Joint Pharmaceutical Analysis Group
Analytical support for clinical trials: meeting clinical and regulatory needs
Hospital pharmacy departments play a pivotal role in clinical trials,
said V’Iain Fenton-May, of St Mary’s Pharmaceutical Unit,
Cardiff. These trials may be purely commercial with an external sponsor,
or non-commercial, where the hospital itself sponsors the work, perhaps
as part of a research project. Although these trials may be handled in
different ways, with overall responsibility at different locations, the
information required remains the same. Major hospitals will handle up
to 200 concurrent trials, so sponsors should ensure that everything is
done to make their particular trial run smoothly.
Mr Fenton-May recommended a comprehensive checklist that a pharmacy should
complete before a trial is accepted. The checklist should cover
- trial
sites and patient numbers
- the proposed protocol
- the duration of the
study
- the proposed study start date
- randomisation requirements
(and who is responsible for this)
- stability data (supplied by
the manufacturer, and probably established by local quality control)
- specific
storage
and shipment requirements
- dispensing sites
- disposal of
unused active material at the end of the study
- ethics or peer
review approval
As regards drug material used in a trial, any
person accepting
responsibility
for signing off a product must know what is being
used and why. Provided the checklist is satisfactorily completed then
there should
be no
difficulty
in handling conventional investigational medicinal
products, he
said.
However future products will offer a different challenge.
Gene therapy is coming, and that will use viral vectors
for transfer. There are
potential contamination risks and genetically modified
organisms can come into
contact with humans other than the intended patient
via
accidental dissemination during handling and use, disposal
of unused
product or waste products,
and disposal of virus-containing patient excreta.
Different viruses will need different levels of
care but, at whatever level, the pharmacy must
be able
to handle
the products.
Pharmacy
departments already handle hazardous materials
with no apparent contamination problems.
However contamination at some level is inevitable.
The important point is to recognise the significance
of the
possible level
of contamination, so the sponsor must provide relevant
safety information,
and the
facility
must have appropriate decontamination routines, concluded
Mr Fenton-May.
Legal and regulatory aspects: good control of manufacturing process
Elaine Godfrey, of the Medicines and Healthcare products Regulatory
Agency, said that the role of the MHRA in clinical trials is to ensure
the
safety of trial participants and the collection of valid data. The
agency does not act as a consultancy for the trial, although if the
sponsor has particular problems it does no harm to discuss these with
the agency.
The agency makes its decisions solely on the information given by the
sponsor in the investigational medicinal products (IMP) dossier, the
trial protocol and
the investigator’s brochure. The agency will review inclusion and exclusion
criteria, safety monitoring and reporting, non-clinical data and safety with
respect to quality of the product, Dr Godfrey said.
To generate credible trial data, there must be adequate control of the manufacturing
process and of the product. and also of the clinical data being produced. There
is a guideline on the requirements for the chemical and pharmaceutical quality
documentation concerning IMPs in clinical trials available in Volume 10 of “The
rules governing medicinal products in the EU”.
In addition, there are good
manufacturing practice requirements covering the manufacture of IMPs. The guideline
applies to chemical substances, synthetic peptides, herbal substances or products,
and radioactive or radiolabelled substances. It does not apply to biotechnological
or biological substances. This guideline covers both drug substances and drug
products, and is divided into information for phase I trials and information
for phase II and III trials. There are no specific requirements for phase IV
trials since these are performed on marketed products.
The suitability of the analytical methods should be described, and the acceptance
limits and parameters for performing validation should be presented in a tabular
format, but there is no requirement for a detailed validation of the analytical
methods. For pharmacopoeial substances, reference to the relevant pharmacopoeial
monograph is sufficient. For biological and biotechnological products, there
is no similar guidance, but sponsors may wish to follow similar principles.
