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David Allen is chief executive officer
of ADAllen Pharma
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The United Kingdom Government recently announced further investment
in UK biotechnology. Great news, you may have thought, but a separate
Government
proposal threatens to kill off a significant portion of other UK research
and development activity. The EU Clinical Trials Directive and the Medicines
and Healthcare products Regulatory Agency’s (MHRA) consultation
letter are a particular threat for phase I clinical trial activity and
could impinge on the commercial viability of all clinical trials.
The industry was consulted on the directive, and more than 300 letters
were submitted to the MHRA from industry leaders during the consultation
period. I have seen them and they make stark reading. Dr Mark Walport
of the Wellcome Trust stated in the trust’s submission: “The
implementation of the regulations as currently drafted could render non-viable
much of the academically driven and publicly funded clinical research
that addresses major health issues of public concern.”
Clinical research organisations (CROs) are also forecasting negative
results for the wider community. Ray Stringer, chief executive officer
of Phase I Clinical Trials Unit Ltd, stated: “Without the initial
phase I input, the pharmaceutical industry may be inclined to place whole
development programmes overseas.”
Potential fallout
The directive appears to have two objectives: to harmonise the clinical
trial regulatory environment in the EU and to improve the protection
of human subjects. Unfortunately, the potential fallout may mean there
are fewer trials to regulate after May 2004 when the directive comes
into force.
The proposed regulations will, for the first time, encompass any clinical
trial involving human subjects. The definition in the consultative letter
does not conform to the International Conference on Harmonisation’s
Good Clinical Practice 1.12, so phase I trial managers will have to complete
the labyrinthine paperwork of a clinical trial application, wait up to
60 days for an ethics committee decision and 30 days for the competent
authority to approve it.
This will be a significant change for phase I volunteer studies and there
is concern that, according to Charterhouse Clinical Research submission
letter, “the MHRA will not be able to match the response time necessary
for the efficient study scheduling, bed occupation and staff utilisation
of a viable phase I unit”.
In addition, many organisations will have to recruit and train extra
staff to manage this paperwork, which will add significant bureaucracy
and cost, with no additional benefit to patient safety.
Investigational medicinal products (IMPs) also come under intense scrutiny
in the directive. In the draft regulations, an IMP is defined as a “pharmaceutical
form of an active substance or placebo being tested, or to be tested,
or used, or to be used, as a reference in a clinical trial”, and
includes a medicinal product which has a marketing authorisation (MA)
but is, for the purposes of the trial used in some way other than that
for which the form received an MA. It is therefore no wonder that Dr
Robert Harris of Sanofi-Synthelabo described the definition as “inappropriately
restrictive” in his response to the consultation.
If a clinical trial product is designated an IMP and, given that any
active substance from the moment of manufacture might, at some stage, “be
used . . . as a reference in a clinical trial”, would not every
pharmaceutical product be designated a potential IMP? And surely, if
an IMP is not going to be used in the way in which the MA authorises
it, then it must be accompanied by a Qualified Person (QP) certificate
and the “manufacturer” has to have manufacturing authorisation?
If some IMPs are repackaged (a manufacturing process), for example, any
organisation doing this will also require manufacturing authorisation
and a QP to certify that good manufacturing practice (GMP) was followed.
As Charterhouse Clinical Research also stated: “For the volume
and relative simplicity of the manufacturing and/or import which we undertake,
it is unsustainable to employ personnel as head of manufacturing, head
of quality control and a QP.”
Further requirements
For non-EEA manufactured IMPs the proposals will also require that:
1. The importer has an IMP manufacturing authorisation. This is not
an import licence but a manufacturing authorisation. The importer must
operate to GMP, not good distribution practice standards, and may even
be required to meet good clinical practice (GCP) in some circumstances.
This will increase the indirect costs of GMP and GCP inspections.
2. The IMP is accompanied by a QP sign off that the batch was manufactured
to GMP. Which GMP is supposed to apply is unclear, but an attempt to
impose EU GMP on US Food and Drug Administration registered facilities
might be an entertaining sideshow. As MDS Pharma said in its response: “This
could be a substantial disincentive for sponsors located in third countries
to conduct investigational clinical studies in the EU.”
3. The importer will extract from the manufacturer of the IMP an undertaking
to open up its premises to inspection by the MHRA. Remembering the current
barriers that some pharmaceutical companies create to hinder the sourcing
of comparators, this further layer of bureaucracy will simply add time,
paperwork and expense to the process. The MHRA already lacks sufficient
resource for inspections.
A death threat
Imposing EU guidelines on non-EU countries may appeal to Eurocrats, but
as Dr P. Rolan from Medeval said in his letter: “Complete or
extensive retesting of conformity for IMPs would have a catastrophic
impact on the phase I CRO industry within the UK.”
The impact of the directive reaches across all sectors of the clinical
trials industry. Unless changes are made following the now completed
consultation exercise, it is clear that, come May 2004, the money recently
invested in biotechnology may be of little use.
One company has already pointed out that it is “anecdotally aware
of major pharma companies having already made or contemplating the decision
to withdraw their phase I activities from the UK and transfer them to
the US”. This is clearly not the result the Government was after
when the directive was first suggested. As a specialist in the sourcing
of comparators for clinical trials, it is clear to me that the directive’s
import regulations will need to be relaxed or significantly amended by
the Government since they impose huge financial burdens on the industry.
The effect of stringent implementation will be to curb the majority of
phase I and II studies in the UK, pushing them into other less developed
countries with, I suspect, lower operational costs and greater risks
to patients. There will inevitably also be a greater risk of fraudulent
data and a return to pre-1968 Medicines Act activity.
This directive is clearly a death threat to the UK and European pharmaceutical
industries. Let us hope the Government takes note and redresses the balance
before it is too late. |
