot studies (1)

Small scale, exploratory studies often employed in early clinical development. Phase 1 - first in human evaluation, pilot POC (phase 1/IIa), involve healthy volunteers and patients. Employed to examine practical feasibility or when outcome is unsure

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Describe features of pilot studies (2)

Not statistically powered. Should employ full rigour of a controlled study design without compromising flexibility. Randomised, placebo/comparator controlled, blinded designs. Not quick and poorly structured

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Describe features of pilot studies (3)

Pilot studies – exploratory study (only rely on preclinical data, first in man, no previous data of use of drug in humans

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Describe features of pivotal studies (1)

Critical studies in submission dossier for a product licence (phase 2b/3). Define crucial landmarks in a drug's development e.g. confirmation of efficacy, confirmation of bioequivalence. Attracts scrutiny by Sponsors and Regulators

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Describe features of pivotal studies (2)

Doesn't imply one type of design. Must be a controlled randomised statistically powered design. Subject numbers must be sufficient to enable the objectives to be met. Likely to be subject of regulatory audits for a product licence application

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Describe features of pivotal studies (3)

Pivotal studies – phase 2b/3 studies, confirm safety profile (drug licensing), power calculation (reason for requiring lots of data sets to be completed). (483) - Repeated missing samples, unsuitable subjects, dosing errors, no waivers allowed

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Describe features of open label studies (feasibility study)

Use controversial. Leads to problems of bias in interpreting data. All parties aware of treatments being administered. Avoid unless - employed on compassionate grounds, treatment IND, phase I dose ranging studies in terminally ill patients

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Describe aspects of design - Blinding (1)

Blinding. Identity of treatment in trial in unknown by one or more parties. Single blind (one party unaware, PK study solution vs tablet - analyst blind)

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Describe aspects of design - Blinding (2)

Double blind (two parties unaware, efficacy study when neither the investigator or subject is aware of the identity of the treatment). Avoid bias in the interpretation of data. Increasing level of blindness increases complexity and costs of studies

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Describe aspects of design - Blinding (3)

Common sense approach needed for safety and practicality

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Describe aspects of design - Randomisation (1)

Randomisation - process by which subjects are assigned to a treatment group by chance, reduces bias with interpretation of data

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Describe aspects of design - Randomisation (2)

Randomisation can be stratified/balanced for treatments and subjects e.g. age and gender, smoking status, alcohol intake, disease staging - BP, genetic profile

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Describe aspects of design - Randomisation (3)

Randomisation – subjects assigned to a treatment group by chance e.g. epigenetic profiles of disease (determine effective treatments for particular genes)

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Describe aspects of design - Use of Controls (1)

Benchmarks the effect of new therapy. Confirms/supports validity of study design. Use should be concurrent. Choice of control depends on phase of development and specific objectives of trial

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Describe aspects of design - Use of Controls (2)

Type of controls (placebo - FIM and POC studies, active comparator - early POC and phase III efficacy and studies, reference standard - PK studies). Confirm/validate study design, historical controls not recommended

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Describe aspects of design - Use of Placebo (1)

Inert medication. Reduces bias and background and noice in interpreting data. Distinguishes pharmacodynamic effects from psychological effects, avoids incorrect conclusions

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Describe aspects of design - Use of Placebo (2)

Value of placebo in early clinical development studies evaluation cannot be emphasised. In later phase studies, can be used only when no standard treatment exists or existing standard treatment is ineffective or unproven

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Describe aspects of design - Use of Parallel Designs (1)

Subjects are randomly allocated to one of the treatment groups. High inter-subject variability. Subject numbers are increased to achieve statistical power. No carry over period effects. Ideally a stable disease condition required

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Describe aspects of design - Use of Parallel Designs (2)

Useful when a drug has a long half life. Employed in definitive dose ranging and therapeutic efficacy studies

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Describe aspects of design - Use of Parallel Designs (3)

Parallel designs – no carry over or period effects (subjects get one treatment), for phase III trials e.g. one group receive placebo, one group receive drug (parallel design, two treatments)

