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licensing a new drug Flashcards

1
Q

what is meant by clinical trails

A

A clinical study seeks to establish facts and contributes to knowledge by confirming an existing or establishing a new theory, based on a conceptual framework. They should be tightly controlled to avoid bias and should be designed on a scale that the results can be statistically evaluated.

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2
Q

what is meant by observational studies

A

Observational studies require researches to only observe patients and make no interventions that may interfere with the study.

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3
Q

what is meant by epidemiology studies

A

Epidemiology studies measure how often diseases occur in different groups of people, and the causes. They are useful to plan and evaluate strategies to prevent illnesses. Epidemiology studies are a type of observational study.

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4
Q

what us meant by cross sectional studies

A

Cross-sectional studies measure the frequency of a disease in a population at a given time.

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5
Q

what is meant by case studies

A

Case studies are another form of observational study; medical history of a single patient is taken and reasons for their medical condition may be investigated.

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6
Q

what is meant by case control studies

A

Case control studies compare patients with a specific condition to those who do not, evaluating risk factors that may cause/ precipitate the condition. They are quick to establish and are useful for studying rare diseases but limited in that clinical records may be inconsistent and there is a degree of reliance on memory – recall bias.

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7
Q

what is meany by cohort studies

A

Cohort studies observe a group of with a disease over a long period of time. There may be a comparison to a control group.

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8
Q

what is meant by strobe

A

STROBE (The Strengthening the Reporting of Observational Studies in Epidemiology) initiatives are involved in the conduct & dissemination – spreading of information – of observational studies.

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9
Q

what is meany by detailed scientific studies

A

Detailed scientific studies require specialised, skilled operators to design, analyse and interpret the data. They are expensive.

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10
Q

what is meant by meta analysis

A

Meta-analysis is a form of systematic review that focuses on numerical results from clinical trials. The aim is to combine the results of many trials to produce an estimate of the average overall effect size – no new data is collected.

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11
Q

in clinical trails what are new substances tested for

A

A new substance with therapeutic potential is administered under controlled conditions for the purpose of determining its efficacy, bioavailability, safety, tolerability and acceptability.

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12
Q

what does the the medicines for human use act say about good clinical practice

A

An area of The Medicines for Human Use (Clinical Trials) Regulations 2004 includes Good Clinical Practice:

  • Risks and potential benefits must be assessed before trials are started
  • Interests of the individual study subject must take precedence over those of science or society
  • All trial subjects must give consent
  • Trials must be scientifically sound
  • Trials must have a clear protocol
  • Trials must be approved by a properly constituted ethics committee
  • Only properly qualified staff may be involved (including physicians to provide care if needed)
  • Should be adequate preclinical testing of the product
  • Product should be of adequate quality (as defined in ICH guidelines for medicines)
  • Trial subject’s privacy and confidentiality must be respected and assured
  • Data must be recorded, handled and stored in a way that allows accurate reporting, interpretation and verification
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13
Q

what must clinical trails do

A

Clinical trials must mirror the treatment population; an inclusion & exclusion criterion identifies the treatment population. Clinical diagnosis and standardised measurement scales are useful to determine those who meet the inclusion criteria. Exclusion criteria is met by those for whom the treatment would not apply (e.g. type 1 diabetics in a trial for type 2 diabetes treatment - the drug won’t work). Demographics (age, gender, ethnicity, social background) should also be considered, since diseases vary within population groups.

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14
Q

what is meant by a blind study

A

In a single-blind study, patients do not know which study group they are in (for example whether they are taking the experimental drug or a placebo). In a double-blind study, neither the patients nor the researchers/doctors know which study group the patients are in. In a triple-blind study, the patients, clinicians and the people carrying out the statistical analysis do not know which treatment patients had.

