MDM: clinical trials

Question 1

What are clinical trials?

Answer 1

An investigation on human subjects to detemrine ADME, side effects, safety, efficacy, pharmacological or pharmacodynamics of a medicine

Question 2

Why are clinical trials performed?

Answer 2

• Different indications for existing drugs
• to improve current treatment e.g. reduce side effects
• to investigate new drugs, new formulations and new delivery methods
• for disease prevention
• Devices e.g. pacemakers

Question 3

How are clinicla trials done?

Answer 3

In stages

• Phase I: PK, PD, safety and tolerance, activity of drug
• Phase II: Therapeutic exploratory (does the drug effect patient group?)
• Phase III: Therapeutic confirmatory (does it work how expected?)
• Phase IV: post marketing surveillance (how does it work in larger populaiton)

Question 4

Describe Phase I

Answer 4

• In small group of healthy individuals
• simplest formulations (IV, capsule)
• PK, PD, safe, tolerate?

Question 5

Describe phase II

Answer 5

• Small group of patients
• dose and regimen for future studies
• dosage form should be same as one intended for market
• can be placebo or comparator and can be blinded

Question 6

Describe phase III

Answer 6

• Range of patients with range of severity of the indication
• largest trial. multi centered and multinational studies
• base don evidence from phase II
• should be placebo or comparator controlled and blinded
• as close to final product as possible

Question 7

Describe phase IV

Answer 7

• Post marketing surveillance, additional patient groups or additional indications
• actual product to market used

Question 8

What is randomisation?

Answer 8

• Allocating trial subjects to control groups or treatment using an element of chance to reduce bias

Question 9

What is blinding? what types is there?

Answer 9

• single blind: only the trial subject is unaware of what treatment group they have been assigned too
• double bind: both the investigator and trial subject are unaware of which treatment group the subject has been assigned too

Question 10

What is control? what are the classes?

Answer 10

• PLacebo - using an inacitve form of the drug to allow for blinding and comparions to be made
• gold standard - using currently available best treatment. Need to modify appearance to avoid bias

Question 11

What is IMP?

Answer 11

Investigational medicinal product

trial drug, placebo, current gold standard comparator

Question 12

When do we require placebo and comparator?

Answer 12

• placebo - to prevent bias from dosage form
• compartor - to see if better than currently avaiable med

both tend to occur in phase III

Question 13

Who is involved in the CT regulation?

Answer 13

• Clinical trials directive - Define laws/ regulations
• Good clinical practic - ICH guidlines

Question 14

What is the decleration of helsinki

Answer 14

aims to protect rights of trial subjects. can withdrawlat any point and must have consent rhat is voluntary

Question 15

What formulations are involved in phase I trials?

Answer 15

• drug dissolve in water
• API powder in capsule
• powder for reconsituted
• prepare various strengths

Question 16

What formualtions are involved in stage II

Answer 16

Formulation as similar as possible to final pridyct and as simple as possible

Question 17

Describe phase III in terms of requirements and preperative activities

Answer 17

• IMP need to be blinded - look, taste, sound the same
• Development of drug tested, -ve control (placebo), +ve control (comparator), modification of -ve, +ve and drug being testes

Question 18

What are methods used to blind IMPs?

Answer 18

Over encapsulation

• putting tablet/ capsule into a larger capsule then filling with an inert filler
• inert filler must not react with API or effect absorbance

Film coating

• Application of thin coating to orignal tablet
• only applicable if can be made to look identical to the gold standard
• opacifying agents e.g. titanium dioxide used to cover colour or prints
• use water sol polymer

sugar coating

• Coat tablet with several layers of sugar, takes longer to carry out
• used if imps slightly different shape or cant fit into a capsule
• coating sugars used - waxes, titanium dioxide
• final product should be smooth, well rounded edges and shinny

COnsiderations for blinding liquids

• must look, taste, smell same
• use same taste and may add bitter flavouring to mask taste
• appearance can be modified by adding opacifying agent and colours
• for suspensions tastes may need to be added to settling powder
• stability needs assed
  *

Question 19

After modifying drugs what must be done any why?

Answer 19

stability needs to be tested therefore dissolution and distigration tests will be done for SDFs to ensure drug release remians the same

Question 20

What are CT packaging basic concepts?

Answer 20

• BLinded studies - randomly allocated group and double blind
• insert extra risks - multiple packets with idenitical apearance. Labels same apart from patient number. Lack of identification of packaging
• complications - usually hand assembled. Zero tolerance errors. Complicated construction - not just one product in packet

Question 21

What are the 3 levels of blindness

why is blinding used?

