I.D.

Number __________________________________ Desk No _____________

Faculty of Science, Engineering and Computing

Postgraduate Regulations

April/May Examinations 2016/2017

Level 7

MODULE: CH7060: Manufacture and Clinical Trials of Medicines

DURATION: Three Hours

Instructions to Candidates

This paper contains TWENTY-SIX questions in THREE sections: Sections A, B and C

Answer TWENTY-FOUR questions only

Section A: THIS SECTION HAS BEEN WITHHELD BY THE FACULTY

Section B: Answer TWO questions only with each answer in a separate
yellow answer book (30 marks)
Section C: Answer TWO questions only with each answer in a separate
yellow answer book (30 marks)

THIS PAPER MUST BE HANDED IN AT THE END OF THIS EXAMINATION

CANDIDATES ARE PERMITTED TO BRING ONE APPROVED

CALCULATOR INTO THIS EXAMINATION: from either Casio FX83 or Casio
FX85 series (with any suffix), FX115MS, FX570ES or FX991ES

Invigilators are under instruction to remove any other calculators

Stationery MCQ Answer Sheet

Yellow Answer Books x 4

Number of Pages: 1 – 13
 SECTION A

THIS SECTION HAS BEEN WITHHELD BY THE FACULTY

Continued…

1
 SECTION B

Answer TWO questions only from this section

21. Answer BOTH parts of this question.

(a) What do the terminologies LL, MedDRA, SmPC and PT stand for?
(4 marks)

(b) A patient called to report to your company the symptoms he

experienced when taking Seitoin, a medicine that your company has on
the market. He describes that he has been feeling sick, tired, having
difficulty in sleeping, and his heart flutters. Although he is fine now, he
did feel awful that he had to go to A&E to have his heart checked out.
Fill out the missing information in the bolded columns as per the LL
below. An extract of Seitoin’s SmPC is provided below.

Extract of SmPC Seitoin

4.8 Undesirable effects

The most notable signs of toxicity are cardiovascular collapse and/or depression of
the central nervous system.

Severe cardiotoxic reactions such as tachycardia and fatalities have been reported,
most commonly in gravely ill patients or the elderly (see Warnings).

These are the most common reactions encountered with Seitoin and include nausea,
vomiting and constipation. Less common side effects include slurred speech,
decreased coordination and mental confusion. Cases of dizziness, insomnia,
transient nervousness, motor twitchings, lethargy and headaches have also been
reported. These side effects are usually dose related.

A measle-like rash is the most common dermatological manifestation. Rashes are

sometimes accompanied by fever, and are generally more common in children and
young adults. Other types of rashes are more rare, and more serious forms which
may be fatal include bullous, exfoliative or purpuric dermatitis, lupus erythematosus,
Stevens-Johnson syndrome and toxic epidermal necrolysis

Question 21 continued on page 8…

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Continuation of Question 21:

LL for Molecule: Seitoin

Date Case ref MHRA ref C A Dose Treatment Onset Preferred Outcome Serious Listed Comments SDEA
received O G duration or Term
U E start date (MedDRA v
N / 19.1)
T S
R E
Y X

SEI To be UK unk Unk Unk n/a

001/17 confirmed

(11 marks)

Total 15 marks

Continued...

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22. Answer BOTH parts of this question.
(a) Consider the Delegation Log & the IMP Accountability Log for the trial
entitled ‘Double Blind, Placebo Controlled, Cluster Randomised Trial for
compound CH7060 to improve blood flow to the brain. Indicate errors
or inconsistencies in the log and explain the corrective actions and/or
implications if the log is in use for the period of the clinical trial.
Delegation of Responsibilities Log:
Title: Double blind, placebo controlled, cluster randomized trial for
compound CH7060 to improve blood flow to the brain Investigator
Name: Kingston Clinical Trails / Stuart Karl Malcolm (Principal
Investigator) Protocol: 7XGc 2016 Site Number: 418
Signatur Initial *Responsibilit Start End
Name e s ies Date Date Role
Alex 21/11/2010 to Research
Alex Mathew Mann mnnn AMM 1, 10, 14 31/10/2011 Assistant

Clinical
Research
Adam Geoffrey 21/11/2010 to Coordinato
Sinclair A G SIn AGS 1,5,6,11,13,14 31/10/2011 r

Clinical
Mora L 01/10/2009 to Research
Mora Lina Whittles W MLW 2,3,4,5,9,12,13 31/10/2011 Nurse

