October 25, 2024 • 47 mins
Medication-related-harm (MRH) is especially prevalent in older adults due to changing physiology as the body ages, increased frailty, and the incidence of polypharmacy in this patient group. Giovanni Furlan, Worldwide Safety Site Lead for Thessaloniki of Pfizer discusses what makes this patient group so vulnerable to adverse drug reactions, how poor representation and using age alone to define older adults exacerbates this problem, and suggests ways forward in monitoring drug safety in older patients.
Tune in to find out:
- What makes older adults especially at risk of experiencing adverse drug reactions and medication errors
- Why frailty is far more useful than age in predicting adverse drug reaction risk
- How pharmacovigilance in older patients may be improved through pharmaceutical practice and better representation in clinical trials.
Want to know more?
This interview all started with Giovanni's Uppsala Reports article on how age is insufficient a measure of adverse event risk. Read it here.
For a summary of the key points discussed in this interview, read Giovanni’s paper on the status of drug safety in geriatric patients.
If our discussion of frailty piqued your interest, read this paper on the biology of frailty and how this impacts clinical pharmacology, this multi-centre cohort study that shows frailty is significantly correlated with MRH, and this commentary advocating for consideration of MRH as a geriatric syndrome, which needs to be managed as such.
As Giovanni mentioned in the interview, Harlan Krumholz was the first to describe post-hospital syndrome. Learn more about this syndrome by reading his paper.
For more on prescribing cascades, their prevention, detection, and reversal, read this paper by Brath and colleagues.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Alexandra Coutinho (00:15):
As our bodies age, we experience a
number of physiological changesthat affect how we respond to
medicines.
As older adults, we are alsothe most likely to be taking
multiple medications at once.
These and other factorsincrease the risk of us
experiencing adverse drugreactions.
How, then, do pharmacovigilancescientists do their due
(00:36):
diligence in monitoring medicinesafety in this patient group?
My name is Alexandra Coutinho,and this is Drug Safety Matters,
a podcast by Uppsala MonitoringCentre, where we explore
current issues inpharmacovigilance and patient
safety.
Joining me today is GiovanniFurlan, worldwide Safety Site
Lead and Safety Risk Lead atPfizer.
(00:56):
This interview goes deep inexplaining what differentiates
older patients from otherpatient groups, why age alone is
not enough to define them andwhat can be done to improve
pharmacovigilance in apopulation group that is most
likely to suffer from sideeffects to medicines.
I hope you enjoy listening.
Hi, Giovanni, and welcome toDrug Safety Matters.
(01:25):
How are you doing today?
Giovanni Furlan (01:26):
Fine, I am very well.
Nice to talk to you today,Alexandra.
Alexandra Coutinho (01:31):
Likewise, Giovanni.
So we first became acquaintedthrough Uppsala Reports, where
you wrote a really interestingarticle on adverse reaction risk
in older patients.
To kick things off, could youtell our listeners a bit about
your background and how youbecame interested in this topic?
Giovanni Furlan (01:48):
Yes, so I am a pharmacist.
I have been working inpharmacovigilance for 25 years,
and what I realised working inpharmacovigilance is that the
adverse reactions and the risksof experiencing them are not the
same in all patientpopulations.
(02:11):
And I am also becoming older,and so I asked myself "let us
see if in the older patients,the risk of experiencing adverse
reactions is the same as in thegeneral population".
And, as you have read from myarticles, I realised that there
are specific aspects to be takeninto account in the older
(02:35):
patients that are not applicableto the general population.
Alexandra Coutinho (02:40):
So why are older adults especially at risk
of experiencing adverse drugreactions and why should we
regard them as a special patientgroup in terms of
pharmacovigilance?
Giovanni Furlan (02:51):
So there are a number of factors that affect
the safety of the medicationsthat are taken by older patients
.
These are physiological,biological changes, the
increased number of pathologiesthat the elderly tend to
concomitantly suffer from, andthis leads them to taking many
(03:15):
medicinal products at the sametime.
And the more medicinal productsyou take, the more likely it is
that there will be medicationerrors.
Let us see these factors one byone a little bit more in depth.
Now we know that as we age, ourmetabolism changes.
(03:37):
For example, there is areduction of the liver mass and
of the blood flow to the liver,and this can increase the
bioavailability of certainmedications, such as the opioids
, but it can also reduce thebioavailability of other
(03:57):
medications, the so-calledprodrugs.
These are the medications thatare activated by the liver, such
as enalapril or perin dopril.
Another example is the renalfunctionality that also
decreases with age, and this hasan important clinical
(04:21):
consequence for the drugs thathave a narrow therapeutic index
that are cleared by the kidneys,such as, for example, digoxin
or aminoglycoside antibiotics.
Therefore, if we don't takeinto account that the altered
(04:41):
renal function in the elderlymight cause an over-accumulation
of these medications in thebody, there might be adverse
reaction.
But with aging also, how werespond to a medication can
change.
T his is the so-calledpharmacodynamics, and, to go a
(05:04):
little bit more into technicaldetail, the pharmacodynamics
changes because the number ofthe receptor in the body can
change, the affinity of thereceptor changes, the second
messenger response or thecellular response can change.
I understand these are rathertechnical aspects, so I will try
(05:29):
to make some practical examples.
Some older adults can have anincreased response to certain
antihypertensive medications,and this can cause an
exaggerated antihypertensiveeffect.
A similar observation appliesto the medications that are used
(05:53):
to treat certain centralnervous system disorders such as
insomnia, anxiety or agitation,and the increased sedative
effect of these medications inthe older patients can increase
the risk of falls or of hipfractures, and the same applies
(06:15):
to the exaggeratedantihypertensive effect that can
also increase the risk of falls.
Now, apart from thephysiological or the biological
changes that we have just seen,the older adults are often
characterised by a number ofdifferent pathologies, and this
(06:37):
can make it rather challengingto prescribe the appropriate
medication, because amedication that is of use to
treat a certain pathology mightbe associated with an adverse
reaction that aggravates anothercoexisting medical condition.
I am particularly referring tothe so-called geriatric
(07:02):
conditions that characterise theolder patients, such as
delirium, falls, sarcopenia,urinary incontinence, and
several studies have shown thatthe medication with
anticholinergic effect canaggravate some of these diseases
(07:24):
.
If you take multiplemedications, the so-called
polypharmacy, because you sufferfrom many pathologies at the
same time, there is an increasedlikelihood that a medication
might interact with another onethat is taken at the same time.
(07:47):
The interaction can cause areduction of the effect of a
medication or it can increasethe risk of a patient
experiencing an adverse reaction.
And finally, I mentioned beforethe medication errors.
We can easily understand thatthe more drugs we take, the more
(08:11):
likely it is that thecompliance with taking the drugs
as they are prescribed will below, and the poor adherence to
medical regiments can lead to asubstantial worsening of the
disease, to increase health carecosts and in some extreme
(08:33):
instances it can also be fatal.
So, from this point of view,looking for ways to increase
compliance in older adults maylead to an extension of their
healthy and active years of life.
Alexandra Coutinho (08:50):
And we will get a little bit more into that
as we go through the interview.
So it does seem to my mind thatolder patients really have the
odds stacked against them whenit comes to medicine safety.
Let's take one of the problemsthat you mentioned polypharmacy.
One of the papers you sent meto read states that 55% of the
(09:10):
elderly take between five andnine drugs per day, with the
risk of ADRs almost doublingwhen five medications are taken
and increasing to 95% when eightor more medications are taken.
That's huge.
