Short Answer Questions

MSc Clinical Drug Development

Assignment 1 – Short Answer Questions
Module 3 – Clinical Trial Design & Management

Nestor D Salazar Vallejo

24 January 2011
 1. The cross over clinical trial design is sometimes used for
drug development trials. Briefly describe what is meant by
“crossover” in relation to clinical trials and give the
advantages and disadvantages of this design.
A cross over clinical trial design, also known as within patient design, is a
randomised control study featuring two observational periods with the same
group of subjects. The observational periods have a similar design to a parallel
study with a control and test group running simultaneously after an initial
randomisation of the study subjects.

After the first observational period there is a cool off or wash out period that
allows the test group to return to normal after being treated with the drug
candidate in question and therefore allowing the same subjects to be used as
controls in the second observational period. The initial control and test groups
are then switched so that in the second observational period the original control
group is treated with the drug candidate and the original test group acts as the
new control.

Measurements are taken during the wash out period in order to ensure that the
subjects in the first observational test group have returned to the baseline
readings that would have been taken prior to the beginning of the study, making
this a fair and comparable result at the end of the observational periods.

Fig 1. The Cross Over Clinical Trial.

( https://www.accp1.org/pharmacometrics-website/pharmacometrics/theory.htm)
Advantages

• Reduced variability because each subject act as his/her own control. This
is particular important because the study has the potential to show the
true effectiveness of the compound.

• As each subject is his/her own control there is a reduced number of

subjects needed. This is particularly advantageous when there is a low
prevalence of the disease in question.

Disadvantages

• Very difficult to keep a blind control so patients would be aware of the

treatment they are receiving which might induce a placebo effect. This
might also cause an ethical issue, since

• The design is not suitable for medicines that are metabolised slowly
because of the carry over effects and the long wash out period expected.

• As the monitoring tends to be more intense and the duration of the study
might be longer than a normal parallel study (particularly because of the
wash out period), compliance might become an issue and increase the
probability of subjects dropping out.

• The low subject numbers mean that the effects on the potential post-
launch population can not be extrapolated.

Cross over studies are more commonly used in episodic conditions where the
return to baseline values is quicker and more evident than in progressive disease
states.

Word count: 401

 Bibliography

Piantadosi, S (2005) – Clinical Trials: A Methodologic Perspective, Second

Ed, New Jersey, USA: Wiley

Fitzpatrick, S (2008) – Clinical Trial Design, v 1.1: The Institute of Clinical

research Publication

Parry, T (2007) – Statistics in Clinical Research, v 1.2: The Institute of

Clinical research Publication

References

Pharmacometrics, online at https://www.accp1.org/pharmacometrics-

website/pharmacometrics/theory.htm accessed on 18 January 2011
 3. Some drugs go through phase I testing without using
healthy volunteers, give examples and explain why.

Phase I studies are commonly and vaguely described as first in human studies,
this term even though correct is not a full description of the actual aim and
objectives of the trial. The primary purpose of a phase I trial is to monitor the
pharmacodynamic and pharmacokinetics of the new compound in man in order
to fully assess its pharmacological characteristics, as well as identifying any
adverse effect (AE) caused by its administration, in other words its safety.

The phase I studies for most new drugs are carried out in healthy “volunteers”
that are occasionally compensated for their time. The studies are usually carried
out in a specially adapted inpatient unit within a hospital, research university or
increasingly a purpose built facility that allows around the clock collection of
biological samples, as well as around the clock monitoring of the trial subjects’
vital signs and behavioural characteristics.

Phase I trials of new molecules in therapeutic areas such as oncology,

neuropharmacology and new immunosuppressive or retroviral agents commonly
recruit patients with the targeted disease state instead of healthy volunteers.
This is more commonly done in oncology studies because cytotoxic drugs can
potentially damage a healthy subjects’ DNA, while in anti-AIDS drug
development it would be unethical to suppress the immune system of healthy
individuals and increase their risk of infection to common virus. In
neuropharmacology affected individuals are recruited to take Part in Phase I
studies in order to immediately assess efficacy, since many neuropharmacology
agents have a tolerance aspect that might mask its effect, (Atkinson, 2007).

