Transcript Gene Therapy: Technical, Regulatory and Stakeholder issues

Gene Therapy:
Technical, Regulatory and Stakeholder
issues
Shefaly Yogendra
Doctoral Scholar, University of Cambridge, UK
TMP GRADUATE CONSORTIUM
MIT, CAMBRIDGE, USA
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Background
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Status and role of the Parliamentary
Office of Science and Technology
(POST)
Target audience mainly non-science and
non-technical MPs and peers
POSTnote™ and longer reports
POST Fellowships
www.parliament.uk/post
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POSTnote – Gene Therapy
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2003: UK government pledges £50M over 3
years to harness potential of genetic
technologies (£10M for gene therapy)
Late 2003: China approves ‘Gendicine’, a
gene therapy for head and neck cancer
2005: First marketing authorisation
application for a gene therapy for a type of
brain cancer by a UK firm expected
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What is gene therapy?
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Introduction of genetic material into a cell to treat
disease
Various ways:
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Supply functioning copies of a malfunctioning gene
Switch specific genes on or off
Introduce genetic material to kill cancer cells or suppress
tumours
Stimulate immune system to attack certain types of
‘invaders’
Still in clinical trial stage in most cases, regulated as
a research protocol
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Administering gene therapy
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Two ways:
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Insert therapeutic material into cells from affected
tissue outside body and return them to the body
Deliver therapeutic material directly to the affected
tissue or organ
Either way, a ‘vector’ is used
Most vectors are modified viruses, due to
their efficiency in targeting and entering cells
Over 70% of UK trials involve viral vectors
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Success in gene therapy requires…
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Genetic malfunction is understood
Therapeutic material can be delivered
to target cells in affected tissue/ organ
Therapeutic material is active for
intended duration and delivers intended
benefit
Harmful side effects, if any, are
manageable
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UK regulation of gene therapy
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Advice of Clothier Committee 1992
Gene Therapy Advisory Committee (GTAC)
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Medicines and Healthcare Products Regulatory
Agency (MHRA)
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Assess ethical acceptability of proposals taking into account
scientific merit, benefits and risks
Ministerial advice, regulatory ‘networking’ and foresight
License clinical trials in the UK
Competent to regulate medicinal products and devices
UK Clinical Trials Regulation 2004 prohibits germ line
gene therapy for ethical and safety reasons
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UK gene therapy clinical trials
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Since 1993, 96 trials approved
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72% cancer
13% for single-gene disorders
7% for vascular diseases
Majority very small Phase I trials (with
as few as 16-18 patients sometimes)
In UK, only 3 Phase III trials – one in
HIV and two in a type of brain cancer
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Technical issues
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Gene delivery
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Not easy or predictable e.g. contrast between CF
and X-SCID
Durability and integration
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Where long-term effect desirable, therapeutic
material must remain active for the duration
Achieved through multiple rounds of therapy or
through integrating therapeutic material
Raises concerns about undesirable side effects,
e.g. X-SCID
Ongoing search for stable, non-integrating vectors
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Technical issues
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Durability and integration
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Where more immediate effect required, integration
is not an aim e.g. in cancer
Immune response
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Body responds to viral vector as invader
In some cases, such as cancer, triggering such
immune response is the aim of the therapy
In most cases, immune response may reduce
efficacy of gene therapy by reducing patient
responsiveness and increasing resistance to
multiple rounds of therapy
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Technical issues
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Safety of vectors
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Only 2 fatalities directly attributable to
gene therapy, yet concerns raised
Animal research may provide vital
information about vector safety
Uncertainty
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Complexity of process makes undesirable
outcomes difficult to explain
Uncertainty inherent to the process
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Regulatory challenges
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Paediatric research
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Ethical issues
No European guidelines yet
Informed consent hard to obtain
Accountability, openness and transparency
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Case-by-case approach but GTAC/ MHRA criticised
for ‘closed door’ approach
Public database in UK for NHS-sponsored clinical
trials as well as recently announced voluntary
measures by industry welcome steps
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Regulatory challenges
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Resources
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Growing research investment
More work likely for GTAC/ MHRA
Future challenges
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New technologies emerge e.g. RNAi,
presently reviewed case-by-case
Blurred boundaries of science
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Stakeholder issues: insights
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This slide under Chatham House Rule
Department of Health
Regulators
Research community
Patient interest groups
Industry
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Future prospects
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Much funding directed at disease-led research
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Satisfactory for patient interest groups
Researchers demand more basic research into
vector safety, delivery techniques and uncertainty
of outcomes
Varied expectations of a commercial gene
therapy product in the UK market
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Patient interest groups realistic about a 10-15 year
horizon
Complications arising from European centralised
approval process for biologics
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