Why is this the case?
Giovanni Furlan (09:26):
Yes, you're absolutely right.
So there are various factorsthat we need to take into
account.
So each medication is absorbedby the body, distributed,
metabolised, and eliminated.
This is called thepharmacokinetics of a medication
(09:47):
.
In simple terms, we can saythat the journey of a medication
in the body is not onlydetermined by the
characteristics of themedication, but also how it
interacts with the body.
So, to simplify it to themaximum, we can say that a
(10:08):
medication is absorbed and it isdistributed in the body thanks
to its binding with carriers andpumps, it passes through many
channels or it binds to theproteins that carry it in the
blood.
Albumin is an example of aprotein with which a medication
(10:31):
can bind, and albumin will carrythe medication throughout the
whole body through thecardiovascular system.
A medication is also metabolisedby a number of enzymes, such as
the cytochrome, and a drug caninterfere with how another drug
(10:54):
interacts with these proteinsand enzymes, thereby altering
its bioavailability and theplasmatic concentration.
This can cause an increase ofthe concentration of the
(11:15):
medication or of its activemetabolites, and if there is an
increase in the concentration ofthe medication, there can be an
increased risk of adversereaction.
If, instead, we see a decreaseof the concentration of the
medication or of its activemetabolites, there is an
impairment of the drugtherapeutic effect, and a
(11:38):
similar concept applies to adrug's mechanism of action.
A medication is able to alterthe biochemical pathways of the
body, and if more than onemedication is taken at the same
(12:02):
time, they might interact withthe same bio-pathway, thereby
altering each other's effects.
Alexandra Coutinho (12:10):
Right.
Polypharmacy aside, youmentioned that the biological
changes that occur as we agecontribute to this increased
risk of experiencing an adversereaction.
In your article for UppsalaReports, however, you do argue
that using age to define anddescribe this patient group does
not adequately reflect who ismost at risk of experiencing
(12:32):
adverse drug reactions.
For those who have not read thearticle, can you explain why
age alone shouldn't be used asthe main characteristic for
pharmacovigilance in olderpatients?
Giovanni Furlan (12:49):
Absolutely.
I think that how we age isprobably one of the most
fascinating and challengingaspects.
We don't all age with the samespeed and in the same way.
Let us consider, for example,the world record for running the
marathon.
A marathon is of 42.2kilometres.
The world record for those whoare more than 80 years of age is
(13:15):
of 3 hours and 15 minutes.
That is much, much faster thanwhat the vast majority of the
20-year-old adults will ever beable to accomplish.
Therefore, how do you classifythe physiological age of the
(13:36):
80-year-old athlete who has runthe marathon in this time?
According to the currentguidelines, if this person were
ever to take part in a clinicalstudy, he would be included in
the age category from 75 to 85years of age.
(13:58):
Now the question is would he becomparable to other subjects of
the same age who maybe havemultiple comorbidities and they
may be confined in a chair or ina bed?
You can very well understandthat we are talking about an
extremely heterogeneouspopulation.
(14:21):
The aging in fact reflects thecomplex and cumulative interplay
between the genes, thelifestyle, what we eat, the
psychological, the socialcircumstances, the environment,
and chance.
Therefore, the chronologicalage is not, per se, the most
(14:46):
important factor.
It is rather the functional age, and frailty is probably the
most well-known method tomeasure the biological age, and
it is used to characterise thepatients based on their
functional age.
The frailty is defined and youcan find it in every textbook as
(15:12):
the increased stressors todue to a decline in the
physiological reserves and tothe severe dysregulation in the
physiological system.
So, to talk in more plain terms, frailty tells us how well the
(15:33):
body is able to adapt tochanging circumstances, and it
may be much more relevant thanage per se.
Alexandra Coutinho (15:43):
And for those of you who want to know
more about frailty and how itmay be used in pharmacovigilance
practice to measure adversereaction risk in this patient
group, feel free to readGiovanni Uppsala Reports,
article which I linked in theshow notes.
Apart from this issue, there isalso the problem of lack of
representation of elderlypatients in clinical studies,
(16:11):
which adds to this risk ofmedical harm.
Why are the elderlyunderrepresented in clinical
studies, and how does thisaffect pharmacovigilance?
Giovanni Furlan (16:15):
There are many reasons why the older adults,
but especially the frail olderadults, are underrepresented in
the clinical study.
Broadly, we can categorisethese reasons in three main
categories, that are, thepatient-related, the
(16:35):
investigator-related, and thetrial-related reasons.
Let us go to thepatient-related reasons.
The elderly patients mightperceive the clinical trial will
not be of benefit because thestudy endpoints are not relevant
to the condition they sufferfrom.
(16:56):
And if we think about anelderly who cannot take public
transportation or who can'tdrive a car, they might not be
able to reach the clinical trialcentre.
When it comes to theinvestigator-related reasons,
the investigator might bereluctant to enrol the elderly
(17:19):
patients because they might fearthey are at increased risk of
experiencing adverse reaction.
And if we think about anelderly patient who might have a
cognitive impairment, a visualimpairment or other impairments,
investigators might be afraidthat it will take too much time
(17:43):
to explain to them what theclinical trial is about, or it
might take too much time tovisit the patient.
Then we have the clinicaltrial-related barriers, and
these are mainly caused by theprotocol exclusion criteria.
These can say, for example,that the patients who suffer
(18:06):
from multiple comorbidities havephysical disabilities or
cognitive impairment, theycannot be enrolled in a study.
Therefore, the older adults whoare also frail, such as those
who are not capable ofconducting an independent life,
(18:28):
are particularlyunderrepresented in the clinical
studies.
Alexandra Coutinho (18:32):
And I guess this underrepresentation must
then make it that much harder tobe able to measure adverse
reaction risk in this patientgroup right to be able to
measure adverse reaction risk inthis patient group right?
However, we do seem to havesome idea of how older patients
may react to certain types ofmedication.
That being said, are therespecific medications older
(18:56):
patients should take withparticular care, and is there
any advice on how to reducetheir risk of experiencing
adverse reactions to thesemedications?
Giovanni Furlan (19:09):
So, as you all know, I am an employee of a
pharma company, so I have firstof all to disclose this conflict
of interest, since I might beperceived as being biased.
Having said that, I havealready mentioned before the
risk of medications that have ananticholinergic effect, since,
especially in the older patients, they are associated with dry
(19:32):
mouth, constipation, confusion,increased risk of falls.
Now, for a more comprehensiveand objective list on which
medication to use with increasedcaution in the older patients,
I would suggest you refer tointernational guidelines, such
(19:54):
as the Beers criteria that areregularly updated by the
American Geriatric Society.
There are also other guidelines, such as the START and STOP
criteria, that are thought andthey are designed to facilitate
the review of the medicines thatare taken by the patients, and
(20:17):
they are designed to find notonly the potentially
inappropriate medications, butalso the omission of a treatment
that can be useful to a patient.
I would like to underline theword potentially, since all of
these criteria are only asuggestion that has to be
(20:40):
adapted to the clinicalcharacteristics of each patient.
In fact, even a potentiallyinappropriate medication might
be the correct one for specificpatients.
We mentioned beforeanticholinergic medications.
We know that they can cause aurinary retention as an adverse
(21:06):
reaction, but if the patientsuffers from a urinary
incontinence, it will not be aproblem at all.
Anoth er main issue that we needto take into account is that
the prescribers need torecognise adverse reaction and
they should not confuse themwith symptoms of other
(21:30):
pathologies.
