Master Thesis
Continuous Benefit-Risk
Assessment of Oral Antidiabetics
and Safety-Related Regulatory
Actions
By: Daniel Nogueras Zondag
Supervisor and examiner: Dr. O.H. (Olaf) Klungel
Second Reviewer: Dr. A. K. (Aukje) Mantel-Teeuwisse
September 2014
MSc Epidemiology, Specialization in Pharmacoepidemiology
Utrecht Institute for Pharmaceutical Sciences (UIPS)
Graduate School of Life Sciences
Utrecht University
Abstract
The benefit-risk assessment of drugs has become a complex and dynamic process. The model
has moved from a one-off marketing authorization to an ongoing life-cycle approach where
decisions has to be made based on the information available at every given time point.
Especially interesting is the case of antidiabetics, characterized in the recent years for the
increasing number of drugs approved together with the emergence of safety concerns that
have brought controversial cases to the medical, pharmaceutical and regulatory world. The
aim of this thesis is to consider the benefit-risk assessment process of different novel oral
antidiabetics and safety-related regulatory actions, identifying the factors and challenges
surrounding this process and possible ways to address the problems identified. A literature
research was performed using the databases MEDLINE and the Cochrane library for all
scientific publications until July 2014, prioritizing systematic reviews and meta-analyses.
Safety-regulatory actions were retrieved from FDA’s MedWatch, European Medicines Agency
and the Medicines Evaluation Board. The controversial cases of the thiazolidinediones as well
as the more recently approved GLP-1 analogues and DPP-4 inhibitors are presented. Together
with the descriptive analysis, a graphical display of the use of the different drugs during the
last years in the Netherlands and the safety-related regulatory actions taken by the authorities
given the available evidence at that moment is shown.
2
Table of Contents
1.
Introduction ....................................................................................................................... 5
1.1 Continuous benefit-risk assessment throughout a drug’s life-cycle ......................... 5
1.2 A regulatory perspective ................................................................................................. 5
1.3 Post-Marketing Drug Safety ........................................................................................... 7
1.4 Use of electronic healthcare databases ....................................................................... 8
1.5 Novel approaches for an early access to drugs .......................................................... 9
1.5 Safety-Related Regulatory Actions ............................................................................. 10
2.
Aim of this thesis............................................................................................................ 11
3.
Diabetes Background and Oral Antidiabetic Agents ............................................ 11
3.1 Epidemiology of Diabetes ..................................................................................... 11
3.2 Diabetes Treatment ....................................................................................................... 12
4.
Methodology .................................................................................................................... 12
5.
Benefit-Risk Assessment of Novel Oral Antidiabetics ......................................... 13
5.1 The troglitazone story .................................................................................................... 13
5.2 The controversial rosiglitazone case .......................................................................... 14
5.3 Pioglitazone .................................................................................................................... 15
5.4 Glucagon-like peptide-1 analogues (GLP-1 analogues).......................................... 17
5.5 Dipeptidyl Peptidase-4 (DDP-4) Inhibitors ................................................................. 20
6.
Current challenges in the evaluation of diabetes medication ............................ 21
6.1 Surrogate outcomes ...................................................................................................... 21
6.2 Data availability .............................................................................................................. 23
6.3 Alternative treatments ................................................................................................... 23
6.5 Drug companies and regulatory agencies’ performance ......................................... 25
6.6 Patients’ preference....................................................................................................... 25
6.7 New targets in diabetes ................................................................................................ 26
7.
Conclusions ..................................................................................................................... 26
8.
