Open label extension studies: research or marketing?
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.331.7516.572 (Published 08 September 2005) Cite this as: BMJ 2005;331:572All rapid responses
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While I agree with the authors that participants should be fully
informed (including, e.g. unblinding), and preferably reconsented, before
beginning the phase of open label extension studies, there are several
issues raised in the article that I feel rather uncomfortable with.
First of all, the minor issues. The authors raised several concerns which
are not specific to open label extension studies, or issues that can
easily be handled by research ethics committees (ECs). For example, the
pressure to get a high recruitment rate exists in all types of studies,
and I can't see how this is particularly the case for extension studies.
The possibility that an open label extension study may provide undue
inducement to participants is easily handled by either not allowing the
extension or requiring that the researchers recruit and reconsent
participants after the phase III study. The problem of scientific merit is
sometimes difficult to judge. But as the authors themselves mentioned, if
the EC is worried about scientific validity, then let the researchers
design a more valid study! Is this not what is required of all types of
studies whether phase III or IV drug trials which are poorly designed? Of
course there is a limitation for extension studies in that the
participants must be recruited from those in the prior phase III study.
But if (and this is a big if) the benefit of the phase III study has been
"reasonably" demonstrated, then the benefit of the extension study may
outweigh the inevitable design defect of selection bias. This assumes of
course that the published study will mention the selection bias so that
the reader may judge the merit of the study him/herself. Most of these
issues are nothing special to extension studies, and in some instances are
worse for some other research studies such as post-marketing or phase IV
drug trials.
There is one major issue that needs to be discussed. This is compassionate
use of an investigational treatment. Even if an investigational treatment
is used out of compassion, or for clinical reasons, the very nature of
investigational treatments requires oversight. The benefit and the risk of
such treatment have not been clearly established. The EC is in an
excellent position to oversee its use. Its objective is to protect
participants/patients. It has the necessary mechanisms to determine or
help researchers (or clinicians) determine when the risk of the
investigational treatment is doing more harm than good, and to therefore
protect participants/patients. And compassionate use, whether "research"
or not, should be done within a research framework if only to document the
outcomes, in published reports, for the benefit of others who will be
using the new treatment for future patients. The argument that some ECs
cannot "make ethical judgments about clinical decision involving the
longterm use of novel treatments" seems weak. If I interpret this
statement correctly, neither can anybody else, including the "experts" (or
else the treatment is by defintion not investigational). As the authors
mentioned, some ECs can make such judgements (whether by itself or by
consultation), by which I presume to mean the judgement, or informed
guess, of whether the longterm risk/benefit of the investigational
treatment is favourable or not. ECs without such a role should not
function as ECs! This oversight needs to have flexibility, of course. All
compassionate use protocols must have a built-in clause allowing clinical
judgement to sometimes overrule protocol, but this is subjected to
oversight and review. Although complicated and daunting at times for
researchers/clinicians, I cannot see a better model than "compassionate
treatment within research" (overseen by ECs) to fully benefit clinicians,
researchers and participants/patients (including future patients) all at
the same time.
Competing interests:
None declared
Competing interests: No competing interests
Compassionate use of investigational treatments: a key role for Local Ethics Committees
The article by Taylor and Wainwright (1) raises many important issues
on the role of market rules in planning clinical research. From the point
of view of a Local Ethics Committee (Azienda Ospedaliera di Verona, Italy,
accounting for the evaluation of about 150 studies per year) we agree with
all the ethical considerations made by the authors in their article.
However, contrary on what the authors declare, we believe that the use of
new drugs on compassionate grounds should be considered within the
research framework, and that Local Ethics Committees (LECs) are in the
best position for evaluating compassionate use protocols, as well as for
registering and monitoring these uses.
In Italy, a network of LECs in each hospital/ local health authority has
been set by the Ministry of Health seven years ago (2), and trial
registration is compulsory for sponsors and LECs through a web-based
national register of ongoing clinical trials (3).
In our country, extension studies are not the only way to make available
new treatments to the patients in the time frame of drug approval. A
recent Ministerial Decree (4) regulates compassionate use. According to
the decree, an experimental drug can be used in a patient or in a group of
patients outside a clinical trial when: 1) there is no valid therapeutic
alternative for severe diseases; 2) there is no valid therapeutic
alternative for rare diseases; or 3) the patient is in a life threatening
situation.
Physicians, individually or in group, can ask the authorization of such
use for new patients or for patients previously treated in a clinical
trial, and for which they believe the treatment will be beneficial.
Authorization should be submitted to the LEC. Safety and outcome data
should be collected. The treatment is provided free of charge by the
manufacturer.
The importance of LECs involvement in this issue is pivotal. Nowadays,
new drugs are tested in a very small number of patients before marketing,
especially those eligible for accelerated approval. Moreover,
registration trials are often testing equivalence or non inferiority
hypotheses, thus the information on safety and efficacy of new treatments
at the time of registration are becoming less informative. LECs can
easily monitor the outcomes of these treatments, as well as adverse
events. The presence of a national registry for clinical trials can
facilitate this monitoring.
Data on 16 out of 24 LECs in the Veneto Region (North-East of Italy) show
that, over a 17-month period, LECs evaluated 49 compassionate use
protocols, authorizing the use of 18 drugs not yet available on the
Italian market. In the following nine months, 7 out of 18 new treatments
have been marketed in our country for the disease they were asked for.
The majority of LECs (11/16) evaluated these protocols with a priority
rule, organizing an extraordinary meeting, if necessary.
In order to prevent the problem of drug reimbursement once the new
treatment is marketed, in the Veneto Region a recent regional directive
(5) has established that drugs used in compassionate use protocols or in
extension studies, should be offered free of charge by the manufacturer
after marketing until the drug is included in the Regional Formulary. In
this way, we avoid that the patient encounter difficulties in accessing to
the new drug in the timeframe between drug marketing and Formulary
inclusion.
References
1.Taylor GJ, Wainwright P. Open label extension studies: research or
marketing? BMJ 2005; 331: 572-4.
2.Ministerial Decree 18 March 1998. Guidelines for Ethics
Committees. Gazzetta Ufficiale della Repubblica Italiana n. 122, 28/5/98.
3.Martini N, Tomino C, Liberati A. Role of a research ethics
committee in follow up and publication of results. Lancet 2003; 361: 2246.
4.Ministerial Decree 8 May 2003: Therapeutic use of investigational
drugs”. Gazzetta Ufficiale della Repubblica Italiana n. 173, 28/7/2003.
5.Veneto Region Committee. Regional regulation of therapeutic use of
investigational drugs. Delibera Regione Veneto n. 4284, 29/12/2004.
Competing interests:
None declared
Competing interests: No competing interests