This is challenging in olderpatients who suffer from
multiple pathologies and takemultiple medications.
If an adverse reaction is notrecognised as such, then the
patient might be administeredwith another medication to treat
(21:52):
the adverse reaction, and theother medication can cause other
adverse reactions, and this cango on indefinitely, and it is
called the prescribing cascade.
So as an example because Ialways like to make practical
examples, we can make theexample of an elderly patient
(22:15):
who is taking non-steroidalanti-inflammatory medications to
treat some kind of pain.
But we know that thenon-steroidal anti-inflammatory
medication can cause heartburnor they can cause hypertension,
and if these conditions are notcorrectly recognised as adverse
(22:40):
reactions, the patient mighttake the proton pump inhibitor
or antihypertensive medicationsthat, in turn, can cause other
adverse reactions.
It is therefore of extremeimportance that whenever a
patient suffers from a newmedical condition, the treating
(23:03):
physician reviews all of themedication the patient is taking
, including over-the-counterherbal drugs and whatever else,
can have an effect on thetreatment of a certain pathology
.
And if the medical condition isthought to be caused by a
(23:28):
medicine, the question then isif we really need the patient to
take the medication, if itshould be stopped, or if it
should be changed with anotherdrug.
It is also very important notto misjudge a new pathology as
(23:49):
caused by a medication when itis not, since this might cause
the interruption of a medicationthat the patient actually has
to take and that is benefitingthe patient.
It is therefore very importantthat the physicians are well
trained to recognise adversereactions.
Alexandra Coutinho (24:13):
Yes, indeed, I think we need education for
all sorts of differentpharmacovigilance issues.
You also mentioned medicationerrors before, so let's look a
bit more into medication errorsin this patient group.
There is research on the riskof medication errors occurring
during transition of care,especially when patients are
(24:35):
discharged from hospital.
Officially, the name for it ispost-hospital syndrome.
Can you speak to this and whyelderly patients are more at
risk of developing this syndrome?
Giovanni Furlan (24:45):
Yes, we mentioned it at the beginning of
the interview and this is anextremely important aspect to
take into account.
In general, compliance with thetreatment as prescribed and the
medication error are animportant cause of harm to the
(25:07):
elderly.
One reason can be that theelderly patients with multiple
comorbidities might visit manydoctors from a variety of
specialties and one doctor mightnot be aware of the complete
medical history of the patientor of all the medications they
(25:29):
are taking, and this can lead toa non-appropriate prescribing.
So for this reason, it is veryimportant that all of the
medications taken by an elderlypatient are reviewed and they
are also reconciled.
If a patient is at a hospital,they might be prescribed with
(25:53):
certain medications and theycontinue to take them once they
are at home, but the MD who islooking after the patients when
they are at home might not beaware of the additional
medications the patient istaking, and he could provide the
(26:15):
patients with other medicationsto treat the same pathology for
which the patient is alreadybeing treated.
Therefore, there can be aredundancy in the medications
that the patient is taking.
Or another instance is that thepatients might not continue to
(26:40):
take the therapy they have beengiven at the hospital as they
have been prescribed.
Now, this can be understood ifwe take into account the
characteristics of the patients.
For example, a patient who istaking multiple medications and
(27:06):
is cognitively impaired mightforget to take the medication,
or he might take it at a wrongdose, or he could confuse a
medication with another.
This can also be the case ofthe patients who have a visual
impairment.
They can also confuse amedication with another or they
(27:30):
can take a wrong quantity of amedication, especially if it is
a liquid pharmaceutical form.
The patients that have impairedhand dexterity might not be
able to open a bottle or to usean inhaler.
An elderly patient who does notproduce enough saliva that is
(27:55):
called xerostomia or has issueswith ingesting, might not be
able to ingest a tablet, or toingest it, they might break a
tablet that is not designed tobe broken, and maybe it is a
slow release tablet.
So what I'm trying to say isthat when a patient is
(28:19):
discharged from hospital, thetherapy needs also to be adapted
to the impairments, to thecharacteristics of the patient
and to the level of assistancethey have at home once they are
discharged.
But to provide a more completeanswer, we have to remember that
(28:43):
the concept of thepost-hospital syndrome has been
described by Dr Krumholtz, whofound that the majority of the
30-day readmissions are notassociated to the original
illness for which the patienthas been hospitalised.
(29:05):
Now, if we think about it, whena patient is taken from home to
the hospital, at hospital theydon't have the same environment
as they have at home.
For example, the environment atthe hospital can be a rather
(29:26):
noisy environment as compared towhen they are at home.
So the patients that arehospitalised might have issues
with sleeping and this canaffect their metabolism, the
cognitive performance, or theircoordination.
It might be decided at ahospital that they should not
(29:50):
take anything by mouth.
As we know, when you are in ahospital, you are in bed, you
don't go around, you don't move,and this can cause a loss of
the muscle strength and a lossof coordination.
All of these issues can affect afrail, older patient with a
(30:13):
greater severity and frequency.
As we might remember, frailtyis the reduced capability of
adapting to a stressor, and thestressor can also be the
hospitalisation.
Therefore, if frail olderadults go home after having been
(30:37):
hospitalised, but in thehospital they have not slept,
they have been malnourished orthey are particularly weak, they
might not be able to take themedication as they have been
prescribed unless they areadequately helped, and they
(30:59):
might also be at risk ofsuffering from additional
pathologies.
Alexandra Coutinho (31:05):
Yeah, and there again, it becomes
important to have moreinformation on the frailty of
older patients to be able toprovide adequate support
following hospital dischargeshould they need it.
Giovanni Furlan (31:17):
Exactly.
Alexandra Coutinho (31:19):
That being said, what is currently being
done in terms of practice andresearch regarding
pharmacovigilance in elderlypatients?
For example, are more and morehospitals and organisations
using frailty to conductpharmacovigilance in this
patient group?
Giovanni Furlan (31:43):
So, if we look from a regulatory point of view,
in the last few years there hasbeen a big push to consider the
characteristic of the elderlypatients in all of the phases of
a medicine, from when it isgiven for the first time to
human beings, throughoutpost-marketing.
For example, the regulatoryguidelines state that the
(32:06):
medically complex patientsshould be enrolled in the
clinical studies whenever it issafe to do so.
The guidelines on the diversityof the patients included in
clinical trials state that thephase 3 clinical trials have to
(32:26):
enrol the patients that reflectas much as possible those who
will take the drug in thepost-approval phase.
For the non-technical peoplewho are listening to the podcast
, the phase 3 studies are thosethat provide the evidence of the
(32:47):
safety and of the efficacy ofthe medicine, and they provide
the evidence of its value inclinical practice.
The guidelines state that theclinical studies should be made
less burdensome for theparticipant and they should use
real-world data to facilitateenrolment.
(33:10):
There are also specificguidelines on the inclusions of
older adults in the cancerclinical studies, and these
guidelines state that thespectrum of older adults that
are included in these studiesshould be representative of the
(33:30):
intended population, includingthose with frailty and organ
impairment.
There are also regulationssaying what kind of information
specifically for the elderly hasto be included in the label.
So, for example, on the labelwe have to say if the safety and
(33:55):
the efficacy in the elderly isthe same as compared to the
general population or if it isdivergent from the general
population.
And there are also guidelinesthat specify how to identify the
most appropriate pharmaceuticalforms for older patients who
(34:21):
have impairments and functionallimitations.
Now, from the perspective offrailty, we are starting to see
the first studies thatinvestigate the efficacy of
medicinal products in frailolder patients.