References ....................................................................................................................... 27
3
4
1. Introduction
1.1 Continuous benefit-risk assessment throughout a drug’s life-cycle
From the early beginning of the development process of a drug, we start getting information
about the potential benefits and risks that the drug might have on patients. In order to get
marketing authorization by a regulatory agency, a drug has to demonstrate that, on a population
level, its benefits outweigh its potential risks, or in other words, that it has a positive benefit-risk
balance1. However, at the time of a license application, the information that regulators have
about the effects of a drug comes from clinical trials where the drug has been tested under “ideal
conditions”, on a limited number of patients, for a short period of time. This differs with the
usual healthcare practice situation, where drugs are taken by larger numbers of patients, with
different comorbidities, on treatment with different drugs and for longer periods of time 2. As a
consequence, assessing the benefit-risk balance becomes a very complex and dynamic process,
where decisions have to be made all the way throughout the life-cycle of a drug, based on the
information available at a given time point.
The benefit-risk balance of a drug might therefore change significantly through time and a drug
that was first considered to be safe and effective, might be withdrawn from the market or its
prescription and use might be restricted after new evidence is collected and evaluated, resulting
in a negative imbalance. This is not a new issue; the difference in effects between how a drug
performs under clinical trial conditions and how it performs in usual circumstances of
healthcare practice has been long known as the “efficacy-effectiveness gap”. Some authors have
pointed that the cause of this difference in effects relates mainly to a problem of inter-individual
drug response variability2.
Once a drug is licensed, healthcare professionals frequently start prescribing it for non-approved
conditions (off-label) or they can also not follow recommendations or warnings in the label 3. On
the other hand, patient’s adherence to the treatment can usually become a problem as well as an
increasing susceptibility to side-effects in some patients with other comorbidities4. All these
factors contribute to a widening variability in drug response from the clinical trial scenario to
the real clinical practice, which consequently might affect the benefit-risk profile of a drug5.
1.2 A regulatory perspective
Under current European law, regulators should take new authorization decisions based on the
objective scientific criteria of quality, safety and efficacy, excluding economical considerations
such as “cost-effectiveness” 6. However, data on safety from pre-marketing studies is quite
limited, since most clinical trials are powered to demonstrate efficacy, but they are not able to
detect rare adverse drug reactions or events with a long latency7 (Figure 1).
5
Figure 1. The challenges of identifying rare adverse drug reactions in clinical trials [Eichler H.,
2008]
In the light of all this, it is a fact that all regulatory decisions are taken under some level of
uncertainty and there is always the risk of making a bad decision, being it a positive decision to
license a drug where it turns up to cause more harm than good, or denying a drug a license,
withdrawing it from the market or restricting its indication where it would have caused more
benefits than harm. Furthermore, there is the risk of delaying the possible public health benefits
that a new drug could bring to society, due to regulators not willing to accept some level of
uncertainty, and therefore spending R&D resources that could have been invested somewhere
else (something known in economics as opportunity cost). As Eichler et al. argue, excessive
risk-tolerance from regulatory agencies would not serve public health interest, resulting in
unsafe or ineffective drugs into the market, but an excessive risk-aversion attitude would also
not be beneficial, given the high opportunity cost and patients being denied potentially valuable
treatments8.
When facing the approval of a new drug, regulators are confronted with a dilemma where
different stakeholders with their different needs and interests are hardly reconcilable (Figure 2).
And the problem is that the level of acceptable uncertainty or the threshold for a positive
regulatory approval has never been fixed or defined and has been the centre of much debate9 -when is the right time for allowing a drug into the market and when are there enough data that
can ensure that the product will bring benefits for the public health?. To some extent, it has
always been dependent on different factors such as the severity of the disease for which the
treatment is targeted and the alternatives already available on the market for that same
indication.
6
Figure 2. The regulator’s dilemma. [Eichler H-G. 2008]
The whole evaluation process has therefore always consisted of extensive discussions between
agencies, field experts and advisory committees based on different sources of scientific data and
always according to applicable legal and regulatory standards. However, in the last decade, a
lack of a structured approach as well as some level of consistency and transparency in the
process has been recognized. This has led to great efforts from both the Food and Drug
Administration (FDA) in the United States and the European Medicines Agency (EMA) in
Europe, to start different projects to enhance the principles and methods of the benefit-risk
assessment of medicinal products10,11.