KP 12/11/2010 to Pharmacis
Kate Patricia Newman Newman KPN 3,7,8 31/10/2011 t

12/11/2010 to Pharmacy
Anna Gabriel Stephan AGS 7,8 31/10/2011 Technician
*
Responsibilities legend
1. Administer 6. Randomize 11. Complete
Consent Subjects Study Forms
2. Screen 7. Dispense 12. Provide
Subjects Study Drug (IMP) Discharge Instructions
3. Un-blind 8. Drug (IMP) 13. Make Follow-
Accountability up phone calls
4. Perform
Physical Exam 9. Assess 14. Query
Adverse Events Management
5. Determine
Eligibility 10. Complete
Source Documents
By signing below, I, the PI, declare that during the conduct of the above study, I have
delegated the above listed study-related activities to those individuals listed above
Signature of Principal Investigator: _Malcolm Stuart _ Date: _01 November 2010_
(10.5 marks)

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 Question 22 continued on page 10…
Continuation of Question 22:

(b) With reference to Home Office animal research legislation; briefly define what
the “3Rs’’ stand for.
(4.5 marks)

23. Answer BOTH parts of this question.

(a) Critically evaluate the merits and limitations of crossover trials in a clinical
trial study.
(8 marks)

(b) Outline and discuss the factors considered in choosing a randomisation

strategy within a clinical trial study.
(7 marks)

Total 15 marks

5
 Continued...

6
 SECTION C

Answer TWO questions only from this section

24. Answer ALL parts of this question.

Read the abstract below and answer the questions on it.
Lancet 2012, Aug 1;380(9842):651-9. Doi: 10.1016/S0140-6736(12)60988-X

Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre,

double-blind, placebo-controlled trial

Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, Ortega H, Chanez P

Abstract

BACKGROUND: Some patients with severe asthma have recurrent asthma

exacerbations associated with eosinophilic airway inflammation. Early
studies suggest that inhibition of eosinophilic airway inflammation with
mepolizumab-a monoclonal antibody against interleukin 5-is associated
with a reduced risk of exacerbations. We aimed to establish efficacy,
safety, and patient characteristics associated with the response to
mepolizumab.

METHODS: We undertook a multicentre, double-blind, placebo-controlled

trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011.
Eligible patients were aged 12-74 years, had a history of recurrent severe
asthma exacerbations, and had signs of eosinophilic inflammation. They
were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of
intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo
(100 mL 0·9% NaCl) with a central telephone-based system and computer-
generated randomly permuted block schedule stratified by whether
treatment with oral corticosteroids was required. Patients received 13
infusions at 4-week intervals. The primary outcome was the rate of
clinically significant asthma exacerbations, which were defined as
validated episodes of acute asthma requiring treatment with oral
corticosteroids, admission, or a visit to an emergency department.
Patients, clinicians, and data analysts were masked to treatment
assignment. Analyses were by intention to treat. This trial is registered with
ClinicalTrials.gov, number NCT01000506.

FINDINGS: 621 patients were randomised: 159 were assigned to placebo,

154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg
mepolizumab. 776 exacerbations were deemed to be clinically significant.
The rate of clinically significant exacerbations was 2·40 per patient per year
in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction,

Question 24 continued on page 12…

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Continuation of Question 24:

(a) Briefly discuss the outcomes of the study in terms of the primary end
point and its statistical significance.

(8 marks)

(b) What data is presented on the safety of the drug?

(2 marks)

(c) The conclusions have been removed from the abstract. What are your
conclusions of this study?
(2 marks)

(d) This study is a placebo controlled trial in a serious disease. The drug
has been shown to be effective in the treatment of metastatic renal cell
carcinoma. Briefly outline why in this study the use of a placebo does
not break ethical standards.
(2 marks)

(e) Comment briefly on the source of this abstract and how this would
influence your opinion on the reliability of the research.
(1 mark)

Total 15 marks

25. Answer BOTH parts of this question.

(a) Discuss various challenges that are encountered in handling

therapeutic peptides and proteins.
(7 marks)

(b) Evaluate various formulation strategies adopted in improving the

stability and the delivery of therapeutic peptides and proteins.
(8 marks)

Total 15 marks

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 Continued…
26. Answer BOTH parts of this question.

(a) The following ternary phase diagram is for a three-component lipid-

based system comprising: A (normal saline), B (soybean oil), C (Tween
80 and ethanol at a fixed ratio of 1:1) at 25 degree Celsius. The arrow
represents the phase boundary between the one-phase (F2) and two-
phase (F1) regions.

(i) Describe (quantitatively) the compositions of formulations F1 and

F2.

(4 marks)

(ii) Compare and contrast both formulations (F1 and F2) in terms of
composition.

(2 marks)

(iii) What is in-common between systems formulated on the arrow

and what are some of the limitations associated with using such
systems as pharmaceutical formulations.

(4 marks)

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(b) Describe using a diagram the antisense mechanism.
(5 marks)

Total 15 marks
END OF EXAMINATION PAPER

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