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15
Q

what is the 4 stages of a clinical trail

A

I. First administration & safety evaluation using healthy volunteers – exploratory
II. Early exploratory & dose-establishing studies in diseased volunteers – exploratory & confirmatory
III. Large scale studies in diseased volunteers – confirmatory
IV. Post-marketing safety monitoring – post-market surveillance

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16
Q

what does phase 1 of a clinical trail entail

A

The aim is to find preliminary information about the effects of a drug when introduced to a human – safety, tolerability, bioavailability, pharmacokinetics and pharmacodynamics are established in healthy volunteers. Healthy is defined in the inclusion and exclusion criteria, and usually means one without disease, representative of the population as a whole. It is randomised, with a double-blind placebo control given to compare the drug against.
The main limitation that are that most volunteers are men; in the EU, only post-menopausal women can participate due to fertility/ foetal effects. Genetic polymorphisms may affect pharmacokinetic factors, and the target population cannot always be
representative of the whole population.

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17
Q

what does phase 1a of a clinical trial include

A

4-8 cohorts (cohort = 6-8 people) take the drug for 6 months, escalating the dose from one cohort to the next. The maximum tolerated dose is determined, and pharmacokinetic parameters are established:
• Cmax – peak concentration
• Tmax – time taken to reach peak concentration
• AUC – bioavailability, total exposure
• T½ - half-life indicates rate of elimination
• Vd – volume of distribution
• MRT – mean residence time

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18
Q

what des 1b of a clinical trial include

A

Doses are repeated at escalating levels, to establish the time needed to reach steady state. This is also 6 months.

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19
Q

what does phase 2 of Clinical trails entail

A

The aim is to ensure safety & efficacy, and indicate the dose required for therapeutic effects in a larger group of diseased volunteers.

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20
Q

what does phase 2a include in a clinical trail

A

The dose and regimen are based on the findings in Phase I. It is randomised, with a double-blind placebo control given to compare the drug against. This stage takes 9 months – 2 years.

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21
Q

what does phase 2b of a clinical trail include

A

This part of phase II trials is confirmatory – the dose selection supports previous trial findings. Patients with one or more indications are trialled at different doses. It is randomised, with a double-blind placebo control given to compare the drug against. This stage takes 2-3 years.

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22
Q

what does phase 3 of a clinical trail entail

A

This stage sees a big increase in number of participants, providing confirmatory efficacy and safety data to support registration. The aim is to find statistically rigorous results that clearly demonstrate efficacy and safety and may include pharmacoeconomic data, as an indicator to compare against any drugs existing on the market (if applicable). A power calculation should be performed to ensure all findings are valid.
Patients are chosen if they meet the criteria of the target indication and different sub-groups should be included – age, ethnicity etc. It is randomised, with a double-blind placebo control given to compare the drug against. As a minimum, this stage takes 2 years.

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23
Q

why might drugs fail in the phase 3 stage of clinical trails

A

Drugs may fail at this stage due to:
• Insufficient biological activity
• Unacceptable toxicity
• Design flaws (end-point, patient selection, duration, sample size)
• Execution failures (randomisation of patients, analysis of data)

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24
Q

what does the medicines of healthcare products regulatory agency ensure?

A

The Medicines & Healthcare products Regulatory Agency (MHRA) ensures that all medicines and devices meet applicable standards of safety, quality and efficacy. It influences the UK, the EU & international regulatory frameworks to ensure the protection of public health. The Human Medicines Regulations 2012 ensures compliance with EU directives. Regulation of medicines ensures quality, safety and efficacy. A product must demonstrate efficacy, tolerability and acceptability, providing means for a therapeutic intervention that will be of benefit to the patient.

25
Q

what does phase 4 of clinical trails entail

A

This stage is concerned with post-marketing surveillance of the drug, to investigate unexpected adverse/ toxic events. Cohort studies are run looking at patients who are being treated by the new drug.

26
Q

what does the back triangle show

A

Indicates that a drug is new to the market; healthcare professionals are asked to report all suspected adverse drug reactions to these products through the Yellow Card Scheme. There is limited information about safety of new drugs from clinical trials in the UK because trials generally involve only small numbers of eligible patients who take the medicine for a relatively short period of time and patients in clinical trials may not be fully representative of those who will use the medicine when it is marketed.