There are also initiatives toinclude the patient's frailty
(34:46):
status in their medical recordsand the NHS is using the
electronic frailty index toidentify patients with moderate
and severe frailty.
Alexandra Coutinho (34:59):
What other examples exist of pharmaceutical
practice being specificallytailored to elderly patients?
Giovanni Furlan (35:07):
So we have mentioned before the
pharmaceutical forms and thepackaging, but I would suggest
that we expand on the concept.
So the older patients, as wehave said, might have
impairments that affect theirability to take the medications.
(35:29):
For example, they might not seewell, they might have issues
with swallowing, hyposalivation,reduced hand and eye movement
coordinations.
These are all examples that canmake it challenging for an
older patient to take amedication.
(35:50):
Let us think about a patientwith a reduced hand dexterity
who might find it not easy tohandle an inhaler, whereas those
with hyposalivation might notfind it easy to ingest the
tablet, and this can be evenmore challenging if they have to
(36:13):
take many tablets at the sametime.
So, if this is the issue with apatient, they might find it
easier to take a liquidpharmaceutical form instead of a
solid pharmaceutical formpharmaceutical form, but if the
(36:38):
patient is visually impaired,they might not be able to
measure the quantity of theliquid that they have to take.
Another issue is that of thepolypharmacy and of the complex
medication schedules, and theycan be challenging for the
elderly, who tend to forgetthings.
So for this reason, the elderlymight use a multi-compartment
(37:01):
compliance aid.
This is a box that is dividedin smaller compartments, and
each compartment clearly statesthe name of the day and the time
when the medication in thespecific compartment needs to be
taken.
(37:22):
So each compartment is filledwith all of the solid
preparation that the patient hasto take at the same time.
However, there are also riskswhen you use the
multi-compartment complianceaids.
This is the case when amedication has to be stored at a
(37:45):
low temperature, while in themulti-compartment aid it might
stay at a much highertemperature for a longer period
of time, and this can lead tostability issues.
So what I'm trying to point outis that there is not one size
(38:06):
fits all for all of the olderpatients.
W e have to have in mind whatare the characteristics of each
and every patient, who will takethe medication, what are their
impairments, and how we candesign the pharmaceutical form
that is most appropriate for theimpairments that these patients
(38:31):
have.
There has been a veryinteresting development in the
field, especially for thepatient who take multiple
medication, and this is the caseof the polypill that is
prepared with the use of a 3Dextrusion based printer.
So the polypill is made ofmultiple modular units and they
(38:58):
are assembled in the same pillthat contains many active
ingredients.
So ideally, the 3D printershould be available in all of
the pharmacies so thatpersonalised polypills with the
correct quantity of activeingredients can be prepared for
(39:23):
each patient.
Unluckily, we are not yet there, because this has a cost.
There are the formulationchallenges and we need to comply
with all of the goodmanufacturing practices, and it
might not be easy to comply withthese good manufacturing
(39:46):
practices in each and everypharmacy.
Alexandra Coutinho (39:50):
Wow, that was so interesting.
I've never heard of was itpolypills?
Is that what you said?
Giovanni Furlan (39:54):
Yes, the polypills.
So a polypill is one singlethat contains active
ingredients.
So instead of taking one tabletfor each active ingredient, you
(40:19):
only take on tablet thatcontains all of the active
ingredients that you have totake at the same time.
Alexandra Coutinho (40:22):
It reminds me a bit of this argument that
I've been hearing over the yearsfor personalised medicine being
the future of care and of idealcare.
This is like a great steptowards it, if we can finally
progress with that.
Giovanni Furlan (40:39):
Exactly.
Alexandra Coutinho (40:40):
Well, it does seem that, regardless of
how far we still have yet to go,we are certainly well on the
way to making medicines safer inthis patient population.
What more can be done toimprove pharmacovigilance in
frail elderly patients andminimise their risk of medical
harm?
Giovanni Furlan (40:57):
So, in my opinion, the first step is to
develop an internationallyagreed standard on how to
identify and categorise frailtyseverity, because today there
are various ways to measure thefrailty and there are a number
(41:19):
of parameters to measure it,such as, for example, the
patient's pathologies, theirability to independently perform
the activities of daily life,their physical capabilities,
such as the gait speed or thetime that is required to stand
(41:41):
up from when you sit in a chair.
So the lack of aninternationally agreed standard
on which parameters to use, andon what weight each parameter
has on the overall frailty index, can make it challenging to
(42:04):
compare the results of studiesthat use different frailty
indexes.
So once an internationalstandard has been agreed upon,
the frailty should be includedin patient medical records and,
in all adverse events,individual case reports.
This would be the basis toperform an adequate analysis on
(42:30):
how frailty influences the riskof experiencing adverse
reactions for each medicine.
As for the studies that wementioned before, it is
important not only to includethe elderly, but especially the
frail elderly, and it is ofparticular importance if the
(42:54):
medication that is investigatedwill be taken by the frail
elderly patients.
(43:21):
Fo r this reason, the exclusioncriteria in the clinical trial
should be kept to the minimum,and, this is very important, we
should consider if the frailolder patient and the non-frail
older patient have the samepreferences as to what they want
to achieve with the medicationthat they take.
For example, a frail, olderpatient with multiple
pathologies who is having atreatment for cancer might not
be interested in having alimited increase in life
(43:46):
expectancy if this is at thecost of experiencing adverse
reaction that might impair theirindependence or their social
interaction.
They might be more interested intaking the medication that will
help them to maintain a goodquality of life.
(44:08):
The same might not be the samefor older patients who are not
frail, because these patientsmight benefit from a longer
increase in the life expectancythanks to the cancer medication
that is being investigated.
(44:28):
Therefore, prior to conductinga study, we should ask frail
older patients what they want toachieve with the medication,
and there could be clinicaltrial endpoints that are not the
same for the frail and thenon-frail older patients.
(44:50):
And to conclude, there is stilla lot to be understood on the
evolution of the frailty and howmild, moderate or severe
frailty can influence the riskof experiencing adverse
reactions.
This is because there is anevolution in the severity of
(45:14):
frailty.
So the question is how doeseach stage of frailty impact the
risk of experiencing adversereactions?
Alexandra Coutinho (45:25):
Yeah, and that seems to be the logical
next step in improvingpharmacovigilance in older
patients, is further researchinto frailty.
It seems that these divisionsin frailty kind of also form
separate patient groups,depending on how frail they are,
right?
Giovanni Furlan (45:42):
Exactly, this is, I think, the proposal that I
have.
We are now starting, only now,to looking into frailty, but we
are not giving a look at thevarious severities.
Alexandra Coutinho (45:59):
Well, I mean it's great that there, as you
mentioned before, for examplewith the NHS, that they are
including at least measures offrailty already in routine sort
of studies, and so we're takingthese first steps into looking
more into frailty.
Hopefully that will then in duecourse also come to research
more into severity of frailty.
Giovanni Furlan (46:19):
Yes indeed.
Alexandra Coutinho (46:20):
Well, Giovanni, thank you.
This was a very, veryinteresting interview into what
I feel is a very importantaspect of pharmacovigilance that
I don't feel is spoken aboutenough.
So thank you very much for yourtime and for making yourself
available for this interview.
Giovanni Furlan (46:36):
I thank you very much and thank you for
being interested in the topic.
Alexandra Coutinho (46:43):
That's all for now, but we'll be back soon
with more conversations onmedicine safety.
If you would like to know moreabout pharmacovigilance in older
patient groups, check out theepisode show notes for useful
links.