Answer 21

open blind

single blind

double blind

to remove bias

Question 22

CT packaging process

Answer 22

Question 23

What are examples of why patients may not comply to medicines and ways to fix

Answer 23

• forgetfulness - blister packs with graphics/ dosage instuctions
• complex instructions - clear labels, large font, colours
• physical problems - child proof, make capsules as small as possible

Question 24

What are CT packaing considerations

Answer 24

• •Primary pack design.
• Material handling.
• Label content.
• Patient / site pack design.
• Climatic zone.
• Tamper evidence.
• Child proof packaging.
• Reconciliation.
• Analytical testing

Question 25

What are the features of Capsugels DB caps which make them suitable for use in clinical trials?

Answer 25

DBcaps® two-piece gelatin or HPMC capsules were developed with a tamper evident design to specifically address the clinical trial challenges of testing without bias.

Allows for IMD to be put blinded without having to alter drug structure – capulses wide enough to fit drug but also short enough that makes them easy to swallow.

Question 26

1. When was the Declaration of Helsinki last updated?

Answer 26

2013

Answer 27

• •Secure – no unauthorised access.
• •Label type – adhesive; single / double / triple panel; booklets; colour; fonts.
• •Inspection – legibility, GMP compliance, patient suitability.
• blinding
• validated systems
• •Reconciliation, storage.
• •Expiry / use before / retest dates

Question 28

Describe the purpose of the Declaration of Helsinki?

Answer 28

Aims to protect all patients taking part in clinical trials. Makes sure consent is obtained and that it is voluntary. Allows subjects to withdraw themselves at any point

Question 29

What is the purpose of an ‘ethics committee’ in the context of clinical trials?

Answer 29

Ethics committee is an independent body that plays the pivotal role in ensuring that a trial is conducted in accordance with GCP guidelines and to safeguard the safety and well-being of subjects participating in a clinical trial

Question 30

Briefly describe what is meant by the term ‘informed consent’.

Answer 30

permission granted in full knowledge of the possible consequences

Question 31

Explain the following terms when used in the context of clinical trials:

1. Blinding;
2. Randomisation
3. Sponor

Answer 31

a. Certain people involved within the trials are unaware of which treatment group a subject has been assigned too. Open label – both the subject and investigators are aware. Single blind – the subject is unaware but investigators are aware. Double blind – the subject and investigators are both unaware
b. The subjects are allocated into a treatment group using an element of chance to reduce bias
c. a sponsor is an individual, institution, company or organization (for example, a contract research organization) that takes the responsibility to initiate, manage or finance the clinical trial,¹ but does not actually conduct the investigation

Question 32

Where the comparator product is modified to allow a blinded study to take place what must be ensured in these products?

Answer 32

That they look the same, taste the same, sound the same, smell the same and that stability is monitored therefore dissolution and distigration tests should be done to ensure absorbance isn’t altered if SDF

Question 33

Briefly explain why the packaging of IMPs is more complex than standard medicinal product?

Answer 33

• Usually hand assembled.
• Blinded therefore contents not identified on label.
• Complicated construction – not just one product in one pack.
• Zero tolerance of errors.

Question 34

What information should be included on the labels for IMPs

Answer 34

• name, address and telephone number of the sponsor, contract research organisation or investigator (the main contact for information on the product, clinical trial and emergency unblinding);
• (b) pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/potency;
• (c) the batch and/or code number to identify the contents and packaging operation;
• (d) a trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere;
• (e) the trial subject identification number/treatment number and where relevant, the visit number;
• (f) the name of the investigator (if not included in (a) or (d));
• (g) directions for use (reference may be made to a leaflet or other explanatory document intended for the trial subject or person administering the product);
• (h) “For clinical trial use only” or similar wording;
• (i) the storage conditions;
• (j) period of use (use-by date, expiry date or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity.
• (k) “keep out of reach of children” except when the product is for use in trials where the product is not taken home by subjects.

Question 35

1. Which of the above pieces of information must be omitted in the case of blinded clinical trials?

Answer 35

• a) name of sponsor, contract research organisation or investigator;
• (b) pharmaceutical dosage form, route of administration (may be excluded for oral solid dose forms), quantity of dosage units and in the case of open label trials, the name/identifier and strength/potency;
• (c) batch and/or code number to identify the contents and packaging operation;
• (d) a trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere;
• (e) the trial subject identification number/treatment number and where relevant, the visit number.

Question 36

1. For how long should the reference and retention samples be retained?

Answer 36

Reference sample: a sample of a batch of starting material, packaging material, product contained in its primary packaging or finished product which is stored for the purpose of being analysed should the need arise.

Retention sample: a sample of a packaged unit from a batch of finished product for each packaging run/trial period. It is stored for identification purposes.

Reference and retention should be kept for at least two years after completion or formal discontinuation of the last clinical trial in which the batch was used, whichever period is the longer.