Drug safety and regulation
BMJ 2005; 331 doi: https://doi.org/10.1136/bmj.331.7507.4 (Published 30 June 2005) Cite this as: BMJ 2005;331:4All rapid responses
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Drug Safety and Regulation: Clostridium difficile, antibiotics and
PPIs.
Dear Editor,
Patrick Waller et al (Drug Safety and Regulation. BMJ 331, 2nd July
2005, p4,5.) write about the responsibilities of the pharmaceutical
companies and the regulating agencies such as UK’s Medicines and
Healthcare products Regulatory Agency to improve the safety of the drugs
that are licensed for our prescription. Although Cox 2 inhibitors and
SSRIs have been the high profile drugs under the spotlight in recent
months, there are others which may be of greater concern.
NICE guidance came out for the use of the Proton Pump Inhibitors
(PPIs) in 2000 on the treatment of dyspepsia. In January 2005 in our
hospital, a deceased patient record audit of 50 patients identified 20 who
were on PPIs. Twelve of the 50 patients had had Clostridium difficile
isolated in recent months, and 8 of these had been taking PPIs. 43
patients received one or more antibiotics, 29 received three or more.
(cephalosporins 27, Augmentin 19, metronidazole 19, clarithromycin 14, and
5 or fewer for nine other antibiotics).
Studies in Plymouth in 2003 and Montreal in 2004 indicated that PPI
use, especially long term, compounded with other precipitators such as
multiple antibiotic usage and nasogastric feeding, more than doubled the
incidence of Clostridium difficile.
As a profession, we have the responsibility to follow the advice of
agencies such as the National Institute for Clinical Excellence over our
prescribing habits, and to audit the effects of our treatments on our
patients. At the Luton & Dunstable Hospital we are looking at blocks
of 50 deceased patients’ records using some of the Trigger Tools
recommended by the Institute for Healthcare Improvement. This audit has
led to several improvements already, and highlighted the rapidly
increasing popularity of PPIs in the treatment of the infirm elderly who
are most at risk of Clostridium difficile infection. Although some of
these patients with Clostridium difficile have died due to the organisms’
effects, we have not had the new North American strain identified here
yet.
Yours sincerely
Dr Michael I Carter MA MB BChir DA FRCA
Consultant Anaesthetist
Jane Murkin RGN, RM
Patient Safety Manager
Luton & Dunstable Hospital NHS Trust
1. Proton Pump Inhibitors as a risk factor for Clostridium difficile
diarrhoea. R. Cunningham, B. Dale, B. Undy, N. Gaunt. Journal of Hospital
Infection (2003) 54, 243-245.
2. Risk of Clostridium difficile diarrhoea among hospital inpatients
prescribed proton pump inhibitors: cohort and case-control studies. S.
Dial, K. Alrasadi, C. Manoukian, A Huang, R. Menzies. Canadian Medical
Association Journal. July 6, 2004; 171, 33-38.
3. National Institute for Clinical Excellence. Technology Appraisal
Guidance- No.7. Guidance on the use of Proton Pump Inhibitors in the
Treatment of Dyspepsia, July 2000.
Competing interests:
None declared
Competing interests: No competing interests
The adverse drug reaction monitoring is a tedious and complex
process, which is most wanted but is underdone at best. Historically,
spontaneous drug reporting has been its backbone. Indeed this kind of
reporting by the astute physicians has often provided plausible hint of
the suspected link regarding the causality.
Spontaneous Adverse Drug Reaction Monitoring
Spontaneous adverse drug reaction monitoring has become inculcated in
governmental drug regulation around the world1-2. Main problem is however
that the numbers of participating physicians are very less and the numbers
of reports sent are low3. Even in the countries, which are the members of
the WHO Pharmacovigilance program originated, report annually only about
200 or more ADRs per million inhabitants and the percentage of reporting
physicians does not go beyond ten percent4-5. In many counties, however,
the reporting rates are much lower2. It does not give the exact
information about the frequency of adverse effects. Underreporting delay
the signal detection and cause underestimation of the size of the problem.
Accumulating evidence suggests that physians attitude to their National
ADR Monitoring Program are a significant determinant of reporting rates1,
most physicians consider monitoring of adverse drug reactions just a paper
work, unconnected with their routine clinical work. In India, junior
doctors report most cases of spontaneous monitoring3, which may not be
adequately experienced in assessing the severity and determining the
causality. Senior physicians are seemingly uninterested. Being busy is one
explanation offered by these clinicians. All sorts of biases may therefore
influence reporting.
Intensive Adverse Drug Reaction Monitoring
Intensive drug reaction monitoring on the other hand, is based upon
the systematic evaluation of the link between adverse effect and drug in a
systematic fashion. Pharmacologists in India usually carry it out.
Moreover it is a full time business requires big manpower and economic
resources, affording which may not always be possible for a developing
country like India. The yield of this type of surveillance is low and
often the reports are considered to be suboptimal as pharmacologists
collect the data passively largely on the basis of observations made by
clinicians. Unfortunately, because of the disinterest by the physician
community, the burden often lies on the shoulders of pharmacologists.