1.3 Post-Marketing Drug Safety
Given the complexity of the evaluation process of medicines, regulatory agencies have evolved
to offer different approaches to the drug development process and licensing. Thus, the model
has moved from a one-off marketing authorization to an ongoing life-cycle approach. The need
for a continuous monitoring of drugs after they have received an approval, underscores the
science of pharmacovigilance.
The WHO defines pharmacovigilance as the science and activities relating to the detection,
assessment, understanding and prevention of adverse effects or any other medicine-related
problems12.
Post-marketing drug safety activities consist therefore of (a) drug risk assessment, which
consists in the identification and characterization of safety issues and the risks associated with
the use of medicines and (b) risk management, which consists in activities and interventions
aimed to mitigate or prevent the known or suspected risks associated with medicinal products.
Under current European law, the marketing authorization holder is legally obliged to
continuously collect data and conduct pharmacovigilance13. Drug safety data have to be
transmitted to authorities in defined timelines and any serious concern about the benefit-risk
balance has to be immediately notified13. On the other hand, as of 2005 all sponsors are
requested by law to submit a risk management plan (RMP) within the application dossier, where
they give the proposed detailed risk management system14. They also need to describe all postmarketing studies that they commit to conduct15.
New safety signals may emerge from:
-
Adverse Events Reporting Systems (AERS).
7
-
Controlled clinical trials
Pharmacoepidemiological studies
Literature reports
The strengthening of the reporting rules and the whole safety evaluation system in the last years
may bring a series of intended and unintended consequences: it is predictable that the number of
safety signals coming from spontaneously reported suspected ADRs and post-marketing
surveillance studies will increase16. A broader benefit-risk assessment of one drug or one class
of drugs comes also now from Periodic Safety Update Reports (PSUR; also known as Periodic
Benefit Risk Evaluation Reports). The data from both sources might result in a request for more
research, drug labelling changes, prescription restrictions or even withdrawals.
In this sense, regulators might be more willing to give an earlier market authorization trusting
on the new pharmacovigilance model and on the condition of pre-agreed post-marketing studies
to be conducted after the approval. However, experience shows that in many cases, there is a
failure of commitment from part of the MAH and many of these studies are not carried out17.
This might reflect the fact that performing randomized controlled studies with an approved drug
is a difficult task, given that not many patients agree to participate in such studies when they can
have access to the same drug by regular care5. So, in a way, an earlier approval could mean a
great difficulty to perform the studies that regulators themselves would like to have to follow
their positive decision on the approval of a drug. Furthermore, by the time these studies are
finished, the drug patent in question is usually also finished, so there is no inconvenience, in
terms of big monetary losses, for the marketing authorization holder.
1.4 Use of electronic healthcare databases
The access to big electronic clinical databases, where information of millions of drug
prescriptions could be linked to healthcare outcomes, provides great opportunities for the
performance of pharmacoepidemiological studies that could assess the benefits and risks of
drugs under real-life conditions18,19. By this, some of the problems of post-marketing studies
could be overcome, given that these studies could extract information based on millions of
patients using the prescribed drugs in a fast and very cheap way18. However, these drug
utilization studies have also many drawbacks, given that they are observational and there is
neither randomization nor blinding in the methodology of the studies and there is ample space
for the introduction of bias in their results20. In spite of the difficulties, it is expected that these
studies will enhance the drug safety process and will also strengthen regulator’s confidence for
drug approvals5.
By using electronic healthcare databases, pharmacoepidemiological studies can address research
questions about the use and effects of drugs and the effects of programs aimed at improving
drug use. Pharmacoepidemiological studies may use data that is prospectively collected for the
purpose of a defined study (i.e. primary data), or data that were already collected for some other
purpose, but that contains useful information for the study (i.e. secondary data)20. It is this kind
of secondary data, especially in the form of electronic medical records and administrative
healthcare databases, that have been growing in use in the recent years for the purpose of
pharmacoepidemiology research, given their wider availability. Their large sample size allows
the study of rare, very rare and/or late drug adverse events, including those derived from chronic
exposure, that might have been otherwise missed in randomized clinical trials (RCTs).
