Rosiglitazone: what went wrong?
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c4848 (Published 06 September 2010) Cite this as: BMJ 2010;341:c4848
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In your article Rosiglitazone: What went wrong? you wistfully ask
will regulators, industry and the clinical community do a better job next
time? (1)
Firstly, what is the evidence that 'anything' went wrong or
'anyone' did anything wrong? It is extraordinary that claims can be made
by a drug safety regulator that a drug may have called thousands of excess
deaths and yet to date no public independent enquiry has ever taken place
(2). Even when there is overwhelming proof of public harm as with
thalidomide, no public enquiry has occurred so speculation of wrongdoing
exists until this day (3). This contrasts greatly with other sectors of
society where public investigation is well accepted, routine and regarded
as essential so that Society can learn and do better next time (4) (5). In
particular, the detail and transparency of the investigations performed by
organisations such as the US Chemical Safety Board show how feasible this
can even for sectors working to tight profit margins (6). So even in these
cash strapped times, the sad reality is that without at least a far-
reaching public debate, let alone a public enquiry, how on earth can
Society possibly learn from alleged drug safety crises? After all, safety
investigations have shown convincingly how important the safety of the
system is and yet the focus of drug safety continues to be on the product
and allocating blame. As you describe in your article the safety concerns
were as much about the behaviour of different players as the product
itself. As you correctly point out, 'unpicking the evidence behind
rosiglitazone has not been easy' and yet has the role of all the
stakeholders been considered? What are the incentives and motivators
within the pharmaceutical sector to make safe decisions and act safely?
How can shareholders and investors influence Safety within a company and
what should their role be? What about professional associations? What is
the impact of patent law? What about insurance companies? Was adequate
quality management in place for all the players? Is it possible to be
compliant with GCP and still be unsafe? How does blame culture affect our
approach to safety of medicines? These and other questions remain
unanswered.
Unfortunately the article appears under the subheading Drug
Regulation rather than Safety of Medicines. Repeated safety investigations
in other sectors of society have shown that relying on regulations alone
will never improve safety. Indeed how do we know that increasing
complexity and detail of regulations will help Society achieve safer
medicines? The evidence suggests otherwise (7) (8). Human performance is
ultimately what underlies Safety (9). The aim of all those interested in
safety of medicines is to ascertain what if anything went wrong and then
identify the root causes so that we might learn from our mistakes and
perform better next time.
As the costs of developing medicines inexorably increase year on
year, can Society really afford not to obtain answers through an
independent international enquiry? As an enquiry proceeds, maybe only
then will it become clearer exactly how society should adjust the Safety
System for medicines and more transparently align it for all concerned
with the commercial reality of developing and marketing of medicines. Let
the debate begin! After all the reasons why we do not have independent
investigations into drug safety may well be illuminating in their own
right.
1)Cohen D Rosiglitazone: What Went Wrong BMJ 2010; 341: 530-534
2)http://avandiarecallnews.com/avandia-study-blocked-dr-david-graham-email
-fda-margaret-hamburg/ (accessed October 24th 2010)
3)http://blogs.wsj.com/iainmartin/2010/01/14/the-thalidomide-scandal-and-
the-forgotten-role-of-enoch-powell/ (accessed October 24th 2010)
4)http://www.etsc.eu/oldsite/accinv.pdf (accessed October 24th 2010)
5) http://www.see.ed.ac.uk/feh5/pdfs/FEH_pdf_pp002.pdf (accessed October
24th 2010)
6) http://www.csb.gov/ (accessed October 24th 2010)
7) Krokstad T, Edwards B An aviation perspective of safety in the
pharmaceutical sector Pharmacol Epidemiol Drug Safety 2008; 17: 1-3.
8) Edwards Olsen A, Whalen M, Gold M Guiding Principles of Safety as
a basis for developing a pharmaceutical safety culture Current Drug
Safety 2007; 2:135-139
9) Seal C, Edwards B Morrisroe J Aviation Crew Resource Management (CRM) -
a pharmacovigilance perspective Pipeline 2008; 20: 7-9
Competing interests: I consult with numerous pharmaceutical companies about safety of their medicines and their systems
On many aspects, the tale[1] of the thiazolidinedione (TZD) antidiabetic
drug rosiglitazone appears as a model of what might go wrong[2] when both the pharmaceutical
industry and drug regulation agencies lose sight of drug marketing primary
objectives[3,4], i.e. improving overall patients clinical outcome. The original
rationale for rosiglitazone's indication in diabetes treatment lies into
translational medicine, a process in which fundamental research results are
pushed towards clinical applications pertinent to public health problems. Thus,
in addition to insulin-sensitizing properties, TZDs were thought to possess
potentially favourable effects on the cardiovascular complications usually
associated with type 2 diabetes mellitus[5,6]. Here,
translational medicine's focus was clearly to provide type 2 diabetic patients
with improved glycaemic control and reduced cardiovascular risks.