Score of causality given by the physians are very high as opposed to
causality assessment method evaluated by full time clinical
Pharmacologists6. Falsies of the both systems are therefore, well
recognized. Indeed a recent metanalysis of the large number of studies
have shown that 80% of the reporting is sub optimal6. Coupled with the
meager report rate, this means that we actually may know little about the
exact scenario. Various other means of improving the yield have met with
variable success. Recent suggestion of incorporating postal monitoring in
ADR monitoring in India has also met limited success7.
Combined Approach
A plausible solution to this problem therefore appears that both
these systems should be integrated. Physians routinely use record detailed
history and perform elaborate physical examination. This they call as
“case work up”. If not formally involved in drug monitoring, while
recording patient details; they just note whether or not the patient is
sensitive to some drug or not. In case he\she is found to be so this is
written on the front page of the history sheet or case sheet, as it is
known here in India. Physicians while performing the detailed work up of
their patients can note down the salient details required for monitoring
of adverse drug reactions on a separate page meant to be ‘ADR sheet’ in
the existing history sheet. It should be printed before hand and contain
details like drug, dose, diagnosis and duration and their own assessment
of causality. Other points like name, age, sex, socioeconomic status are
well record routinely, therefore can be avoided. This should not be taken
to be a different approach of recording ADR data as, there is evidence
that all national ADR monitoring centres do not use the WHO proforma
strictly and local variants of this are used. This is just the recording
of essential data in the most concise manner. Although no evidence is
available to suggest that these proforma are better then the one
recommended by WHO, they are used because they are handy and provide
necessary details. Similarly, on outpatient department cards adverse
drug reaction data may be recorded by the attending physicians on a
separate small column. The necessary details mentioned above should be
printed on the OPD cards in a concise manner. Pharmacologists, while on
there routine visits to wards (in hospital patients) or OPDs should
evaluate such cases before or after physician’s assessment. Thus both
pharmacologists and physicians should make their independent assement,
which should later be compared. Potential advantages of the combined
approach are-
· Improved quality of ADR reports, as they would be properly
discussed
· Increased yield of ADRS reports as both pillars of pharmacovigilance
would be working together
· Physician and pharmacologist cooperation and mutual education
· Health professional education can be achieved
· Patient education can be done
· Indigenous data would be generated
· Prevention of ADRs can be done
References
1.Belton KJ et all-Eur J-Clin Pharmacol 1997; 52: 423-427.
2.Meyboom RHB-Detecting adverse drug reactions: Pharmacovigilance in the
Netherlands. Netherlands Pharmacovigilance foundation. pp-61-17, 1998
3.Balasubramanium S, Gogtay SN, Kshirsagar NA-Mortality due to adverse dug
reactions in a large hospital. Natl Med J Ind, 12:300, 1999
4.Rawlings MD-Pharmacovigilance: paradise lost, regained or postponed? J
Royal Coll Physicians, 21: 29-41, 1999
5. Vander Kbauw MM, Strickler BHch, Herrings RMC, Cost WS, Velkenberg HA,
Vilson JHP-A population based case control study of drug-induced
anaphylaxis. Br J Clinc Pharmacol 35:400-408, 1995
6. G. Miremont, F haramburu, Begad B, Pere JC, Dangoumau. Adverse drug
reactions: Physician’s opinions versus causality assessment method-Br J
Clinic Pharmacol. 46:285-289, 1994
7. Balasubramanium S, Gogtay SN, Kshirsagar NA-Postal survey as a method
of ADR monitoring in India-letter to editor. Pharmacoepdemiol & Drug
Safety; 9:21,2000
Competing interests:
None declared
Competing interests: No competing interests
Drug safety project in Germany (AMSP). Adverse drug reactions in psychiatry
The relevance of drug safety has become increasingly important in
clinical practice and with regard to economic aspects. The benefits of
drugs are connected and limited with the risks of adverse drug reactions
(ADR).
The AMSP ("Arzneimittelsicherheit in der Psychiatrie") project is an
innovative, independent and multinational drug safety program in
Germany,Switzerland,Austria and Hungary.From 1993 until now,about 190000
patients were monitored (30000 patients in the last year) in 55
psychiatric hospitals.
Aims of the AMSP study group are the continous assessment and analysis of
severe ADR in psychiatric inpatients under naturalistic conditions.
The goals of the study are the collecting,rating,and interpretation of
informations on type and frequency of ADR associated with psychotropic
drugs and to indentify specific risk factors and drug interactions.The
overall incidence of severe ADR of antidepressants was 1.4%
(antipsychotics 1.1%) of exposed patients.
The data of this "real-life" setting of routine treatment are a completion
to results of controlled clinical trials and to safety programs of
governments.
Competing interests:
None declared
Competing interests: No competing interests