If you like our podcast,subscribe to it in your
favourite player so you won'tmiss an episode, and spread the
word on social media so otherlisteners can find us.
Apart from these in-depthconversations with experts, we
(47:06):
host a series called UppsalaReports Long Reads, a selection
of audio stories from UMC'spharmacovigilance news site, so
do check that out too.
Uppsala Monitoring Centre is onFacebook, Linkedin, and X, and
we'd love to hear from you.
Send us comments or suggestionsfor the show or send in
questions for our guests nexttime we open up for that.
For Drug Safety Matters, I'mAlexandra Coutinho.
(47:28):
I'd like to thank GiovanniFurlan for his time, Frederick
Bronéus and Matthew Barwick forpost-production support and, of
course, you for tuning in.
Till next time.
As our bodies age, we experience a
number of physiological changesthat affect how we respond to
medicines.
As older adults, we are alsothe most likely to be taking
multiple medications at once.
These and other factorsincrease the risk of us
experiencing adverse drugreactions.
How, then, do pharmacovigilancescientists do their due
(00:36):
diligence in monitoring medicinesafety in this patient group?
My name is Alexandra Coutinho,and this is Drug Safety Matters,
a podcast by Uppsala MonitoringCentre, where we explore
current issues inpharmacovigilance and patient
safety.
Joining me today is GiovanniFurlan, worldwide Safety Site
Lead and Safety Risk Lead atPfizer.
(00:56):
This interview goes deep inexplaining what differentiates
older patients from otherpatient groups, why age alone is
not enough to define them andwhat can be done to improve
pharmacovigilance in apopulation group that is most
likely to suffer from sideeffects to medicines.
I hope you enjoy listening.
Hi, Giovanni, and welcome toDrug Safety Matters.
(01:25):
How are you doing today?
Giovanni Furlan (01:26):
Fine, I am very well.
Nice to talk to you today,Alexandra.
Alexandra Coutinho (01:31):
Likewise, Giovanni.
So we first became acquaintedthrough Uppsala Reports, where
you wrote a really interestingarticle on adverse reaction risk
in older patients.
To kick things off, could youtell our listeners a bit about
your background and how youbecame interested in this topic?
Giovanni Furlan (01:48):
Yes, so I am a pharmacist.
I have been working inpharmacovigilance for 25 years,
and what I realised working inpharmacovigilance is that the
adverse reactions and the risksof experiencing them are not the
same in all patientpopulations.
(02:11):
And I am also becoming older,and so I asked myself "let us
see if in the older patients,the risk of experiencing adverse
reactions is the same as in thegeneral population".
And, as you have read from myarticles, I realised that there
are specific aspects to be takeninto account in the older
(02:35):
patients that are not applicableto the general population.
Alexandra Coutinho (02:40):
So why are older adults especially at risk
of experiencing adverse drugreactions and why should we
regard them as a special patientgroup in terms of
pharmacovigilance?
Giovanni Furlan (02:51):
So there are a number of factors that affect
the safety of the medicationsthat are taken by older patients
.
These are physiological,biological changes, the
increased number of pathologiesthat the elderly tend to
concomitantly suffer from, andthis leads them to taking many
(03:15):
medicinal products at the sametime.
And the more medicinal productsyou take, the more likely it is
that there will be medicationerrors.
Let us see these factors one byone a little bit more in depth.
Now we know that as we age, ourmetabolism changes.
(03:37):
For example, there is areduction of the liver mass and
of the blood flow to the liver,and this can increase the
bioavailability of certainmedications, such as the opioids
, but it can also reduce thebioavailability of other
(03:57):
medications, the so-calledprodrugs.
These are the medications thatare activated by the liver, such
as enalapril or perin dopril.
Another example is the renalfunctionality that also
decreases with age, and this hasan important clinical
(04:21):
consequence for the drugs thathave a narrow therapeutic index
that are cleared by the kidneys,such as, for example, digoxin
or aminoglycoside antibiotics.
Therefore, if we don't takeinto account that the altered
(04:41):
renal function in the elderlymight cause an over-accumulation
of these medications in thebody, there might be adverse
reaction.
But with aging also, how werespond to a medication can
change.
T his is the so-calledpharmacodynamics, and, to go a
(05:04):
little bit more into technicaldetail, the pharmacodynamics
changes because the number ofthe receptor in the body can
change, the affinity of thereceptor changes, the second
messenger response or thecellular response can change.
I understand these are rathertechnical aspects, so I will try
(05:29):
to make some practical examples.
Some older adults can have anincreased response to certain
antihypertensive medications,and this can cause an
exaggerated antihypertensiveeffect.
A similar observation appliesto the medications that are used
(05:53):
to treat certain centralnervous system disorders such as
insomnia, anxiety or agitation,and the increased sedative
effect of these medications inthe older patients can increase
the risk of falls or of hipfractures, and the same applies
(06:15):
to the exaggeratedantihypertensive effect that can
also increase the risk of falls.
Now, apart from thephysiological or the biological
changes that we have just seen,the older adults are often
characterised by a number ofdifferent pathologies, and this
(06:37):
can make it rather challengingto prescribe the appropriate
medication, because amedication that is of use to
treat a certain pathology mightbe associated with an adverse
reaction that aggravates anothercoexisting medical condition.
I am particularly referring tothe so-called geriatric
(07:02):
conditions that characterise theolder patients, such as
delirium, falls, sarcopenia,urinary incontinence, and
several studies have shown thatthe medication with
anticholinergic effect canaggravate some of these diseases
(07:24):
.
If you take multiplemedications, the so-called
polypharmacy, because you sufferfrom many pathologies at the
same time, there is an increasedlikelihood that a medication
might interact with another onethat is taken at the same time.
(07:47):
The interaction can cause areduction of the effect of a
medication or it can increasethe risk of a patient
experiencing an adverse reaction.
And finally, I mentioned beforethe medication errors.
We can easily understand thatthe more drugs we take, the more
(08:11):
likely it is that thecompliance with taking the drugs
as they are prescribed will below, and the poor adherence to
medical regiments can lead to asubstantial worsening of the
disease, to increase health carecosts and in some extreme
(08:33):
instances it can also be fatal.
So, from this point of view,looking for ways to increase
compliance in older adults maylead to an extension of their
healthy and active years of life.
Alexandra Coutinho (08:50):
And we will get a little bit more into that
as we go through the interview.
So it does seem to my mind thatolder patients really have the
odds stacked against them whenit comes to medicine safety.
Let's take one of the problemsthat you mentioned polypharmacy.
One of the papers you sent meto read states that 55% of the
(09:10):
elderly take between five andnine drugs per day, with the
risk of ADRs almost doublingwhen five medications are taken
and increasing to 95% when eightor more medications are taken.
That's huge.
Why is this the case?
Giovanni Furlan (09:26):
Yes, you're absolutely right.
So there are various factorsthat we need to take into
account.
So each medication is absorbedby the body, distributed,
metabolised, and eliminated.
This is called thepharmacokinetics of a medication
(09:47):
.
In simple terms, we can saythat the journey of a medication
in the body is not onlydetermined by the
characteristics of themedication, but also how it
interacts with the body.
So, to simplify it to themaximum, we can say that a
(10:08):
medication is absorbed and it isdistributed in the body thanks
to its binding with carriers andpumps, it passes through many
channels or it binds to theproteins that carry it in the
blood.
Albumin is an example of aprotein with which a medication
(10:31):
can bind, and albumin will carrythe medication throughout the
whole body through thecardiovascular system.
