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Making drugs into medicines ☆ > Clinical trials > Flashcards

Clinical trials Flashcards

1
Q

What are the 10 Principles from the Nuremberg Code (10)

A
  1. The voluntary consent of the human subject is essential.
  2. The experiment should be such as to yield fruitful results for the good of society and not random and unnecessary.
  3. The experiment should be designed based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study, and the anticipated results should justify the experiment’s performance.
  4. The experiment should avoid all unnecessary physical and mental suffering and injury.
  5. No experiment should be conducted where there is a reason to believe that death or disabling injury will occur, except in those experiments where the experimental physicians also serve as subjects.
  6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
  7. Proper preparations should be made, and adequate facilities should be provided to protect the experimental subject against even remote possibilities of injury, disability, or death.
  8. The experiment should be conducted only by scientifically qualified persons.
  9. During the experiment, the human subject should be at liberty to bring the experiment to an end.
  10. During the experiment, the scientist in charge must be prepared to terminate the experiment at any stage if he has probable cause to believe
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2
Q

What is Clinical Research? (8)

A
  1. Investigations into human disease using human subjects.

research into:

  1. Causes and origin of disease
  2. Prevention of disease
  3. Diagnosis of disease
  4. Outcome of disease
  5. Treatment of disease
  6. The continuum from laboratory → patients → health of the whole population
  7. Follows on from Pre-clinical development
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3
Q

What are Clinical Trials (4)

A
  1. They are generally considered biomedical or health-related research studies in humans that follow a pre-defined protocol.
  2. Research in which human volunteers are tested with new health treatments
  3. Establish the effectiveness of new drugs, drug combinations, surgery, and preventative medicines compared to suitable controls.
  4. Aim to prove the trial hypothesis and reject the null hypothesis.
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4
Q

Who conducts clinical trials? (4)

A
  1. Research councils
  2. University institutes
  3. Government
  4. Pharmaceutical industry…
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5
Q

What are the Clinical Trial Phases (4)

A
  1. Phase I - Human safety, days & weeks, tens of people
  2. Phase II - Expanded safety, weeks & months, hundreds
  3. Phase III - Efficacy & safety, several years, thousands
  4. Phase IV
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6
Q

What are Phase I Studies (6)

A
  1. Mainly uses healthy volunteers.
  2. A very small number of subjects, 20-80
  3. Collect safety data
  4. Tolerability, pharmacokinetics, pharmacodynamics
  5. Dose-response relationship in low numbers of people
  6. Sometimes conducted with severely ill subjects (e.g. cancer patients)
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7
Q

What are Phase II Studies (7)

A
  1. Subjects have target disease.
  2. Trial conducted on a relatively small number of subjects (100-300) for a limited period
  3. Data on pharmacological activity, dose requirement, short-term safety, efficacy of the drug/procedure
  4. Placebos used
  5. Specialist investigators
  6. Regulatory approval
  7. Ethics approval
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8
Q

What are Phase III studies (11)

A
  1. Pivotal stage ~ Real-life situation
  2. Subjects with the target disease
  3. Larger scale trial (1000-3000) in multiple centres for longer periods
  4. Regulatory & Ethics approval mandatory
  5. Not “very ill” or child-bearing
  6. Test intervention compared to current market lead (efficacy)
  7. Adverse effects monitored
  8. Specific safety data
  9. Stage Ia – before submission of a new drug application (NDA)
  10. Stage IIIb – the period between submission for NDA and receipt of marketing authorisation.
  11. Start pre-launch
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9
Q

What are Phase IV Studies (4)

A
  1. After a medicine is marketed – Post-marketing surveillance
  2. Very large numbers of subjects – patients taking medication
  3. Provide additional details about the product’s long-term safety – Pharmacovigilance (adverse effects)
  4. Continued monitoring of efficacy.
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10
Q

What are Clinical trials for drugs today (10)

A
  1. Clinical trials are designed.
  2. Institutional reviews are completed.
  3. True volunteers, free to leave trial
  4. Careful monitoring of safety
  5. Informed consent
  6. Good Manufacturing Practice (GMP)
  7. Good Clinical Practice (GCP) guidelines
  8. Standard Operating Procedures (SOPs)
  9. Clinical trials have evolved into a standard procedure, focusing on patient safety and requiring informed consent from all participants.
  10. There will always be a balance between medical progress and patient safety, and the regulation of clinical trials helps to ensure that this balance is acceptable.
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11
Q

What is Clinical Trial Design (3)