Furthermore, given their longer follow-up time and more representative and wider patient
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population, they provide useful data for real-world effectiveness assessment and utilization
patterns 21.
Observational studies using large healthcare databases can thus contribute to the life-cycle
assessment of drugs complementing findings from RCTs. Although more prone to bias and
lower in the hierarchy of evidence than RCTs, with a clear and comprehensive understanding
about the strengths and weaknesses of the methodology used, the trend of use of these databases
in pharmacoepidemiology research is expected to continue growing in the coming years21.
1.5 Novel approaches for an early access to drugs
There are two novel approaches from drug regulatory agencies for the license of drugs22,23.
These are conditional (in the EU)/accelerated (in the US) approval and staggered approval:
Conditional/accelerated approval: This type of early approval of medicines is reserved for
special situations like seriously debilitating or life-threatening diseases, emerging threats
(WHO, EU commission) or for the case of orphan drugs. It may be granted when there is a high
level of uncertainty about the efficacy or safety of the product, but this is only temporary, and
the benefits of an immediate availability outweigh the risks of requiring additional data. The
approval is given for one year and comes with specific obligations for the MAH to complete
ongoing studies or conduct new studies that might be necessary to confirm a positive benefitrisk balance. In this case, regulators need to be reassured that this information will become
available, with the possibility of applying financial penalties in the case of non-compliance. It is
however a regulatory approach that probably needs further experience in order to see its full
potential.
Staggered approval: This novel approach also known as progressive authorization aims at
providing an early access to medicines with limited clinical experience, for patients with a high
unmet clinical need. It works by granting the license to a narrowed, well-defined subgroup of
patients expected to benefit most from the drug and limiting the prescription of the product to
specific centres of excellence. The indication might later on be expanded to other subgroups of
patients and conditions, once additional clinical data is provided. This regulatory approach is
guided mostly by genotypic and phenotypic biomarkers data that enables to define the first
subgroup of patients most likely to benefit from the drug, and including in further steps, new
subgroups of patients in clinical studies in which the benefit-risk balance can also be positive
(Figure 3)
9
Figure 3. The onion skin model of drug licensing [Eichler H-G. 2011]
1.5 Safety-Related Regulatory Actions
Given the life-cycle approach of drugs, market authorization does not mean the end of drug
development, but the beginning of a continuous evaluation process where actions might be
taken to ensure that the drug’s benefits outweigh its risks during the entire market life. Once a
drug is approved, healthcare professionals start prescribing it and large numbers of patients start
using it. These patients at the clinic may differ widely from those in which the drug was tested;
they are usually not that healthy (they may suffer from comorbidities, or be in a worse state of a
disease etc.) or they might be part of a subgroup of patients not included in the clinical trials
(children, pregnant women, elderly, etc.). As discussed before, this will eventually lead to a
widening variability in drug response. It is therefore inevitably that new adverse drug reactions
will be often identified as time passes. These could have important consequences for the
prescription, use or marketing of the drug.
One of the main components of a risk management plan for a medicinal product includes risk
communication and/or intervention. Therefore, any identified safety risks must be
communicated to health professionals and patients in an accurate and timely manner 24.
Regulatory agencies and the pharmaceutical industry make use mainly of three different safety
warnings to inform healthcare professionals2526:
-
-
-
Dear Healthcare Professional Letters (DHPLs) in the US and Direct Healthcare
Professional Communications (DHPCs) in the EU: These are personalized paper-based
messages to healthcare professionals with the aim of informing clinical practice and
ensuring a safe and effective use of drugs.
A black box warning (US only): Highest level warning issued by the FDA which
consists of a printed framed box in the label of a drug which highlights its potential
risks of severe injury or death.