A medication is also metabolisedby a number of enzymes, such as
the cytochrome, and a drug caninterfere with how another drug
(10:54):
interacts with these proteinsand enzymes, thereby altering
its bioavailability and theplasmatic concentration.
This can cause an increase ofthe concentration of the
(11:15):
medication or of its activemetabolites, and if there is an
increase in the concentration ofthe medication, there can be an
increased risk of adversereaction.
If, instead, we see a decreaseof the concentration of the
medication or of its activemetabolites, there is an
impairment of the drugtherapeutic effect, and a
(11:38):
similar concept applies to adrug's mechanism of action.
A medication is able to alterthe biochemical pathways of the
body, and if more than onemedication is taken at the same
(12:02):
time, they might interact withthe same bio-pathway, thereby
altering each other's effects.
Alexandra Coutinho (12:10):
Right.
Polypharmacy aside, youmentioned that the biological
changes that occur as we agecontribute to this increased
risk of experiencing an adversereaction.
In your article for UppsalaReports, however, you do argue
that using age to define anddescribe this patient group does
not adequately reflect who ismost at risk of experiencing
(12:32):
adverse drug reactions.
For those who have not read thearticle, can you explain why
age alone shouldn't be used asthe main characteristic for
pharmacovigilance in olderpatients?
Giovanni Furlan (12:49):
Absolutely.
I think that how we age isprobably one of the most
fascinating and challengingaspects.
We don't all age with the samespeed and in the same way.
Let us consider, for example,the world record for running the
marathon.
A marathon is of 42.2kilometres.
The world record for those whoare more than 80 years of age is
(13:15):
of 3 hours and 15 minutes.
That is much, much faster thanwhat the vast majority of the
20-year-old adults will ever beable to accomplish.
Therefore, how do you classifythe physiological age of the
(13:36):
80-year-old athlete who has runthe marathon in this time?
According to the currentguidelines, if this person were
ever to take part in a clinicalstudy, he would be included in
the age category from 75 to 85years of age.
(13:58):
Now the question is would he becomparable to other subjects of
the same age who maybe havemultiple comorbidities and they
may be confined in a chair or ina bed?
You can very well understandthat we are talking about an
extremely heterogeneouspopulation.
(14:21):
The aging in fact reflects thecomplex and cumulative interplay
between the genes, thelifestyle, what we eat, the
psychological, the socialcircumstances, the environment,
and chance.
Therefore, the chronologicalage is not, per se, the most
(14:46):
important factor.
It is rather the functional age, and frailty is probably the
most well-known method tomeasure the biological age, and
it is used to characterise thepatients based on their
functional age.
The frailty is defined and youcan find it in every textbook as
(15:12):
the increased stressors todue to a decline in the
physiological reserves and tothe severe dysregulation in the
physiological system.
So, to talk in more plain terms, frailty tells us how well the
(15:33):
body is able to adapt tochanging circumstances, and it
may be much more relevant thanage per se.
Alexandra Coutinho (15:43):
And for those of you who want to know
more about frailty and how itmay be used in pharmacovigilance
practice to measure adversereaction risk in this patient
group, feel free to readGiovanni Uppsala Reports,
article which I linked in theshow notes.
Apart from this issue, there isalso the problem of lack of
representation of elderlypatients in clinical studies,
(16:11):
which adds to this risk ofmedical harm.
Why are the elderlyunderrepresented in clinical
studies, and how does thisaffect pharmacovigilance?
Giovanni Furlan (16:15):
There are many reasons why the older adults,
but especially the frail olderadults, are underrepresented in
the clinical study.
Broadly, we can categorisethese reasons in three main
categories, that are, thepatient-related, the
(16:35):
investigator-related, and thetrial-related reasons.
Let us go to thepatient-related reasons.
The elderly patients mightperceive the clinical trial will
not be of benefit because thestudy endpoints are not relevant
to the condition they sufferfrom.
(16:56):
And if we think about anelderly who cannot take public
transportation or who can'tdrive a car, they might not be
able to reach the clinical trialcentre.
When it comes to theinvestigator-related reasons,
the investigator might bereluctant to enrol the elderly
(17:19):
patients because they might fearthey are at increased risk of
experiencing adverse reaction.
And if we think about anelderly patient who might have a
cognitive impairment, a visualimpairment or other impairments,
investigators might be afraidthat it will take too much time
(17:43):
to explain to them what theclinical trial is about, or it
might take too much time tovisit the patient.
Then we have the clinicaltrial-related barriers, and
these are mainly caused by theprotocol exclusion criteria.
These can say, for example,that the patients who suffer
(18:06):
from multiple comorbidities havephysical disabilities or
cognitive impairment, theycannot be enrolled in a study.
Therefore, the older adults whoare also frail, such as those
who are not capable ofconducting an independent life,
(18:28):
are particularlyunderrepresented in the clinical
studies.
Alexandra Coutinho (18:32):
And I guess this underrepresentation must
then make it that much harder tobe able to measure adverse
reaction risk in this patientgroup right to be able to
measure adverse reaction risk inthis patient group right?
However, we do seem to havesome idea of how older patients
may react to certain types ofmedication.
That being said, are therespecific medications older
(18:56):
patients should take withparticular care, and is there
any advice on how to reducetheir risk of experiencing
adverse reactions to thesemedications?
Giovanni Furlan (19:09):
So, as you all know, I am an employee of a
pharma company, so I have firstof all to disclose this conflict
of interest, since I might beperceived as being biased.
Having said that, I havealready mentioned before the
risk of medications that have ananticholinergic effect, since,
especially in the older patients, they are associated with dry
(19:32):
mouth, constipation, confusion,increased risk of falls.
Now, for a more comprehensiveand objective list on which
medication to use with increasedcaution in the older patients,
I would suggest you refer tointernational guidelines, such
(19:54):
as the Beers criteria that areregularly updated by the
American Geriatric Society.
There are also other guidelines, such as the START and STOP
criteria, that are thought andthey are designed to facilitate
the review of the medicines thatare taken by the patients, and
(20:17):
they are designed to find notonly the potentially
inappropriate medications, butalso the omission of a treatment
that can be useful to a patient.
I would like to underline theword potentially, since all of
these criteria are only asuggestion that has to be
(20:40):
adapted to the clinicalcharacteristics of each patient.
In fact, even a potentiallyinappropriate medication might
be the correct one for specificpatients.
We mentioned beforeanticholinergic medications.
We know that they can cause aurinary retention as an adverse
(21:06):
reaction, but if the patientsuffers from a urinary
incontinence, it will not be aproblem at all.
Anoth er main issue that we needto take into account is that
the prescribers need torecognise adverse reaction and
they should not confuse themwith symptoms of other
(21:30):
pathologies.
This is challenging in olderpatients who suffer from
multiple pathologies and takemultiple medications.
If an adverse reaction is notrecognised as such, then the
patient might be administeredwith another medication to treat
(21:52):
the adverse reaction, and theother medication can cause other
adverse reactions, and this cango on indefinitely, and it is
called the prescribing cascade.
So as an example because Ialways like to make practical
examples, we can make theexample of an elderly patient
(22:15):
who is taking non-steroidalanti-inflammatory medications to
treat some kind of pain.
But we know that thenon-steroidal anti-inflammatory
medication can cause heartburnor they can cause hypertension,
and if these conditions are notcorrectly recognised as adverse
(22:40):
reactions, the patient mighttake the proton pump inhibitor
or antihypertensive medicationsthat, in turn, can cause other
adverse reactions.
