Rosiglitazone and implications for pharmacovigilance
BMJ 2007; 334 doi: https://doi.org/10.1136/bmj.39245.502546.BE (Published 14 June 2007) Cite this as: BMJ 2007;334:1233
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The recent Meta-analysis[1] of trials comparing the risks of
Rosiglitazone to a range of comparative treatments in the NEJM presented
the increased risk of myocardial infarction as a Peto Odds Ratio of 1.43
(95% confidence interval 1.02 to 1.98). This is not easy to interpret as a
risk to individual patients, but has been described as a increase in risk
of about 40%[2]. It has also been described as similar in magnitude to the
effect of statins, but in the opposite direction[3].
The Meta-analysis did not include the interim analysis of the ongoing
RECORD study[4], which showed a similar sized increase in Hazard Ratio.
There were 49 patients with myocardial infarction out of 2220 on
Rosiglitazone and 40 out of 2227 on metformin plus sulfonylurea, when
pending and adjudicated events were considered. Since the direction and
size of the increase in myocardial infarction in RECORD are very similar
to the other study results, little comfort can be drawn from the wide
confidence interval.
When the results of the meta-analysis and the RECORD study are measured as
risk differences the results are homogeneous, (I2 is zero for the small
studies, the three large studies and the overall comined result). The
smaller studies were of shorter duration than the three large studies, so
it is not surprising that the risk differnce is lower in the smaller
studies (see Figure).
Figure: Risk Difference of Myocardial Infarction with Rosiglitazone
compared to control using the raw data presented by Nissen et al and Home
et al (Fixed effects, RevMan 4.2).
However, the combined result is an increase of
myocardial infarction with Rosiglitazone that can be described as a Risk
Difference of 0.0024 (95% confidence interval 0.0002 to 0.0045). The risk
of myocardial infarction was low in the studies, as there were less than
eight per thousand in the control group, and the additional risk of
Rosiglitazone would increase this number to ten per thousand over 84
months (the weighted average duration of all the trials).
For this 2 year duration the Number Needed to Treat for one extra patient
in the trials to suffer a myocardial infarction on Rosiglitazone is 424
(95% confidence interval 221 to 5159). This may be a useful alternative
way to describe the increased risk for patients who need to decide whether
to change their treatment.
[1] Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of
Myocardial Infarction and Death from Cardiovascular Causes. 2007 May 21,
2007:NEJMoa072761.
[2] Drazen JM, Morrissey S, Curfman GD. Rosiglitazone -- Continued
Uncertainty about Safety. 2007:NEJMe078118.
[3] Psaty BM, Furberg CD. The Record on Rosiglitazone and the Risk of
Myocardial Infarction. 2007:NEJMe078116.
[4] Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Jones NP, et
al. Rosiglitazone Evaluated for Cardiovascular Outcomes -- An Interim
Analysis. 2007 June 5, 2007:NEJMoa073394.
Competing interests:
None declared
Competing interests: No competing interests
After the analysis of the editorial about Rosiglitazone and implications for pharmacovigilance written by Dhruv Kazi published in the BMJ, we recognize the importance of this topic and would like to comment.1
The control of medication security should be a part of everyday clinical practice. The way in which the clinical staff embraces the principles of pharmacovigilance and exerts their labor has a great effect on the quality of their health care provision. The theoretical and practical formation of the health staff about the safety of medications, the exchange of information and the existence of communication channels between clinical experience and health policy are elements that should not be left apart if we want to improve the patient’s heath care. In this sense we recognize the importance of the published article, since the systematic exchange of information places the pharmacovigilance programs in the ideal position to discover fissures in our knowledge about induced or related to medication diseases . 1, 2, 3
References:
1. Kazi D. Rosiglitazone and implications for pharmacovigilance. BMJ 2007;334:1233-1234.
2. Linquist AM. Seeing and observing in international pharma- covigilance. Uppsala, Centro Colaborador de la OMS para la Vigilancia Farmacéutica Internacional, 2003.
3. OMS. Safety monitoring of medicinal products. The impor- tance of pharmacovigilance. Ginebra, Organización Mundial de la Salud, 2002.
Competing interests:
None declared
Competing interests: No competing interests
Dhruv Kazi is correct to note that passive safety surveillance systems relying on spontaneous reports of suspected adverse drug reactions are poor at detecting increases in the risk of common events associated with drugs[1]. As he states, case series are a weak form of epidemiological evidence, which neither confirm the incidence of the reaction, nor quantify any increased risk to individual patients.
However, it is important to note that the spontaneous reporting of suspected adverse drug reactions to regulatory authorities (in the UK to the Yellow Card scheme) continues to be of major importance in detecting potential safety signals. An analysis of 21 drugs withdrawn in France between 1998 and 2004 showed that 19 withdrawals were linked to spontaneous case reports[2]. A similar analysis of 11 product withdrawals between 1999 and 2001 in the UK and US showed evidence from spontaneous reports supported the withdrawal of 8 products[3].
A recent BMA report on adverse drug reactions has indicated a significant decrease in the number of spontaneous reports from general practitioners[4]. It is therefore important to emphasise that despite high profile cases such as rosiglitazone and rofecoxib, where spontaneous reporting was arguably of limited use, those doctors who do report suspected adverse drug reactions to the Yellow Card scheme continue to perform a valuable service to public health.