Market withdrawal of the drug due to safety reasons.
Other forms of safety-related regulatory actions are updates or changes in the labelling of a
drug, Public Health Advisories (US only), and FDA, EMEA and national agencies’ alerts.
10
The number of DHPCs has increased over the last decade and may increase further in the future,
most likely due to several factors such as an overall increased risk awareness, the type of drugs
approved (i.e. orphan drugs, biological) and regulatory processes such as conditional
approvals27. During this time, the impact and effectiveness of the safety-related regulatory
actions, especially of DHPLs and DHPCs, has been questioned28. However, recent studies and
literature reviews have shown that these regulatory actions can have an impact on clinical
practice, although firm conclusions are still difficult to draw, due to methodology drawbacks of
the studies assessing their impact and a lack of consideration of both intended and unintended
effects of these measures29,3031.
2. Aim of this thesis
The antidiabetic drug field has been recently characterized by two main features; an increasing
number of drugs approved during the last years and the emergence of safety concerns of
established drugs that has brought controversial cases and scandals in the medical,
pharmaceutical and drug regulatory world.
The aim of this thesis is to consider the continuous benefit-risk assessment process during the
life cycle of the different novel oral antidiabetics and any safety-related regulatory actions taken
by the competent authorities as well as the factors related to these actions, and discuss the
challenges of this complex process in this group of drugs and possible ways to address the
problems identified.
In order to get a grasp of the complex challenges surrounding the licensing and the evaluation of
benefits and risks of these drugs, it might be useful to look back to some of the cases that have
marked the history of diabetes care. In this sense, we will undoubtedly refer to the case of
glitazones, otherwise known as thiazolidindiones. But we will also address the more recently
approved drugs dipeptidyl peptidase-4 (DPP-4) inhibitors and the glucagon-like peptide-1
analogues (GLP-1 analogues), given the important position that they have gained on the market
of oral antidiabetics during the last years since they were approved.
3. Diabetes Background and Oral Antidiabetic Agents
3.1 Epidemiology of Diabetes
Diabetes has become a very big public health issue in our society nowadays. Only in Europe,
the International Diabetes Federation estimates that in 2013 there were 56.3 million people with
diabetes, and that this figure will increase to 68.9 million by 203532. Worldwide, the estimation
is of 382 million people with diabetes in 2013, and it is predicted to rise to a staggering 592
million by 203532. Furthermore, in 2013 diabetes accounted for 5.1 million deaths globally, and
caused at least USD 548 billion dollars in healthcare expenditure32.
Diabetes mellitus is a group of metabolic diseases characterized by high blood sugar levels over
a prolonged period of time. While Type 1 Diabetes Mellitus (T1DM) is characterized by the
loss of insulin-producing beta cells of the pancreas leading to an insulin deficiency, and can be
classified as immune-mediated or idiopathic, Type 2 Diabetes Mellitus (T2DM) is characterized
by a progressive insulin resistance, a reduced insulin secretion and inappropriately high levels
of glucagon. Patients with T1DM represent less than 5% of the diabetes cases worldwide and
need insulin injections every day in order to control glucose levels32. On the other hand, T2DM
represents up to 95% of diabetes cases worldwide and its treatment is mainly focused on
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lifestyle changes, weight loss and use of oral antidiabetics and/or insulin injections32. It is for
this reason that I will refer to this type of diabetes in the present review.
3.2 Diabetes Treatment
Given that diabetes is a chronic disease, it requires proper life-long lifestyle management and
pharmacological treatment in order to prevent severe acute complications such as
hypoglycaemia or ketoacidosis, long-term microvascular complications such as retinopathy,
nephropathy and neuropathy, and macrovascular complications such as cardiovascular and
cerebrovascular disease33. Although in some cases intensive lifestyle interventions and surgery
in obese patients with T2DM has demonstrated to improve or even cause a remission of the
disease34,35,36, pharmacological treatment remains the main option for most of these patients.