It is therefore of extremeimportance that whenever a
patient suffers from a newmedical condition, the treating
(23:03):
physician reviews all of themedication the patient is taking
, including over-the-counterherbal drugs and whatever else,
can have an effect on thetreatment of a certain pathology
.
And if the medical condition isthought to be caused by a
(23:28):
medicine, the question then isif we really need the patient to
take the medication, if itshould be stopped, or if it
should be changed with anotherdrug.
It is also very important notto misjudge a new pathology as
(23:49):
caused by a medication when itis not, since this might cause
the interruption of a medicationthat the patient actually has
to take and that is benefitingthe patient.
It is therefore very importantthat the physicians are well
trained to recognise adversereactions.
Alexandra Coutinho (24:13):
Yes, indeed, I think we need education for
all sorts of differentpharmacovigilance issues.
You also mentioned medicationerrors before, so let's look a
bit more into medication errorsin this patient group.
There is research on the riskof medication errors occurring
during transition of care,especially when patients are
(24:35):
discharged from hospital.
Officially, the name for it ispost-hospital syndrome.
Can you speak to this and whyelderly patients are more at
risk of developing this syndrome?
Giovanni Furlan (24:45):
Yes, we mentioned it at the beginning of
the interview and this is anextremely important aspect to
take into account.
In general, compliance with thetreatment as prescribed and the
medication error are animportant cause of harm to the
(25:07):
elderly.
One reason can be that theelderly patients with multiple
comorbidities might visit manydoctors from a variety of
specialties and one doctor mightnot be aware of the complete
medical history of the patientor of all the medications they
(25:29):
are taking, and this can lead toa non-appropriate prescribing.
So for this reason, it is veryimportant that all of the
medications taken by an elderlypatient are reviewed and they
are also reconciled.
If a patient is at a hospital,they might be prescribed with
(25:53):
certain medications and theycontinue to take them once they
are at home, but the MD who islooking after the patients when
they are at home might not beaware of the additional
medications the patient istaking, and he could provide the
(26:15):
patients with other medicationsto treat the same pathology for
which the patient is alreadybeing treated.
Therefore, there can be aredundancy in the medications
that the patient is taking.
Or another instance is that thepatients might not continue to
(26:40):
take the therapy they have beengiven at the hospital as they
have been prescribed.
Now, this can be understood ifwe take into account the
characteristics of the patients.
For example, a patient who istaking multiple medications and
(27:06):
is cognitively impaired mightforget to take the medication,
or he might take it at a wrongdose, or he could confuse a
medication with another.
This can also be the case ofthe patients who have a visual
impairment.
They can also confuse amedication with another or they
(27:30):
can take a wrong quantity of amedication, especially if it is
a liquid pharmaceutical form.
The patients that have impairedhand dexterity might not be
able to open a bottle or to usean inhaler.
An elderly patient who does notproduce enough saliva that is
(27:55):
called xerostomia or has issueswith ingesting, might not be
able to ingest a tablet, or toingest it, they might break a
tablet that is not designed tobe broken, and maybe it is a
slow release tablet.
So what I'm trying to say isthat when a patient is
(28:19):
discharged from hospital, thetherapy needs also to be adapted
to the impairments, to thecharacteristics of the patient
and to the level of assistancethey have at home once they are
discharged.
But to provide a more completeanswer, we have to remember that
(28:43):
the concept of thepost-hospital syndrome has been
described by Dr Krumholtz, whofound that the majority of the
30-day readmissions are notassociated to the original
illness for which the patienthas been hospitalised.
(29:05):
Now, if we think about it, whena patient is taken from home to
the hospital, at hospital theydon't have the same environment
as they have at home.
For example, the environment atthe hospital can be a rather
(29:26):
noisy environment as compared towhen they are at home.
So the patients that arehospitalised might have issues
with sleeping and this canaffect their metabolism, the
cognitive performance, or theircoordination.
It might be decided at ahospital that they should not
(29:50):
take anything by mouth.
As we know, when you are in ahospital, you are in bed, you
don't go around, you don't move,and this can cause a loss of
the muscle strength and a lossof coordination.
All of these issues can affect afrail, older patient with a
(30:13):
greater severity and frequency.
As we might remember, frailtyis the reduced capability of
adapting to a stressor, and thestressor can also be the
hospitalisation.
Therefore, if frail olderadults go home after having been
(30:37):
hospitalised, but in thehospital they have not slept,
they have been malnourished orthey are particularly weak, they
might not be able to take themedication as they have been
prescribed unless they areadequately helped, and they
(30:59):
might also be at risk ofsuffering from additional
pathologies.
Alexandra Coutinho (31:05):
Yeah, and there again, it becomes
important to have moreinformation on the frailty of
older patients to be able toprovide adequate support
following hospital dischargeshould they need it.
Giovanni Furlan (31:17):
Exactly.
Alexandra Coutinho (31:19):
That being said, what is currently being
done in terms of practice andresearch regarding
pharmacovigilance in elderlypatients?
For example, are more and morehospitals and organisations
using frailty to conductpharmacovigilance in this
patient group?
Giovanni Furlan (31:43):
So, if we look from a regulatory point of view,
in the last few years there hasbeen a big push to consider the
characteristic of the elderlypatients in all of the phases of
a medicine, from when it isgiven for the first time to
human beings, throughoutpost-marketing.
For example, the regulatoryguidelines state that the
(32:06):
medically complex patientsshould be enrolled in the
clinical studies whenever it issafe to do so.
The guidelines on the diversityof the patients included in
clinical trials state that thephase 3 clinical trials have to
(32:26):
enrol the patients that reflectas much as possible those who
will take the drug in thepost-approval phase.
For the non-technical peoplewho are listening to the podcast
, the phase 3 studies are thosethat provide the evidence of the
(32:47):
safety and of the efficacy ofthe medicine, and they provide
the evidence of its value inclinical practice.
The guidelines state that theclinical studies should be made
less burdensome for theparticipant and they should use
real-world data to facilitateenrolment.
(33:10):
There are also specificguidelines on the inclusions of
older adults in the cancerclinical studies, and these
guidelines state that thespectrum of older adults that
are included in these studiesshould be representative of the
(33:30):
intended population, includingthose with frailty and organ
impairment.
There are also regulationssaying what kind of information
specifically for the elderly hasto be included in the label.
So, for example, on the labelwe have to say if the safety and
(33:55):
the efficacy in the elderly isthe same as compared to the
general population or if it isdivergent from the general
population.
And there are also guidelinesthat specify how to identify the
most appropriate pharmaceuticalforms for older patients who
(34:21):
have impairments and functionallimitations.
Now, from the perspective offrailty, we are starting to see
the first studies thatinvestigate the efficacy of
medicinal products in frailolder patients.
There are also initiatives toinclude the patient's frailty
(34:46):
status in their medical recordsand the NHS is using the
electronic frailty index toidentify patients with moderate
and severe frailty.
Alexandra Coutinho (34:59):
What other examples exist of pharmaceutical
practice being specificallytailored to elderly patients?
Giovanni Furlan (35:07):
So we have mentioned before the
pharmaceutical forms and thepackaging, but I would suggest
that we expand on the concept.
So the older patients, as wehave said, might have
impairments that affect theirability to take the medications.
(35:29):
For example, they might not seewell, they might have issues
with swallowing, hyposalivation,reduced hand and eye movement
coordinations.
These are all examples that canmake it challenging for an
older patient to take amedication.