1. Kazi D. Rosiglitazone and implications for pharmacovigilance. BMJ 2007; 334 :1233-4
2. Olivier PA, Montastruc JL. The nature of the scientific evidence leading to drug withdrawals for pharmacovigilance reasons in France. Pharmacoepidemiology and Drug Safety 2006; 15(11): 808-12
3. Clarke A, Deeks JJ, Shakir SAW. An assessment of the publicly disseminated evidence of safety used in decisions to withdraw medicinal products from the UK and US markets, Drug Safety 2006; 29(2): 175-81
4. BMA Board of Science. Reporting Adverse Drug Reactions: a guide for healthcare professionals. London, British Medical Association, 2006.
Competing interests:
The authors also work at the Yellow Card Centre West Midlands,
a regional education centre of the Medicines and Healthcare products Regulatory Agency (MHRA). The viewpoints expressed in this commentary are those of the authors and are not necessarily endorsed by the MHRA.
Competing interests: No competing interests
You have just given the strongest possible evidence that the BMJ's
Chinese wall - between the editorial and commercial sides of the BMJ - is
working. The editors maintain strict confidentiality about what is to be
published in the journal and are not aware of what advertising is going
into the journal until it appears. This is a policy on which we place a
high degree of importance, and I am delighted to have its effectiveness
demonstrated so eloquently.
Competing interests:
I am the editor of the BMJ and am responsible for everything in it including the advertisements
Competing interests: No competing interests
Sir,
I note with interest the final sentence of the editorial, "the
ongoing use of Rosiglitazone merits careful deliberation". A few pages
later the News section proclaimed "FDA places black box warning on
antidiabetes drugs" again highlighting concerns about Rosiglitazone).
This made me wonder if the publishers of the BMJ actually bother to
read what they print as a few pages later there was a glossy (and
presumably expensive) advert for the same drug! Plus Ca Change!
Competing interests:
None declared
Competing interests: No competing interests
Pharmacovigilance: Key Importance for Biopharmaceuticals
The article by Dr Kazi (1) titled ‘Rosiglitazone and Implications for
Pharmacovigilance” discussed the importance of pharmacovigilance as a
broad topic in the context of rosiglitazone. Kazi points out “post-
marketing surveillance, or pharmacovigilance, remains the weakest link in
the regulatory process on both sides of the Atlantic.” This is true not
only for smaller molecular weight chemical drugs such as rosiglitazone,
but also for the higher molecular weight, more complex, biologics that are
increasingly prevalent in the market. Epoetin and its biosimilars (termed
follow-on biologics in the US) illustrate this point well.
It is assumed that epoetin biosmilars have an identical efficacy and
safety profile as the originator or “innovator” product (epoetin-alfa).
However, data from several sources suggests that biosimilars are
different, in terms of activity and protein structure(2,3). As well,
important differences in their degree of aggregation may have implications
for immunogenicity. In many counties, especially in emerging nations,
biosimilars are introduced with very limited regulator scrutiny. As
Nowicki (4) has recently pointed out the history of regulatory laws
regarding biosmilars is exceptionally short. In many countries, companies
are not required to submit a risk management/pharmacovigilance plan. Since
biologics can be immunogenic (neutralizing antibodies to epoetin can
result in pure red cell aplasia (PRCA) (5)) vigilance around this issue is
important. Pharmacovigilance should also emphasize traceability of the
product such that potential adverse reactions can be tracked back to the
dispensed drug. Therefore, limiting or eliminating automatic substitution
for biologics and providing different non-propietary names (INN's) for
biosimilars will augment patient safety and ensure traceability in the
event of an adverse reaction.
1. Kazi D, Rosiglitazone and implications for pharmacovigilance.
Postsurveillance data should be systematically collected and publicly
available. BMJ 2007; 334: 1233-4
2. Combe C, Tredree RL, Schellekens H. Biosimilar epoetins: an
analysis based on recently implemented European medicines evaluation
agency guidelines on comparability of biopharmaceutical proteins.
Pharmacotherapy. 2005 Jul;25(7):954-62.
3. Singh A. Gaps in the Quality and Potential Safety of Biosimilar
Epoetins in the Developing World: An International Survey. In: American
Society of Nephrology: Renal Week; 2006
4. Nowicki M, Basic Facts about Biosimilars. Kidney Blood Press Res
2007;30: 267-272
5. Casadevall N, Nataf J, Viron B, et al. Pure red-cell Aplasia and
Antierythropoietin Antibodies in Patients Treated with Recombinant
Erythropoietin. The New England Journal of Medicine 2002;346(7):469-75.
Competing interests:
Dr. Singh reports receiving consulting fees from Ortho Biotech/Johnson Johnson, Roche, Merck, Watson, Amgen, Wyeth, Abbott. Lecture fees from Ortho Biotech/Johnson Johnson, Genzyme, Watson, Amgen, Abbott. research Support from NIH, Amgen, Ortho Biotech/Johnson and Johnson, Roche, Advanced Magnetics and Watson
Dr. Goldsmith speaker/advisory honoraria from Novartis, nai, Abbott, Roche, Amgen, Astellas,Genzyme, Shire.
Competing interests: No competing interests