A
  1. The trial design is a plan for each element of the clinical trial that is to be undertaken.
  2. Aims is to ensure the results obtained from the trial are valid.
  3. ‘The scientific integrity of the trial and the credibility of the data from the trial depends substantially on the trial design’ (ICH, 1996)
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12
Q

What are Source of bias (5)

A
  1. Subject choice
  2. Nature of the disease (stage of the disorder)
  3. Choice of treatment for individual subjects
  4. Choice and accuracy of clinical measurement
  5. The clinical trial design aims to CONTOL THE SOURSE(S) OF BIAS.
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13
Q

What is Subject choice for clinical trials (5)

A
  1. The Patient population needs to be defined (avoid investigator-specific population → selection bias)
  2. The subject population may change at different stages of the trial:
  3. Phase I – healthy volunteers
  4. Phase II – criteria restrictive
  5. Phase III – samples the whole patient population → trial results should be general.
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14
Q

What is the Recruitment criteria for clinical trials (6)

A
  • Factors that influence whether a subject is adequate as a candidate for the clinical trial:
    1. Target disorder,
    2. The stage of the disorder the subject is at,
    3. Any concurrent disorders,
    4. Use of other medication,
    5. Age and sex of subject, etc.
    6. Clear instructions of the eligible criteria have to be defined so that bias is eliminated.
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15
Q

What is the Nature of the disorder for clinical trials (5)

A
  1. The trial design should consider the type and nature of the treated disorder.

Two broad classes of disorders:

  1. acute
  2. chronic
  3. Influences the duration of the trial, subject population, design of the trial, etc.
  4. Some disorders are cyclical, others seasonal – trials have to take this into account to avoid inherently biased results.
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16
Q

What is the Choice of treatment for clinical trials (3)

A
  1. Most clinical trials are controlled – a comparative treatment is used.
  2. Used to compare the effect of the investigated intervention (efficacy and safety) against a standard
  3. The purpose is to ensure that the difference in the groups originates from the difference in the treatments, not something else.
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17
Q

What are the Three main types of controls for clinical trials (3)

A
  1. NO TREATMENT
  2. TREATMENT with PLACEBO
  3. TREATMENT with ACTIVE COMPARATOR
18
Q

What is Placebo (6)

A
  1. No active is present in the treatment (e.g. saline, excipients, etc.)
  2. Identical in appearance to test compound (bias)
  3. Used to determine the efficacy of the active
  4. Ethical issues
  5. Practical issues – withdrawal, sample size, selection of subjects
  6. May show efficacious results and/or adverse reactions
19
Q

What is an Active comparator (5)

A
  1. A different activity is present in the treatment.
  2. Identical in appearance to test compound (bias)
  3. Used to compare efficacy and safety of the trial active
  4. Practical issues: countries, registration, dosing may be different, marketing
20
Q

How do we decide who gets what treatment in a clinical trial? (5)

A
  1. Randomisation
  2. Randomisation aims to ensure test/control groups are COMPARABLE.
  3. Successive subjects are allocated to treatment groups in a predetermined but random manner.

Two elements to consider:

  1. Test/control group
  2. Subject population
21
Q

What are the types of randomisations (7)

A
  1. Different algorithms are used to randomise subjects into groups. The choice depends on several factors.

Examples of types of randomisation include:

  1. Restricted simple randomisation
  2. Un-restricted simple randomisation
  3. Alternative randomisation
  4. Stratified randomisation
  5. Random Permutated Blocks
  6. In reality, trials use a combination of the different randomisation types.
22
Q

What is Restricted simple randomisation (4)

A
  1. Restricted: No. A = No. B
  2. Subjects are randomly allocated to the treatment groups in equal numbers.

Treatment groups:

  1. Test Group
  2. Control group
23
Q

What is Unrestricted simple randomisation (3)

A
  1. No. A ≠ No. B (analogous to repeated coin-tossing)
  2. Generally, more subjects are in the tested treatment group.
  3. Best on larger population number (>1000)
24
Q

What is Alternative randomisation (3)

A
  1. Subjects are divided into alternative groups as they are enrolled.

