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M2-5 > Phase I trial > Flashcards

Phase I trial Flashcards

1
Q

What is official names for exploratory/confirmatory phase?

A 
IND = Investigational New Drug
NDA = New Drug Application
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2
Q

What is a good practise associated with each phase?

A

Preclinical research: GMP (Good Manufacturing Practice)
Clinical studies for Marketing Authorisation: GLP (Good Laboratory practice)
Postmarketing Surveillance: GCP (Good Clinical Practice)

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3
Q

Length of time and people required for each phase

A 
pre-clinical: 4years
phase1: 1 year; 50-100
phase2: 2 years; 100-500
phase3: 3-4 years; 1000-5000
NDA approval: 1.5years
(phase 4): depends
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4
Q

What is involved in the phase 1 study?

A

„First In Human“ (FIH) Studies
Bioavailability (e.g. i.v. vs. oral)
Interactions (e.g. food effect, drug interactions, genetic polymorphism)
Studies in special populations: elderly, paediatric population, renal and hepatic impairment)

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5
Q

What is „First In Human“ (FIH) Studies

A

Primary objective
Investigation of safety and tolerability
- single ascending dose (SAD)
- multiple ascending dose (MAD)
Additional objective
Data on pharmacokinetics & pharmacodynamics (measurable surrogate parameters)

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6
Q

What is SAD/MAD?

A
  • single ascending dose (SAD)
    Subject given single dose of the study drug; obtain rough understanding of pharmakokinetics
  • multiple ascending dose (MAD)
    Subject given multiple dose of the study drug; examine the steady state (where application dosage = elimination)
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7
Q

First in human studies – integrated study design scheme

A
  1. SAD
    Starting dose subtherapeutic (MABEL), 8 subjects (6 Verum, 2 Placebo) per cohort, escalation to full PD effect
  2. MAD
    Dose adjustment according to safety review, 8 subjects (6 Verum, 2 Placebo) per cohort, escalation to therapeutic exposures
  3. FE (Food Effect)
    2x2 crossover, single dose, 14 d wash-out, fasted /fed, 12 subjects
    FE done preferably with “final” formulation
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8
Q

NOAEL

A

No observed adverse effect level
The highest dose tested in an animal species that does not produce a significant increase in adverse effects in comparison to the control group. Adverse effects that are biologically significant, even if not statistically significant, should be considered in determining an NOAEL. (FDA)
Refers to a dose in animals

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9
Q

MABEL

A

Minimum anticipated biologic effect level
Anticipated!
Derived from human tissue/cells/ex vivo material
Can be supported/adjusted by data from similar compounds Refers to a concentration in vitro <> exposure

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10
Q

PAD

A

Pharmacologically active dose
The lowest dose tested in an animal species with the intended pharmacologic activity. (FDA)
intended pharmacologic activity.
Refers to a dose in animals, at least before FIH trials Refers to a dose in animals

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11
Q

ATD

A

Anticipated therapeutic dose range
Anticipated!
Refers to a dose in !human!, based on modeling

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12
Q

Some Compounds with Impacts

A

Thalidomide
Terfenadine
TGN1412
BIA-2474

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13
Q

New EMA guideline effective since February 2018

A
  • To mitigate risk for study participants (healthy volunteers)
  • Principles on the calculation of the starting dose
  • Precautions to apply between individual subjects (sentinel守る dosing)
  • Adequate dose escalation steps (max. threefold)
  • Criteria for the maximum dose (Maximum Tolerated Dose is no longer applicable)
  • Criteria for stopping rules are given (SAE, severe AE, etc.)
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14
Q

Choice of first dose needs to be balanced between

A
  • mitigate risk for healthy patients

- maximising output & speed up of development

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15
Q

FDA Guideline for Human Starting dose (steps)

A

1 NO OBSERVED ADVERSE EFFECT LEVEL DETERMINATION
2 HUMAN EQUIVALENT DOSE CALCULATION
3 MOST APPROPRIATE SPECIES SELECTION
4 APPLICATION OF SAFETY FACTOR
5 CONSIDERATION OF THE PHARMACOLOGICALLY ACTIVE DOSE

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16
Q

Conversion of Animal Dose to Human Equivalent Dose

A

Allometric Scaling:

  • most substances do not scale with body weight, rather with body surface area
  • Therefore, mg/kg data needs to be converted to mg/m2
  • Conversion table is useful for „standard“ animals – adaption needed in special animals, e.g. obese mice
  • There are exceptions, e.g. intravenously administered large molecules (m > 100 kDa) scale better with body weight – no conversion of mg/kg data needed
17
Q