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Describe aspects of design - Crossover Designs (1)

Subject receives each treatment in a random order separated by an appropriate washout period. Reduces intra-subject variability. Subjects act as their own controls. Smaller subject numbers required to achieve statistical power

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Describe aspects of design - Crossover Designs (2)

Stable disease condition is essential. Subject to carry over and period effects, compromised by withdrawals/dropouts. Often selected for early phase drug development

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Describe aspects of design - Crossover Designs (3)

Subject to carry-over effects (effects in patient in first treatment is carried over to second treatment, no wash out period established), usually used in PK and PD studies

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Describe aspects of design - Crossover Designs (4)

Issue (e.g. patient may withdraw during treatment 4, either replace patient in treatment 4 or add a patient and start from first treatment towards treatment 4, study can be compromised, study may need to be extended)

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Describe aspects of design - Crossover Designs (5)

Useful when investigating bioequivalence studies (given the PK profile of the drug, and establish a wash out period, need to have at least 5 half-lives or greater)

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Describe features of integrated protocols (1)

Single protocols. Very useful in early clinical development. Exploratory, flexible, adaptive. Usually divided into a number of parts. Single dose, multiple dose, food effect, POC in small number of subjects

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Describe features of integrated protocols (2)

Tightly controlled investigation, producing reproducible serial homogenous data without compromising safety or scientific validity

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What are the advantages of integrated protocols? (1)

Allows a more focussed scientific investigation of safety, exposure, activity. Maximises information, gathering under very controlled conditions. Where possible allows a go/no go decision about compound progression to be made earlier

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What are the advantages of integrated protocols? (2)

Permits a more rationale dose selection for later phase studies

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Describe features of classically designed clinical trials (1)

May not offer enough flexibility. Decisions on sampling measures within a trial are made and fixed in advance. In a classical trial patients are allocated equally to one of two different treatment

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Describe features of classically designed clinical trials (2)

At the end of the trial, results are analysed and is made as to which treatment is more effective. Unable to utilise emerging knowledge as trial progresses. Wait till the end of the process to find out what is happening (may not be safe)

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Describe features of adaptive trials (1)

Permit use of accumulating data to decide how to modify aspects of the study as it continues, without undermining the validity and integrity of the trial. Any changes should not be ad hoc but by design

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Describe features of adaptive trials (2)

Not a solution for inadequate planning but are meant to enhance study efficiency while maintaining validity and integrity

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Describe features of adaptive trial designs (1)

Permits interim analyses of critical data (efficacy/safety). Allow the utilisation of emerging data (patient outcomes) to alter patient allocation or some other aspect of study design. Appealing when credible responses can be observed at early stage

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Describe features of adaptive trial designs (2)

Ensures study design is still appropriate for long running trials. Allows improvement of patient outcomes without compromising statistical validity in a timely manner. Can improve safety

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Describe features of adaptive trial designs (3)

Offers significant ethical and cost advantages over standard fixed designs

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Describe features of adaptive trial designs (4)

E.g. pre-determined scientific outcome is measured which allows randomisation to be directed towards patients that are enriched with characteristics predictive of a positive outcome e.g. tumour type or tumour marker

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Describe features of adaptive trial designs (5)

Ongoing assessment of sample size avoids under or over allocation of patients when statistical power is based on the assessment of a critical variable. Fewer patients exposed towards less effective therapy

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Describe features of adaptive trial designs (6)

Modify aspects of the trial without undermining statistical/ethical validity, use accumulating data

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What does the GBT study design demonstrate? (1)

GBT study design – use of previous data on dosing to determine next doses to investigate in the next step of the trial. Adaptive elements described in protocol, efficacy findings (decreased reticulocytes, reduce sickled cells)

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What does the GBT study design demonstrate? (2)

Conclusions (decrease in bilirubin, reduction in reticulocytes, stabilisation and increase in median Hb, approximately 70% median decline in irreversibly sickled cells)

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What are the two types of adaptive trial designs which use precision medicine in oncology studies?