At this time,
whereas rosiglitazone's tale seems to take a new turn, we would like to defend
the idea that the bitter taste of rosiglitazone's story comes from the loss of
focus on translational research primary goals. For this purpose, we will stress
two specific points, the first one on the RECORD study[7] , supposed to address rosiglitazone's
risks, and the second on the assessment of the benefit over risk ratio of oral
antidiabetic drugs in general.
First loss of focus -
overcoming cardiovascular complications: expected benefit vs. real threat.
The RECORD study was designed to evaluate
rosiglitazone's safety as compared to the commonly used antidiabetic combination
metformin plus sulfonylureas[7]. Despite some methodological
weaknesses[7,11](open-label
study design, pertinence of the control group, ...), this study confirmed the
non-inferiority, or equivalence, of rosiglitazone as compared with the combination
of metformin and sulfonylurea on criteria of all-cause deaths and cardiovascular
deaths(RR 0.86 [0.68-1.08] and RR 0.84 [0.59 - 1.18], respectively). But this
equivalence might not be so reassuring. Indeed, in the only Randomized Clinical
Trial (RCT) where the combination of metformin and sulfonylurea have been
studied on clinically relevant criteria (UKPDS-34), a significant excess
mortality (all-causes mortality; RR = 1.6 [1.02- 2.52] CI 95%) was observed
when compared with sulfonylurea alone[8]. Note
that the authors erratically interpreted this finding as resulting from the game
of chance only, albeit results from the same study in favour of metformin were
assigned to metformin. This association has never been re-evaluated in an RCT. Finally,
a meta-analysis of observational studies[9] concluded
on an increased risk of a composite endpoint of cardiovascular hospitalizations
or mortality for the combination metformin plus sulfonylurea (RR = 1.43 [1.10-1.85]
CI 95%). Overall, the RECORD study did not report rosiglitazone's safety of use.
At most, it demonstrated rosiglitazone's equivalence, in terms of risks, to the
already available antidiabetic drugs it was supposed to replace.
Second loss of focus -
clinically relevant benefits: surrogate vs.
endpoint outcomes.
Potential side effects, even serious, should
not be considered alone to decide the withdrawal of a drug from the market.
Indeed, physicians prescribe and patients use potentially dangerous medications
on a daily basis, a situation where the benefits obtained from the drug
consumption makes its associated risks acceptable. For antidiabetic drugs,
including rosiglitazone, the actual problem resides in the lack of evidence for
specifically and clinically relevant efficacy in a placebo double-blind
RCT (e.g., cardiovascular
and microangiopathic risk reduction). As of today, antidiabetic drugs studies
focused on surrogate outcomes like glycated haemoglobin (HbA1c). We
do not question the interest of glycaemic control in diabetes management, however,
surrogate outcomes cannot account for complex drug actions such as those
expected from antidiabetics. For instance, while rosiglitazone lowered HbA1c
levels, the composite risk of myocardial infarction and sudden death increased[7,10]. At this time, most oral
antidiabetic drugs benefits remain uncertain because their effectiveness has
never been proven on clinically relevant criteria (patient-oriented outcomes) even
though serious risks have been documented. How can we, parts of the medical
community, justify this situation and inform our patients of expected benefits
while we only know risks for these treatments?
On September 23, 2010, and after a
10-year controversy over rosiglitazone's safety and benefits[1,2], FDA announced significant
restrictions on the use of rosiglitazone-containing drug Avandia[11,12], while EMA recommended the suspension of marketing authorisations for
rosiglitazone-containing medicines[13]. It
might be time to envision diabetes treatment based on evidences of good
quality.
[1] Godlee F. Rosiglitazone: a
cautionary tale. BMJ
341:doi:10.1136/bmj.c4896.
[2] Cohen D. Drug Regulation:
Rosiglitazone: what went wrong? BMJ
341:doi:10.1136/bmj.c4848.
[3] Freemantle N. Commentary: What can
we learn from the continuing regulatory focus on the thiazolidinediones? BMJ 341:doi:10.1136/bmj.c4812.
[4] Lehman R, Yudkin JS and Krumholz H. Licensing drugs for diabetes. BMJ 341:doi:10.1136/bmj.c4805.
[5] Lebovitz HE and Banerji MA. Insulin
resistance and its treatment by thiazolidinediones. Recent Prog Horm Res. 2001;56:265-94.
[6] Mudaliar S, Henry RR. New oral
therapies for type 2 diabetes mellitus: The glitazones or insulin sensitizers. Annu Rev Med. 2001;52:239-57.
[7] Home PD, Pocock SJ, Beck-Nielsen H,
et al. Rosiglitazone evaluated for
cardiovascular outcomes in oral agent combination therapy for type 2 diabetes
(RECORD): a multicentre, randomized, open-label trial. Lancet 2009;373:2125-35.
[8] UK Prospective Diabetes Study
(UKPDS) Group. Effect of intensive blood-glucose control with metformin on
complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;12:854-65.
[9] Rao AD,
Kuhadiya N, Reynolds K, Fonseca VA. Is the combination of sulfonylureas and
metformin associated with an increased risk of cardiovascular disease or
all-cause mortality? : a meta-analysis of observational studies. Diabetes Care 2008;31:1672-8.