(35:50):
Let us think about a patientwith a reduced hand dexterity
who might find it not easy tohandle an inhaler, whereas those
with hyposalivation might notfind it easy to ingest the
tablet, and this can be evenmore challenging if they have to
(36:13):
take many tablets at the sametime.
So, if this is the issue with apatient, they might find it
easier to take a liquidpharmaceutical form instead of a
solid pharmaceutical formpharmaceutical form, but if the
(36:38):
patient is visually impaired,they might not be able to
measure the quantity of theliquid that they have to take.
Another issue is that of thepolypharmacy and of the complex
medication schedules, and theycan be challenging for the
elderly, who tend to forgetthings.
So for this reason, the elderlymight use a multi-compartment
(37:01):
compliance aid.
This is a box that is dividedin smaller compartments, and
each compartment clearly statesthe name of the day and the time
when the medication in thespecific compartment needs to be
taken.
(37:22):
So each compartment is filledwith all of the solid
preparation that the patient hasto take at the same time.
However, there are also riskswhen you use the
multi-compartment complianceaids.
This is the case when amedication has to be stored at a
(37:45):
low temperature, while in themulti-compartment aid it might
stay at a much highertemperature for a longer period
of time, and this can lead tostability issues.
So what I'm trying to point outis that there is not one size
(38:06):
fits all for all of the olderpatients.
W e have to have in mind whatare the characteristics of each
and every patient, who will takethe medication, what are their
impairments, and how we candesign the pharmaceutical form
that is most appropriate for theimpairments that these patients
(38:31):
have.
There has been a veryinteresting development in the
field, especially for thepatient who take multiple
medication, and this is the caseof the polypill that is
prepared with the use of a 3Dextrusion based printer.
So the polypill is made ofmultiple modular units and they
(38:58):
are assembled in the same pillthat contains many active
ingredients.
So ideally, the 3D printershould be available in all of
the pharmacies so thatpersonalised polypills with the
correct quantity of activeingredients can be prepared for
(39:23):
each patient.
Unluckily, we are not yet there, because this has a cost.
There are the formulationchallenges and we need to comply
with all of the goodmanufacturing practices, and it
might not be easy to comply withthese good manufacturing
(39:46):
practices in each and everypharmacy.
Alexandra Coutinho (39:50):
Wow, that was so interesting.
I've never heard of was itpolypills?
Is that what you said?
Giovanni Furlan (39:54):
Yes, the polypills.
So a polypill is one singlethat contains active
ingredients.
So instead of taking one tabletfor each active ingredient, you
(40:19):
only take on tablet thatcontains all of the active
ingredients that you have totake at the same time.
Alexandra Coutinho (40:22):
It reminds me a bit of this argument that
I've been hearing over the yearsfor personalised medicine being
the future of care and of idealcare.
This is like a great steptowards it, if we can finally
progress with that.
Giovanni Furlan (40:39):
Exactly.
Alexandra Coutinho (40:40):
Well, it does seem that, regardless of
how far we still have yet to go,we are certainly well on the
way to making medicines safer inthis patient population.
What more can be done toimprove pharmacovigilance in
frail elderly patients andminimise their risk of medical
harm?
Giovanni Furlan (40:57):
So, in my opinion, the first step is to
develop an internationallyagreed standard on how to
identify and categorise frailtyseverity, because today there
are various ways to measure thefrailty and there are a number
(41:19):
of parameters to measure it,such as, for example, the
patient's pathologies, theirability to independently perform
the activities of daily life,their physical capabilities,
such as the gait speed or thetime that is required to stand
(41:41):
up from when you sit in a chair.
So the lack of aninternationally agreed standard
on which parameters to use, andon what weight each parameter
has on the overall frailty index, can make it challenging to
(42:04):
compare the results of studiesthat use different frailty
indexes.
So once an internationalstandard has been agreed upon,
the frailty should be includedin patient medical records and,
in all adverse events,individual case reports.
This would be the basis toperform an adequate analysis on
(42:30):
how frailty influences the riskof experiencing adverse
reactions for each medicine.
As for the studies that wementioned before, it is
important not only to includethe elderly, but especially the
frail elderly, and it is ofparticular importance if the
(42:54):
medication that is investigatedwill be taken by the frail
elderly patients.
(43:21):
Fo r this reason, the exclusioncriteria in the clinical trial
should be kept to the minimum,and, this is very important, we
should consider if the frailolder patient and the non-frail
older patient have the samepreferences as to what they want
to achieve with the medicationthat they take.
For example, a frail, olderpatient with multiple
pathologies who is having atreatment for cancer might not
be interested in having alimited increase in life
(43:46):
expectancy if this is at thecost of experiencing adverse
reaction that might impair theirindependence or their social
interaction.
They might be more interested intaking the medication that will
help them to maintain a goodquality of life.
(44:08):
The same might not be the samefor older patients who are not
frail, because these patientsmight benefit from a longer
increase in the life expectancythanks to the cancer medication
that is being investigated.
(44:28):
Therefore, prior to conductinga study, we should ask frail
older patients what they want toachieve with the medication,
and there could be clinicaltrial endpoints that are not the
same for the frail and thenon-frail older patients.
(44:50):
And to conclude, there is stilla lot to be understood on the
evolution of the frailty and howmild, moderate or severe
frailty can influence the riskof experiencing adverse
reactions.
This is because there is anevolution in the severity of
(45:14):
frailty.
So the question is how doeseach stage of frailty impact the
risk of experiencing adversereactions?
Alexandra Coutinho (45:25):
Yeah, and that seems to be the logical
next step in improvingpharmacovigilance in older
patients, is further researchinto frailty.
It seems that these divisionsin frailty kind of also form
separate patient groups,depending on how frail they are,
right?
Giovanni Furlan (45:42):
Exactly, this is, I think, the proposal that I
have.
We are now starting, only now,to looking into frailty, but we
are not giving a look at thevarious severities.
Alexandra Coutinho (45:59):
Well, I mean it's great that there, as you
mentioned before, for examplewith the NHS, that they are
including at least measures offrailty already in routine sort
of studies, and so we're takingthese first steps into looking
more into frailty.
Hopefully that will then in duecourse also come to research
more into severity of frailty.
Giovanni Furlan (46:19):
Yes indeed.
Alexandra Coutinho (46:20):
Well, Giovanni, thank you.
This was a very, veryinteresting interview into what
I feel is a very importantaspect of pharmacovigilance that
I don't feel is spoken aboutenough.
So thank you very much for yourtime and for making yourself
available for this interview.
Giovanni Furlan (46:36):
I thank you very much and thank you for
being interested in the topic.
Alexandra Coutinho (46:43):
That's all for now, but we'll be back soon
with more conversations onmedicine safety.
If you would like to know moreabout pharmacovigilance in older
patient groups, check out theepisode show notes for useful
links.
If you like our podcast,subscribe to it in your
favourite player so you won'tmiss an episode, and spread the
word on social media so otherlisteners can find us.
Apart from these in-depthconversations with experts, we
(47:06):
host a series called UppsalaReports Long Reads, a selection
of audio stories from UMC'spharmacovigilance news site, so
do check that out too.
Uppsala Monitoring Centre is onFacebook, Linkedin, and X, and
we'd love to hear from you.
Send us comments or suggestionsfor the show or send in
questions for our guests nexttime we open up for that.
For Drug Safety Matters, I'mAlexandra Coutinho.
(47:28):
I'd like to thank GiovanniFurlan for his time, Frederick
Bronéus and Matthew Barwick forpost-production support and, of
course, you for tuning in.
Till next time.
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