Translation from animal testing

A
  1. NOAEL (in animal)
  2. HED (HumanEquivalentDose) via allometric scaling
  3. MRSD (Maximum Recommended Starting Dose) divide HED by 10
18
Q

Translation from ex vivo material (e.g. human cell/tissue)

A

MABEL (Minimum Anticipated Biologic Effect Level)

combine PharmacoKinetic data from animal testing with in vitro data from ex vivo material

19
Q

ADME

A

absorption, distribution, metabolism, and excretion

20
Q

Small TI means

A

Therapeutic index
Toxic effect is too big for the therapeutic effect
BIGGER THE BETTER

21
Q

Treatment duration in FIH

A

SingleDose
Duration of follow-up depends on the PK and PD of the active substance
Typically 2-4 days in-house period, 2-3 weeks follow up

MultipleDose
Duration of treatment depends on intended therapeutic regimen, but is limited by duration of toxicology studies
Typically 10-14 days in-house period, 2-3 weeks follow up

22
Q

Conduction of the study in a specially equipped in-patient unit

A
  • Phase-I-Unit of Contract Research Organisations (CRO)
  • Institute for Clinical Pharmacology
  • Human Pharmacology, Department of a Pharmaceutical Company
  • University Hospital
23
Q

When is dose escalation stopped?

A

when one of the pre-defined stopping criteria is reached
e.g.
-DLT (dose limiting toxicity), e.g. CTCAE criteria ≥ 3
-maximal PD/biomarker response or maximal dose
-MTD (maximal tolerated dose)
classical approach was to escalate dose in SAD to reach MTD
This approach is considered inappropriate in healthy volunteers according to new EMA guideline

24
Q

Assessment of safety and tolerability

A

-tolerability (subjective & objective)
-Vital signs (heart rate, blood pressure, body temperature, respiratory rate)
-ECG (rhythm, time intervals)
-Safety lab parameters:
• Hematopoiesis (blood cell count, coagulation)
• Liver function tests (ALT, AST, GGT, AP, Bili., GLDH, CHE)
• Renal function (creatinine, electrolytes, urine and sediment)
• Metabolism (blood glucose, lipid, uric acid, proteins)
• Pancreas (amylase, lipase)
• Muscle (CK. CKMB)

25
Q

SAE

A

Serious Adverse Event includes:

  • Death
  • A life-threatening event
  • In-subject hospitalisation or prolongation of existing hospitalisation
  • A persistent or significant disability/incapacity
  • congenital anomaly/birth defect
  • SUSAR (Suspected Unexpected Serious Adverse Reaction); surprise outcome could be unrelated to dose
26
Q

Reporting Procedures for SAEs and SUSARs

A

Investigator to sponsor: immediately within 24 hours
Sponsor to Responsible Ethic Committee: SUSAR within 7-15 days
Sponsor to all investigators: SUSAR within 7-15 days
Sponsor to Competent Authorities (Government) which will record on Eudravigilance-database

27
Q

PK

A

Pharmakokinetic Parameters
PK investigations are performed following single and multiple doses.
Main pharmacokinetic Parameters:
Half-life (t1/2), volume of distribution (Vd), clearance (renal, hepatic, total), AUC, Cmax, Tmax…
protein-binding, concentrations at steady state, dose proportionality, accumulation factor

28
Q

PD

A

Pharmacodynamic Parameters
PD investigations are performed following single and multiple doses.
Biomarkers and/or surrogate代理 parameters as PD endpoints:
A biomarker is a measurable parameter of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (e.g. troponin, rheumatoid factor, PSA)
A surrogate parameter is a measure of the effect of a certain action of the drug that may correlate with a real clinical endpoint but is more easily to assess (e.g. INR, HbA1C)

29
Q

Other phase I study

A

-Bioavailability Studies:
Absolute bioavailability studies
aim to assess the pharmacokinetics of a pharmaceutical formulation (capsule, fast or slow release tablet) versus an intravenous or oral solution known to be completely available.

Relative bioavailability studies
aim to compare the pharmacokinetics of 2 different formulations (e.g. fast and slow release formulation)

-Studies in Special Populations
Elderly, paediatric population: age-related physiological changes
Patients with renal or hepatic insufficiency:
- mostly PK studies
- patients have no direct therapeutic benefit

30
Q

Safety of phase I study

A
  • The probability for a SAE is 0.04-0.07 %
  • permanent damage in 1 case / ca. 150.000 participant

Most frequent causes of adverse events:

  • Interactions (intake of prohibited drugs)
  • Participation in other studies (concomitantly or too short intervals between participations)
  • Undisclosed disease or medical condition

M2-5 (4 decks)

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