Emphasising that the agency’s role is in the safe conduct of the trial,
Dr Godfrey stated that there is no requirement for detailed analytical methods
and their validation for bioanalytical methods in the IMP dossier. This is a
separate issue. Sponsors should consider what really needs to be in their dossiers
as many of them are far too comprehensive for the purpose, she concluded.
The aim of the biological agents unit of the Health and Safety Executive is
to ensure that risks in the workplace from microbiological hazards are properly
controlled, said Paul Logan, of the HSE. All aspects of genetic modification
procedures and biotechnology related to human health and environmental safety
are covered and the unit provides the secretariat to the Scientific Advisory
Committee on Genetic Modification (SACGM).
The HSE has an interest in the conduct
of clinical trials by virtue of the Health & Safety at Work Act, a European
directive, and Control of Substances Hazardous to Health regulations. The contained
use regulations apply to any activity in which genetically modified (GM) organisms
are cultured, stored, transported, destroyed, disposed of or used in any other
way and for which physical, chemical or biological barriers are used to limit
contact with humans or the environment to ensure a high degree of safety. Therefore
they are considered to cover many, but not all, clinical activities.
Guidance is available on the HSE
website and in the “Compendium
of guidance — part 6 guidance” on the use of genetically modified
micro-organisms in a clinical setting issued by the SACGM. The guidance has come
about because of the increasing use of genetically modified material in clinical
applications. The hospital environment is greatly different from typical laboratory
use, with clinicians, nurses, patients, visitors and pharmacy staff all potentially
affected by clinical agents. Often there is no GM safety committee or biological
safety officer in place, and at present there is no common position in Europe.
Risk assessment considers risk to workers and the wider environment so that it
includes staff and visitors in the hospital. It is based on the properties of
the genetically modified medicine and how it is to be stored, prepared, used
and disposed of. Such properties are usually well understood by the time a drug
reaches the clinic.
Containment is an important consideration. Clinical applications often combine
physical containment (sealed containers, refrigerators, freezers, safety cabinets)
with biological containment. A GM medicine would be regarded as being biologically
contained if it is endowed with inherent or engineered characteristics resulting
in sufficient attenuation, disablement or auxotrophy to impair its ability
to infect, replicate or survive outside of a specialised environment. Most
GM micro-organisms
in clinical trials are either replication defective, or replication conditional,
and are considered to be biologically contained. The physical containment required
to protect workers and the environment will depend on the nature of the gene
being delivered. In most cases minimal physical containment is required.
Appropriate training and instruction is crucial to all aspects of handling
GM medicines. Dr Logan saw no conflict with Good Laboratory Practice in the
conduct
of trials complying with health and safety legislation.
Challenge of batch release testing for a live virus can be overcome
Intercytex is a cell therapy company with products that focus on skin
and hair and address both aesthetical and medicinal needs, said Gary
Wilcock, of Intercytex. Its lead medicinal product, ICX-PRO, is indicated
for the treatment of hard-to-heal venous leg ulcers and consists of
viable human dermal fibroblasts in a human fibrin matrix. The principal
logistical problems associated with the manufacture, testing, release
and supply of such biological drugs relate to the requirement for quality
parametric release after aseptic manufacture, the need for refrigeration
and the extremely short shelf-life of 21 days. Consulting the guidelines
and regulations relating to analytical control of such biological products
reveals a multitude of apparently relevant documents, but it is useful
to go back to basics and consider the main purpose of the analytical
support, that is, to ensure quality, safety and efficacy of the material
during the trial.
Two assays based upon the measurement of cell outputs were therefore
developed for ICX-PRO. The Alamar Blue fluorescent assay for cellular
growth and viability measures a function of the total metabolism of the
cell, whereas the vascular endothelial growth factor secretion assay
measures a discrete molecule secreted from the cells, this molecule being
known to form part of the wound healing process. Both tests require stringently
controlled sample preparation, so much so that the sample preparation
systems employed have required optimisation and validation akin to process
validation. Additionally, in-process checks form an integral part of
the release system helping to maintain consistency of manufacture. Mr
Wilcock commented that proving the safety, efficacy and quality of such
products required the business to move from an R&D culture to a more
operational business culture, the emphasis being firmly placed on continuous
improvements and key performance indicators to optimise every aspect
in the product chain.