Disadvantages:

  1. no blindness
  2. Comparability of the groups?
25
Q

What is Stratified randomisation (6)

A
  1. The subjects are divided into subgroups – STRATA.
  2. Randomisation has to accommodate for this.
  3. Subjects are divided into subgroups.
  4. Each stratum is randomised separately.
  5. Each treatment group contains an equal numbers of subjects from each category.
26
Q

What are Random Permutated Blocks (4)

A
  1. Subjects were randomised in blocks.
  2. Useful when continued enrolment onto the trial.
  3. At various times in the recruitment process, there also may be undesirable differences in the number of patients assigned to each treatment.
  4. If the baseline (entry) characteristics of the patients change with time, for example, the initial patients may be healthier than the later patients; this could result in differences between treatment groups in the distribution of patient characteristics.
27
Q

What are Methods of measurement (5)

A
  1. Measurements of the effect of the intervention/progress of the disease may be OBJECTIVE or SUBJECTIVE.
  2. The used measurements should be clearly defined in the trial protocol.
  3. Define whether these measurements may be influenced by external factors (environment, time of day, a meal taken, etc.)

Endpoints:

  1. primary
  2. secondary
28
Q

How to avoid prejudice affecting measurements? (5)

A
  1. Blinding
  2. Procedure whereby the identity of the treatment is not disclosed to some or all of the participating members of the trial

Types of trials, with regard to blinding:

  1. OPEN
  2. SINGLE-BLINDED
  3. DOUBLE-BLINDED
29
Q

What is Open Study (2)

A
  1. Everyone knows (subjects, investigators, sponsors, statisticians, etc) who is receiving what treatment.
  2. Can only be used when knowing the treatment doesn’t jeopardise the potential of bias.
30
Q

What is Single Blinded Study

A

Only one side knows (investigator or subject) who is receiving what treatment

31
Q

What is Double Blinded Study (3)

A
  1. Maximum control of bias (may even disclose info from sponsor reps and/or statisticians analysing data)
  2. Need contingency plan (when something goes wrong)
  3. The trial design should describe how the blind nature of the trial is to be maintained
32
Q

What is the Practical issue with blinding (2)

A
  1. If test and comparative interventions have different physical characteristics and/or different dosing regimes
  2. One solution: DOUBLE DUMMY BLINDING
33
Q

What are Types of Trial Designs (5)

A

The choice of trial design has to answer the questions:

  1. WHY is a trial being conducted?
  2. What PHASE is the study at?
  3. What are the primary end-point measurements?

Two broad types of design:

  1. NON-COMPARATIVE
  2. COMPARATIVE
34
Q

What are Comparative Trial Designs (2)

A
  1. Parallel - Each subject receives the test OR the control intervention and they are studied together
  2. Crossover - Each subject receives the test AND the control intervention at different times during the trial
35
Q

What are the Advantages/Disadvantages of parallel trial designs (3)

A
  1. No possibility of drug interaction
  2. Subjects groups have to be matched
  3. No issue with the stability of the disorder as the trials are shorter
36
Q

What are the Advantages/Disadvantages of crossover trial designs (7)

A
  1. Subject acts as own control
  2. Good for investigating drug interaction
  3. Number of subjects smaller
  4. Trial time is longer
  5. May cause double blinded study to become un-blinded (side effects)
  6. Possibility of period effect – results due to duration of treatment not the treatment
  7. Affected by the nature of the disorder
37
Q

What is the International Council for Harmonisation (ICH) (3)

A
  1. Founded in 1990
  2. Brings together the regulatory authorities and pharmaceutical industry from Europe, Japan and the United States
  3. Purpose is to achieve greater harmonisation in the interpretation and application of guidelines and requirements for product registration
38
Q

What are the ICH Guideline topics (4)

A
  1. Q – Quality guidelines - Chemical and pharmaceutical quality assurance (Q7 = Good Manufacturing Practice GMP)
  2. S – Safety guidelines – Covering both in vivo and in vitro pre-clinical studies
  3. E – Efficacy guidelines – Design, conduct, safety and reporting of clinical trials (E6 = Good Clinical Practice GCP)
  4. M – Multidisciplinary guidelines – Cross-cutting topics
39
Q

What is the Medical Research Council (MRC) (3)

A
  1. publicly funded
  2. supports research across the biomedical area
  3. Owns research units as well as works closely with other institutes and universities
40
Q

What is the European Medicines Agency (EMA) (3)

A
  1. established by the EU, headquarters in London
  2. promotes improvements in public and animal health, through the evaluation and supervision of medicines for human and veterinary use.
  3. offers advice on quality, safety and efficacy of medicinal products
41
Q

What is the Medicines and Healthcare products Regulatory Agency (MHRA) (3)

A
  1. government agency which is responsible for ensuring that medicines and medical devices work, and are acceptably safe.
  2. set up in April 2003 from a merger of the Medicines Control Agency and the Medical Devices Agency.
  3. an executive agency of the Department of Health.

Making drugs into medicines ☆ (13 decks)

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