27
Q

what is the yellow card scheme

A

Reports of adverse events are made by patients and/ or health professionals and are assessed at the MHRA – medics, pharmacists and other scientists. If a new side effect is identified, information is considered in the context of the overall side effect profile for the medicine, and how the side effect profile compares with other medicines used to treat the same condition. The MHRA takes action to ensure that medicines are used in a way that minimizes risk, while maximizing patient benefit.

28
Q

what is the MHRAs defective medicine report card centre

A

If any issues arise, alerts are sent to healthcare professionals, hospitals, GP surgeries and wholesalers, detailing product recalled or explaining concerns about quality that may affect safety or efficacy.

29
Q

what are the different classes of the MHRAs defective medicines report card centre

A

• Class 1
o Life threatening, immediate recall required
o e.g. contamination with toxic/ active product
• Class 2
o Harmful, recall is required within 48 hours
o e.g. risk of fungal contamination
• Class 3
o Unlikely to harm patients, action required within 5 days
o e.g. errors in the patient information leaflet
• Class 4
o No threat to patient safety, caution advised
o e.g. incorrect number of tablets in packs from a specific batch

30
Q

what is meant by randomised control trails

A

In randomised control trials (RCT), there may be a group of patients being treated by a drug, and a control group taking a placebo for a set period of time. For trials where a condition has serious effects, a placebo wouldn’t be given as it is unethical; instead, the best current treatment is given, and a comparison is made with the new drug.

31
Q

define absolute risk

A

Absolute risk is the actual risk of an event occurring; relative risk is the risk of an event occurring in one group compared to another group(s).

32
Q

what is meant by absolute Absolute risk

A

Absolute risk is the actual risk of an event occurring; relative risk is the risk of an event occurring in one group compared to another group(s).

“ARR = ARC – ART”

33
Q

what is meant. y relative risk reduction (RRR)

A

Relative risk reduction (RRR) is a ratio absolute risk of the treated group (ART) subtracted from absolute risk of control group (ARC):

“RRR = “ “ARC – ART” /”ACC”

34
Q

what is meant by numbers needed to treat

A

This is the number of patients who would have to receive treatment for 1 of them to benefit.

“NNT = “ “1” /”ARR”

35
Q

what is meant by intentions to treat (ITT)

A

An assessment of the people taking part in a trial, based on the group they were initially (and randomly) allocated to. This is regardless of whether or not they dropped out, fully adhered to the treatment or switched to an alternative treatment.
ITT analyses are often used to assess clinical effectiveness because they mirror actual practice, when not everyone adheres to the treatment, and the treatment people have may be changed according to how their condition responds to it. Studies of drug treatments often use a modified ITT analysis, which includes only the people who have taken at least 1 dose of a study drug.

36
Q

what is meant by numbers needed to harm

A

A measure of the chance of experiencing a specified harm in a specified time because of the treatment or other intervention. Ideally, this number should be as large as possible.

37
Q

what is meant by statistical analysis

A

The null hypothesis is essential in testing a hypothesis; it essentially is the opposite of what the trial is aiming to prove (i.e. the hypothesis that there is no significant difference between specified populations). A statistical conclusion is reached if the outcome of the trial disproves the null hypothesis.

38
Q

what is meant by clinical appraisal

A

Critical appraisal is the process of carefully and systematically assessing the outcome of scientific research (evidence) to judge its trustworthiness, value and relevance in a particular context. The validity of a study should be assessed for bias & methods used, and significance of the results should be determined.

39
Q

what are the 8 critical appraisal skills programme tools?