Diabetes therapy has been focused on glucose control, an outcome that is usually evaluated
through the measurement of glycated haemoglobin (HbA1c), which gives information about
plasma glucose levels in the last two to three months. This glucose control has the aim of
reducing complications from the disease, given that a continuous hyperglycemia has been
recognized as one of the main causes of diabetic complications. An intensive glucose control
has been assessed in large studies, where it has shown a reduction in microvascular disease but
not in near-term cardiovascular outcomes, compared to a standard control37. However, in a
longer term follow up of these studies, fewer cardiovascular events were noted, showing
potential benefits even when the intensive control has stopped38. Furthermore, hyperglycemia is
not the only causing factor of complications, and blood pressure control as well as lipid control
are also targets of the current clinical approach33.
4. Methodology
Within the group of oral antidiabetics we find drugs that have already been relatively long on
the market such as biguanides, sulfonylureas, alpha-glucosidase inhibitors, meglitinides and
thiazolidindiones, and other more recently approved drugs such as dipeptidyl peptidase-4 (DPP4) inhibitor, Glucagon-like peptide-1 analogues (GLP-1 analogues), a bile acid sequestrant, a
dopamine agonist and a sodium glucose transport protein-2 inhibitor. Because of the great
importance and how it has marked the history of diabetes drugs, we will review in this thesis the
experience with thiazolidindiones, especially from a regulatory perspective. GLP-1 analogues
and DPP-4 inhibitors will also be addressed, given the importance that they have gained in
recent years since they were approved, getting an important position on the market of oral
antidiabetics nowadays.
A literature research was performed, searching in the databases of MEDLINE and The
Cochrane library for existing publications up to July 2014 using the following terms: glitazones,
thiazolidinediones, troglitazone, rosiglitazone, pioglitazone, glucagon-like peptide-1 analogues,
GLP-1 analogues, GLP-1 analogs, GLP-1 receptor agonists, GLP1R agonists, incretin mimetics,
exenatide, liraglutide, lixisenatide, albiglutide, dipeptidylpeptidase-4 inhibitors, DPP-4
inhibitors, sitagliptin, vildagliptin, saxagliptin, linagliptin, anagliptin, teneligliptin, alogliptin.
All scientific articles and papers published in English that were identified for data source were
assessed, prioritizing systematic reviews and meta-analysis when possible. The references of the
published articles identified were also examined for additional studies potentially useful for the
present review. Safety-related regulatory actions were retrieved from the FDA’s database
MedWatch (http://www.fda.gov/medwatch), from the website of the European Medicines
12
Agency (http://www.ema.europa.eu/ema/) and the website of the Medicines Evaluation Board
in the Netherlands (http://www.cbg-meb.nl). A descriptive analysis of the findings for the
review was performed together with a graphical display of the use of the different drugs during
the last years in the Netherlands and safety-related regulatory actions taken by the authorities in
each case given the available evidence at that moment. Data for the use of the drugs in the
Netherlands were retrieved from the GIPdatabank database (http://www.gipdatabank.nl).
5. Benefit-Risk Assessment of Novel Oral Antidiabetics
5.1 The troglitazone story
Troglitazone was the first approved PPARγ agonist. It was given market authorization by the
FDA in January 1997 as monotherapy for the treatment of T2DM and later extended to
combination therapy with other antidiabetic agents. It was the first drug in its class, a new way
of managing diabetes treatment where, rather than stimulating insulin secretion, the mechanism
of action was enhancing insulin sensitivity by activating peroxisome proliferator-activated
receptors (PPARS)39. Given the novel approach and the high expectations of success, the FDA
granted a six-month fast-track review for the new diabetes pill. The drug was presented as
having several advantages over sulfonylureas, such as better glucose control with less
hypoglycaemic risk and less insulin requirement as well as a convenient once a day
administration40. However, already at the time of approval, concerns were raised to the FDA
committee about potential serious heart and liver damage in animal studies and some elevation
in liver enzymes in patients, but the company made sure to emphasise that the incidence was
comparable to the placebo group (it was later known that at that time the company knew from
pre-marketing studies that patients in the active arm of the clinical trials were 3.6 times more
likely to suffer from hepatic dysfunction compared to the placebo group41).