The main objective of an oncology Phase I clinical trial is to determine the

Maximum Tolerated Dose (MTD). The MTD is the highest possible dose with no
adverse effect or acceptable toxicity (D’Angostino et al, 2007). Because of the
anticipated high level of toxicity associated with the cytotoxic agent, the trial is
only initially offered to patients that have exhausted most alternative
treatments, are severally ill and have a reduced life expectancy. The patients do
not usually get compensated for their time but due to the intense monitoring
required phase I oncology trials could cost up to £30k per patient (Tony Bragg
Lecture, 13/12/2010)

Several toxicity grading systems have been established, the World Health
Organisation toxicity grade 3 is the toxicity level more widely used to start a
dose escalation study in oncology bearing in mind that cytotoxic agents require a
level of toxicity to be effective. This starting dose is predetermined from pre-
clinical animal studies, once the MTD is found the study moves on to Phase II.

Word count: 424

Bibliography

Piantadosi, S (2005) – Clinical Trials: A Methodologic Perspective, Second

Ed, New Jersey, USA: Wiley

Schacter, B. (2006) The New Medicines – How Drugs are Created,

Approved, Marketed and Sold. USA, Praeger Publishers.

Atkinson, J (2007) – Principles of Clinical Pharmacology, Second Ed,

London, Elsevier

D’Agostino, R.B, Sullivan, L & Massaro J. (2008) – Wiley Encyclopedia of

Clinical Trials, Vol 3: Wiley

References

Anthony Bragg Lecture – Phase I Studies in Oncology – 13/12/2010

D’Agostino, R.B, Sullivan, L & Massaro J. (2008) – Wiley Encyclopedia of

Clinical Trials, Vol 3: Wiley

Atkinson, J (2007) – Principles of Clinical Pharmacology, Second Ed,

London, Elsevier
 7. What is a paediatric development plan and when and
why would one be needed?
Paediatric Development Plans (USA) also known as Paediatric Investigation Plans
(PIP) in Europe, as the name suggests are protocols of studies aimed at the
investigation of the effects of new or existing medicines on children’s unique
physiology. Over the years the development of paediatric medicines had been
hindered by the societal view against the inclusion of children in clinical trials.
However, in the past 20 years the USA through its medicines regulatory agency –
FDA – lead a change in mentality, which culminated in the introduction of the
guideline E11 of the ICH (International Conference of Harmonisation) in 1998.
(click here for link to EMEA ICH E11 website)

ICH E11 was adopted by the other regulatory agency members of the ICH by the
year 2000, subsequently it has become an essential requirement for all
medicines intended for paediatric use to have a paediatric development plan
or PIP specifying the timing, measures, age of paediatric population, dosage and
formulations in order to comprehensively assess the quality, safety and efficacy
of the medical candidate on the paediatric population. The plan must also
describe any possible adaptations to the formulation of the medicinal product
that would make its use more effective, safe or feasible in as wide range of
paediatric subsets as possible. The E11 guideline defines the paediatric
populations as:

• Preterm newborn infants

• Term newborn infants (0 to 27 days)
• Infants and toddlers (28 days to 23 months)
• Children (2 to 11 years)
• Adolescents (12 to 16-18 years, depending on the geographic region)
http://www.quintiles.com/elements/media/white-papers/eu-pediatric-
regulations.pdf
Since July 2008 all new Market Authorisation Applications and line extensions of
existing products must include the results of a previously agreed PIP, unless a
waiver has been granted which is only the case when the use of the product is
not suitable for the paediatric population (MHRA Summary of Regulation PDF
-www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE...Latest). For novel compounds,
the timing of the studies in the PIP might be adjusted in relation to the progress
of the adult study protocol in order to further ensure the safety of the paediatric
subjects. However, is recommended for PIPs to be submitted at the end of
Phase I trials. (http://www.quintiles.com/elements/media/white-papers/eu-
pediatric-regulations.pdf)

The implementation of a PIP as a requirement for all marketed medicines

recognises the fact that a growing child’s physiology is completely different to an
adult’s physiology; even in different stages of their development there would be
significant differences. Historically paediatric formulation had been based on the
child’s weight, however this lead to unsafe or ineffective doses being
administered. PIPs address this issue so that studied decisions can be made and
therefore increasing children’s safety.