A
  1. Did the trial address a clearly focussed issue?
    a. The population studied
    b. The intervention given
    c. The comparator given
    d. The outcomes considered
  2. Was the assignment of patients to treatments randomized?
    a. Was the allocation concealed from researchers?
  3. Were patients, health workers and study personnel blinded?
  4. Were the groups similar at the start of the trial?
    a. Factors that may affect the outcome are age, sex and social class
  5. Aside from the experimental intervention, were the groups treated equally?
  6. Were all the patients who entered the trial properly accounted for at its conclusion?
    a. Was the trial stopped early?
  7. How large was the treatment effect?
    a. What outcomes were measured?
    b. Is the primary outcome clearly specified?
    c. What results were found for each outcome?
    d. Is there evidence of selective reporting of outcomes?
  8. How precise was the estimate of the treatment effect?
    a. What are the confidence limits?
    b. Were they statistically significant?
  9. Can the results be applied in your context (the population)?
    a. Is there reason to believe that your population of interest is different to that in the trial
  10. Were all clinically important outcomes considered?
  11. Are the benefits worth the harms and costs?
40
Q

what does statistical errors include

A

Statistical errors include a flawed hypothesis, the statistical set-up and analysis of the data.
There may be a bias that causes the trial to be flawed; may be during the establishing stage of the trial (selection bias) or during the trial (observation).
Confounding factors are variables that the researcher failed to control (i.e. environmental differences).

41
Q

what are the ideal properties of a drug

A

Properties of an ideal drug:

1) Must be chemically stable
2) Must not be toxic
3) Good pharmacodynamic activity
4) Good pharmacokinetic activity

42
Q

define pharmacodynamics

A

Pharmacodynamics is the biochemical & physiological effect(s) the drug has in the body. Target specificity & selectivity must be established, as should the therapeutic range.

43
Q

define absorption

A

Absorption is where the drug moves from the site of administration to a site in the body (blood). Absorption depends on the route – IV vs oral. There is a reliance on passage through membranes – transcellular or paracellular.

44
Q

what does the volume of distribution depend on?

A

The volume of distribution depends on partitioning across various membranes & binding to tissue or blood components.

45
Q

what does metabolism depend on

A

Metabolism depends on the location of the enzymes responsible for metabolism, whether it undergoes first-pass metabolism before systemic circulation, and the induction of metabolising enzymes (i.e. pro-drugs). During synthetic pathway, impurities may form and cause adverse effects.

46
Q

what is the most common way to excrete drugs

A

Elimination is commonly via biliary (bile) or renal (urine) routes.

47
Q

what is meant by toxicology

A

Toxicology is the area concerned with adverse effects a drug may cause.

48
Q

what are the different mechanisms of toxicity

A

• Allergic response
o Can lead to anaphylactic shock e.g. penicillin
o Deplete blood cell types e.g. sulfonamides
• Receptor, ion channel and enzyme mediated
o Animal toxins can block ion channels
• Biochemical pathways
o Inhibition of mitochondrial function (e.g. AZT has mitochondrial toxicity)
• Organ-directed toxicity
o Hepatotoxicity
o Nephrotoxicity
• Mutagenesis and carcinogenesis
• Teratogenicity

49
Q

what are the profiling opportunities during the drug discovery process

A

• Target distribution
o receptor may be expressed in organs other than those intended for therapeutic modulation
o does action at other receptors cause unwanted side effects?
• Gene knock-out
o Genetic manipulation may show direct side effects
• siRNA approach
o silencing the target in specific organs can provide information about whether the drug is causing the toxic effect and confirm the role of the target in a toxicological outcome
• Enantiomers may be inactive but has the same structure, so the potential for chemistry-related toxicity is equivalent