[10] Rosen CJ. The Rosiglitazone Story --
Lessons from an FDA Advisory Committee Meeting. N Engl J Med 2007;357:844-6.
[11] Woodcock J, Sharfstein JM and
Hamburg M. Regulatory Action on Rosiglitazone by the U.S. Food and Drug
Administration. N Engl J Med doi:10.1056/NEJMp1010788.
[12] U S Food and Drug Administration
(FDA). FDA significantly restricts access to the diabetes drug Avandia.
September 23, 2010. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm226975.htm.
[13] European Medicines Agency (EMA).
European Medicines Agency recommends suspension of
Avandia, Avandamet and Avaglim. September 23, 2010.
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/....
Competing interests: No competing interests
The question of whether rosiglitazone should be withdrawn from use
raises concerns that more robust regulatory guidelines are needed [1]. Of
particular interest is whether the primary outcome should be that of
upmost clinical importance and not that of a surrogate believed to be on
the pathway to efficacy.
There are undoubtedly many reasons why surrogates are chosen, with
cost and duration two important considerations. Many trials resort to
surrogates, not only those in diabetes. The primary outcome of upmost
clinical importance will often be long term mortality. However, it is not
only the pharmaceutical industry that is guilty of carrying out many
trials with surrogates as primary outcomes. Academics and clinicians are
guilty of this too, with the lure of easier funding and quicker
publication.
There are will be occasions when surrogates might be important: for
interventions which are very low cost and with small effects (where
unrealistically huge trials would be needed to prove efficacy [2]); in
trials demonstrating initial feasibility; or in trials where the
intervention is certain not to promote harm (lifestyle interventions).
Regulatory guidelines will always be dependent upon the criteria by
which academics judge evidence to be of value. Strong guidelines on choice
of primary outcomes are needed, with clear direction on when it is, and
when it is not, appropriate to use surrogate outcomes. Reliance on
surrogates, even when relegating the main variable as a secondary outcome,
will not even allow effective meta-analyses, since where the primary
outcome of clinical interest is mortality longer term follow-up will also
be required.
It is time that both academics and the pharmaceutical industry
developed strong guidelines on when surrogates are appropriate.
[1] Cohen D. Rosiglitazone: what went wrong? 2010 Sep 6;341:c4848.
doi: 10.1136/bmj.c4848.
[2] Lilford RJ, Chilton PJ, Hemming K, Girling AJ, Taylor CA, Barach
P. Evaluating policy and service interventions: framework to guide
selection and interpretation of study end points. BMJ. 2010 Aug
27;341:c4413. doi: 10.1136/bmj.c4413.
Competing interests: No competing interests
To the Editor,
In the understandably fraught environment surrounding the
cardiovascular effects of rosiglitazone, there has been a tendency to
overlook a second adverse effect of thiazolidinediones (TZDs). TZDs
decrease bone density,1 and approximately double the risk of several types
of fracture.2 3 This is an important consequence in a population (type 2
diabetes) in which risk of fracture is increased,4 and provides an
additional reason to avoid use of TZDs, particularly in older people, who
may have high baseline absolute risk of fracture.
It is noteworthy that the first evidence, to our knowledge, of
adverse skeletal effects of TZDs was presented by investigators from the
Glaxo Research Institute,5 fully 10 years before the publication and
presentation of independent investigator-led clinical studies1 6 prompted
the evaluation of fracture events in commercially sponsored clinical
trials of TZDs.7
1. Grey A, Bolland M, Gamble G, Wattie D, Horne A, Davidson J, et al.
The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone
decreases bone formation and bone mineral density in healthy
postmenopausal women: A randomized, controlled trial. J Clin Endocrinol
Metab 2007;92:1305-10.
2. Grey A. Thiazolidinedione-induced skeletal fragility; mechanisms
and implications. Diabetes Obesity Metab 2009;11:275-84.
3. Douglas IJ, Evans SJ, Pocock S, Smeeth L. The risk of fractures
associated with thiazolidinediones: a self-controlled case-series study.
PLoS Med 2009;6:e1000154.
4. Grey A. Skeletal consequences of thiazolidinedione therapy.
Osteoporos Int 2008;19:129-37.
5. Jennermann C, Triantafillou J, Cowan D, Pennink BGA, Connolly KM,
Morris DC. Effects of thiazolidinediones on bone turnover in the rat. J
Bone Miner Res 1995;10 (suppl 1):S241.
6. Schwartz AV, Sellmeyer DE, Vittinghoff E, Palermo L, Lecka-Czernik
B, Feingold KR, et al. Thiazolidinedione use and bone loss in older
diabetic adults. J Clin Endocrinol Metab 2006;91:3349-54.
7. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et
al. Glycemic durability of rosiglitazone, metformin, or glyburide
monotherapy. N Engl J Med 2006;355:2427-43.
Competing interests: No competing interests
Re: Rosiglitazone: what went wrong?
Much of the problem stems from poor education of the regulators. the drug companies have the best talent money can buy.
Competing interests: No competing interests