Word Count: 423

Bibliography

Machin, D, Day, S & Green S.B. (2006) – Textbook of Clinical Trials, Second
Ed: Wiley

Mann, R.D & Andrews, E.B (2007) – Pharmacovigilance, Second Ed, London,
Wiley

References

ICH Topic E 11 - Clinical Investigation of Medicinal Products in the Paediatric

Population –accessed online at
http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guide
line/2009/09/WC500002926.pdf on 11/01/2011

MHRA Summary of Regulation PDF accessed online at

www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE...Latest on 11/01/2011

Quintiles Assessment of Regulations for Clinical Studies in Paediatric Patients in

the EU, accessed online on 18/01/2011 at
http://www.quintiles.com/elements/media/white-papers/eu-pediatric-
regulations.pdf
 8. What is meant by Source Document Verification? Describe
the process and responsibilities within the process.
Source Document Verification (SDV) is the process through which the information
recorded on the study’s Case Report Forms (CRF) is verified against source
documents and data. Examples of source documents include: hospital records,
laboratory notes, dispensing records, diagnostic records (i.e. x rays). Source data
is all the information in source documents and can be defined as the “first
recorded information” (Khosla, et al 2000). Good Clinical Practice (GCP)
guidelines require SDV to be carried out through all clinical trial phases (I – IV).
Continuous SDV is not only an important compliance requirement, it adds
confidence in the reported data and helps prevent fraud, therefore adding to the
scientific and ethical integrity of the clinical trial (Khosla, et al 2000).

SDV differs to data monitoring (DM) in that DM is a systematic review of the

quality of the information on the CRF while SDV verifies the information on the
CRF by reviewing the original source documents.

SDV Process

The percentage of SDV is not mandatory; it is a company’s decision which is

influenced by many factors such as man power, time availability, phase and size
of clinical trials, etc. The SDV is usually carried out by a Clinical Research
Associate (CRA) also known as a Clinical Trial Monitor. There are two common
methods:

Back to Back – The monitor does not review the data and asks specific
questions to the investigator.

Direct Method – The monitor physically reviews all source documents.

The data to be verified can also be divided into Critical and Non-Critical Data.
Critical data is vital to reach the outcome of the study and should be fully
verified for each trial subject, while non-critical data is verified to a lesser extent
that usually varies as the trial progresses and is inevitably influence by the
confidence in the investigator. Examples of critical data are:

• Informed Consent Forms

• Medical Notes

• Primary and Secondary Efficacy Clinical Endpoints

• Adverse event reports

• Evidence of conformance in patient medication, exclusion criteria and

treatment period as per the study protocol. (Khosla, et al 2000).

It is the sponsor’s responsibility to ensure that there is a written agreement

either in the protocol or separately that shows that the investigator will allow
direct access to the data for trial related monitoring (Khosla, et al 2000). The
sponsor company should also have a SOP (Standard Operating Procedure)
describing the most efficient and agreed SDV procedure while maintaining
patient confidentiality which is also its main responsibility. The SDV process is an
important procedure in indentifying fraud and the sponsor should educate and
encourage its monitors on its importance.

Word count: 412

Bibliography

Jenkins, C (2008) Making SDV More Effective – CR focus, vol 19 no 12

February 2008

References

Khosla R, Verma, D.D, Kapur, A & Khosla, S (2000) Efficient Source Data
Verification – Indian Journal of Pharmacology, Vol 32 p 180-186.
21/02/2000