50
Q

what are the different types of toxicity testing

A

• Single dose toxicity
o The effect of a single dose is observed
o Two mammalian species are studied
o Effects of dose observed for 14 days then mortality is recorded
o Morphological, biochemical, pathological and histological changes are investigated
• Repeat dose toxicity
o Two mammalian species are studied
o Long duration (30-180 days)
o Dose is dependent on dose escalating studies (3 different doses given)
 High dose 10x the maximum clinical dose
 Low dose 2x clinical dose
 Medium dose midway between low and high dose
o Drug administered by clinical route
o Parameters that should be monitored daily include
 Behavioural
 Physiological
 Biochemical
 Histological
• Local toxicity studies - route of administration
o Dermal
o Rectal tolerance
o Parenteral drugs
• Allergenicity/Hypersensitivity toxicological studies
o Guinea pig maximization test
 Determination of maximum non-irritant or minimum irritant dose
o Local lymph node assay
• Carcinogenicity/oncogenicity studies
o Life-time bioassays
o Drug used for >6 months or frequent intermittent use for chronic diseases
o Chemical structure of drug may indicate carcinogenic potential; this test confirms
• Reproductive and developmental toxicity

51
Q

what are the different signs of toxicity

A
  • Respiratory - dyspnea, abdominal breathing, gasping, cyanosis
  • Motor activity - loss of righting reflex, ataxia, tremors
  • Ocular signs – miosis (constriction of pupil)
  • Cardio-vascular signs – arrhythmias, vasodilation
  • Autonomic signs – para-/ sympathomimetic actions or blockers
  • GIT signs – motility, nausea
52
Q

what is meant by by effective dose (ED50)

A

The amount of drug that causes 50% of maximum effect for any measured biological effect of interest.

53
Q

what is meant by lethal dose (LD50)

A

The amount of an drug that kills 50% of a test sample.

54
Q

what is meany by NOAEL

A

The highest concentration that does not a toxic response. When NOAEL is determined, it must be converted to a human equivalent dose (HED), adjusting for anticipated exposure in humans & interspecies difference in affinity and potency. A 10-fold safety factor should be applied.
“Human equivalent dose (mg/kg) = NOAL (mg/kg) x “ “Animal Km” /”Human Km”

 "Km =  "  "Body weight (kg)" /"Body surface area (m2)"
55
Q

what is meant by LOAEL

A

The lowest concentration that produces a toxic response.

56
Q

what is meant by therapeutic index

A

The ratio of the dose of the drug that produces an unwanted (toxic) effect to that producing a wanted (therapeutic) effect.
“LD50” /”ED50”

57
Q

how do you Investigational new drug (IND) application

A

This is an evaluation of what has been discovered/ tests performed, and the plan for the future regarding a potential new drug. It contains:
• Cover sheet (Form FDA-1571)
• Table of contents
• Part A – Introductory statement and general investigational plan
• Part B – Protocols
• Part C – Chemistry, manufacturing and control information
• Part D – Pharmacology and toxicology information
• Part E – Previous human experience with the investigational drug
• Part F – Additional information

58
Q

what are the 4 evidence review panels by the FDA/ MHRA

A
  • The medical panel looks at the plan for the clinical trials
  • The chemistry panel looks at manufacturing and quality assurance for example
  • The pharmacology/toxicology panel looks at preclinical
  • The statistical panel looks at the accuracy of the protocols and to make sure the plan meets the requirements for the hypothesis, whether the sample size is big enough

A safety review is conducted, which indicates the risk if a clinical trial was to be formed. If there is no risk, you can continue the study. If there is a risk, amendments need to be made and the sponsor needs to submit new data

59
Q

what does the new drug application entail

A 
This is the final piece of evidence that is submitted before the drug is brought to market. It is also known as the common technical document.
•	Module 2 – SUMMARIES 
o	Critical discussions and assessments
o	Abbreviated factual data
•	Module 3 – QUALITY
o	International Non-proprietary Name (INN) selected
o	Structural, physical & chemical properties determined
o	Stability tested
•	Module 4 – NON-CLINICAL INFORMATION
o	Pharmacology
o	Pharmacokinetics (ADME)
o	Pharmacodynamics (Drug target)
o	Toxicology
•	Module 5 – CLINICAL INFORMATION
o	Biopharmaceutical studies
o	Efficacy & safety reports

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