Umbrella trial and basket trials. Different types of adaptive trial designs for oncology studies – better understanding of genetic links with various cancers (recognised as different diseases)

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Describe features of the umbrella trial (1)

An umbrella trial enrols patients who share the same basic cancer type. Performs molecular marker testing for a wide array of potential targets

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Describe features of the umbrella trial (2)

Then assigns patients to an arm of the study based on the presence of a mutation matched to a potentially effective treatment for that marker. This makes it possible to a test and develop many potentially active drugs simultaneously

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Describe features of the basket trials (1)

A basket trial enrols patients who have the same genetic mutation, whether their cancer originated in the lung, breast, colon, liver or any other organ. All patients receive the same novel treatment that targets that specific marker

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Describe features of the basket trials (2)

This strategy highlights a different way of thinking about cancers, not based primarily on where they originated but rather based on the mutations that drive them

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What are the key benefits of umbrella and basket trials? (1)

Umbrella and basket trials for molecular targets offer several major benefits. Possible with a marker seen in 1-2% of broad cancer patient population to identify options for small subgroups

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What are the key benefits of umbrella and basket trials? (2)

Patients/oncologists have an actionable result to suggest a plan of action when genetic testing panels report a rare mutation. Patient from many locations can participate in trials for their specific target without needing to travel to distant sites

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What are the key benefits of umbrella and basket trials? (3)

New treatments can be tested and potentially approved for commercial use faster

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Describe features of study methods (1)

Define duration of study and subject commitment. Define/describe safety/efficacy (PD-biomarker) and PK assessments/procedures. Defend choice with scientific rationale. Ensure robust end points. Ensure validity/reproducibility of methods

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Describe features of study methods (2)

Provide rationale for selection and timing of measurements. Do not exhaust for ex-sanguinate subject as data will be compromised. Include AE, SAE, SUSAR reporting procedures

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Describe features of study methods (3)

Ensure number of measurements/assessments and sampling times are - realistic, practical, sufficient to achieve objectives. Decide order of priority as often more than one procedure or measurement is required at same time point

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Describe features of study methods (4)

Define stopping rules where appropriate

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Describe features of study subjects (1)

Choice of subject. Healthy volunteers or patients or both. Depends on study objectives. Depends on nature of treatment under investigation. If risk is considered more than minimal don't include healthy volunteers

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Describe features of study subjects (2)

Consider age/gender/weight/stage of disease. Ensure inclusion and exclusion criteria are realistic and reflect a subject population that can be recruited. Number of study subjects. Depends on study objectives

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Describe features of study subjects (3)

May require a multi-site, approach which increases variability. Define subject dropout and withdrawal criteria

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Describe features of investigational medicinal products (1)

Active, placebo, comparator. Formulation, ROA, stability, storage, compliance with EU GMP and requirement for QP release. Labelling/instructions for handling at site. Supply/safety data sheet. Doses, instructions for dispensing and administration

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Describe features of investigational medicinal products (2)

Accountability procedures from receipt to return and/or destruction. Information on antidotes if known or treatment for expected AEs. Information on permitted co-medication and prohibited medication

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Describe features of data collection, management and reporting (1)

Data to be collected, method of collection and storage (manual/electronic, source data, transcribed data, case report form/electronic data base. Method of analysis (define criteria for analysis on primary secondary variables

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Describe features of data collection, management and reporting (2)

Statistical analysis plan, power calculation. Report - ICH format, integrated or separate reports

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Describe features of study management (1)

Compliance with EU GCP. Ethical review and approval. Written informed consent. Procedure currently depends on local custom and practices and regulation. Must comply with Declaration of Helsinki and ICH GCP and EU GCP Directive

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Describe features of study management (2)

Use non-technical (lay-person) language in 'mother' tongue, explain all aspects of study

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State features of study management (1)

Regulatory review and approval. Roles and responsibilities of investigators and sponsors. Study monitoring and audit procedures. Insurance and indemnity provisions, study termination procedures, confidentiality clause, publication policy,

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State features of study management (2)

Protocol signatures (investigator, sponsor, trial statistician)

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Clinical Trial: Protocol Designs and Future Considerations

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