Similarly, Colin Love, of BioVex, described the sponsor’s expectations
of the contractor, with reference to OncoVex, a lead product for the
treatment of cancer currently being tested in clinical trials for melanoma,
pancreatic and head and neck cancer. The product is based on a proprietary,
engineered form of herpes simplex virus, a potent virus that infects
and destroys cells through the process of lysis, in which the virus replicates
inside a cell and ultimately ruptures the cell membrane, killing it.
The deletion of a specific gene means the virus is able to replicate
in tumour cells but not in the surrounding healthy tissue.
Analytical support at the clinical site is wide-ranging, addressing the
problems of product stability during transport, storage and dispensing,
virus containment and virus efficacy. Thus a range of specific analytical
methods is required to support clinical trials with a live viral product.
Several potency assays may be required because viruses have more than
one mode of action, and further tests are required for purity, impurities,
content and identity. Many of these safety tests require a rapid turn-around
during first dosing of the product to patients in the early stages of
the first clinical trials. For this product the challenges of batch-release
testing for a live virus have been overcome, and product characterisation
can be used to provide support for process change and scale up, concluded
Dr Love.
Bioanalysis and trials: regulatory aspects becoming more stringent
As well as providing analytical support ensuring the quality of material
used in clinical trials, analytical support is also required in the
analysis of biological samples generated in trials carried out in
support of safety data. Thus bioanalysis is a critical element in the
clinical
drug development process, said Andy Brown, of Bioanalytical Systems.
Bioanalysis is traditionally the measurement of small chemical entities
in biological samples, such as plasma, urine, serum, saliva, semen,
sputum, milk, CSF, tissues, tumours and faeces. A high proportion
of such analyses
required in clinical trials is outsourced. These may be for first-time-in-man
studies, where rapid turn-around of data is required for safety and
tolerance, through to lengthy patient studies and bioequivalence
studies.
Modern
drug discovery is directed to highly active molecules and this, in
turn, leads to the need for highly sensitive methods to determine
the pharmacokinetic
parameters needed for those clinical decisions. Although the advent
of LC-MS/MS has enabled highly sensitive and rapid methods to be
developed
it is not the universal solution, not always being sensitive enough
and prone to matrix effects. Other detection methods such as fluorescence
and electrochemistry can offer better sensitivity for certain small
molecules
and immunochemistry methods for biological therapies may also be
appropriate.
Regardless of the assay method used, it must be validated
according
to established properties of precision, accuracy and robustness
for the
duration of the development project. Methods subject to variability
will be troublesome and neither cost-effective nor time-efficient.
However,
none of the methodologies discussed or results obtained is worth
anything if the sample has not been collected correctly, said Mr Brown.
Over
90 per cent of analytical problems related to clinical bioanalysis,
are
due to that miscollection, he claimed. This may be due to simple
labelling problems or more critical issues of stability, such as
inappropriate use of anticoagulants or other stabilisers, collection
devices
which adsorb drug onto surfaces, and inadequate control of temperatures
during
processing as well as during storage. The collection process
itself needs to be validated. Methods need to be appropriate for the
application.
For example, the method should cover expected concentrations
encountered in the clinical study and should remain valid in conditions
encompassing
the targeted disease state in patients, or with co-administered
medicines.
The regulatory aspects of bioanalysis are becoming more stringent,
as evidenced by the first issuance of a US Food and Drug Administration
warning letter to a bioanalytical facility for apparently inadequate
analytical methods. The sphere of bioanalysis may be shifting
to strategic outsourcing providers that have the infrastructure for
permanent regulatory
compliance, but the sponsor will want to make sure the analytical
base is also competent, said Mr Brown. |
The
Pharmaceutical Journal