Later that year, the drug was also approved in Japan and then in the UK and eventually became
one of the fastest selling drugs in history, together with a strong advertisement campaign in the
US42. However, that same year, the FDA started to receive several post-marketing reports of
liver injury. In October 1997, a Dear Healthcare Professional Letter was issued in the US
recommending for liver function tests to be checked and that discontinuation of treatment with
troglitazone had to be done in patients with symptoms of liver damage or continued elevated
liver transaminases. Also, Glaxo Wellcome in the UK (the marketing authorization holder)
issued a Dear Doctor Letter with similar recommendations. The FDA decided to change the
label including safety warnings of “rare cases of severe idiosyncratic hepatocellular injury”43. It
became rapidly clear that troglitazone could cause liver dysfunction in some patients, and in
December that year, Glaxo Wellcome voluntarily decided to withdraw troglitazone from the UK
market explaining that based on the available information, the risks of the drug outweighed its
potential benefits44.
The UK withdrawal did not have short-time big consequences for the US market of the drug,
where sales kept going up and further Dear Healthcare Professional Letters and label changes
took place, advising for a closer monitoring of transaminases levels during treatment and
periodically after it. However, cases of deaths in patients from liver failure as well as liver
transplant following treatment with troglitazone also started to rise45. Despite having a similar
efficacy compared to other antidiabetic agents and despite the mounting death toll associated to
the drug, many doctors continued highlighting the potential advantages of the drug and that it
was essential to many patients for the drug to continue being available on the market. It was not
13
until March 2000, after losing first its approval for monotherapy in 1999, that the FDA
concluded that the benefits from troglitazone were outweighed by its risks, particularly given
the availability of similar drugs with a safer profile, and asked the manufacturer to remove it
from the market. But what is more outrageous is that the data upon which the decision to
withdraw the drug in 2000 was taken, could have been extrapolated from data already available
in 199746. It took 29 months and 11 days since the FDA received the first reports of liver failure
associated with the use of the drug. The agency had confirmed up until that time 63 liver failure
deaths related to troglitazone47. But it would not be the last time that a similar regulatory action
would be taken with years of delay in spite of existing data.
5.2 The controversial rosiglitazone case
Along the first drug of the glitazones class, just when all the safety concerns from troglitazone
were piling up and becoming a serious public health problem, the second PPARγ agonist was
approved. Rosiglitazone hit the US market in 1999 and was quickly heralded as the new hope in
the treatment of T2DM, with the promise of better outcomes and less long-term complications
such as cardiovascular disease. Rosiglitazone was licensed because in terms of efficacy, it had
shown to reduce glycated haemoglobin (HbA1c) by about 1 percentage point which, by that
time, was the only requirement for a diabetes drug to get approval, together with a safe adverse
effects profile48. However, concerns were raised about the short duration of the premarketing
studies, which could not predict the long-term benefit-risk of the drug49. This, together with
other safety issues (a higher LDL-cholesterol concentration and a higher number of ischemic
cardiovascular events in the treatment group), was the reason for a first approval rejection by the
EMA in October 1999. In spite of new evidence, the drug was eventually approved in Europe in
June 2000.
Because of the new mechanism of action, and similarly to the case of troglitazone, rosiglitazone
received an aggressive and strong advertising campaign in the US and it was received in the
medical field as a novel approach and as an important advance in diabetes treatment, with great
expectations of slowing the long-term deteriorations of the disease. It became rapidly another
blockbuster drug for the drugmaker GlaxoSmithKline and eventually the most selling
antidiabetic drug in the world49.
The marketing approval in Europe came nonetheless with restrictions and warnings about its
potential heart failure and the condition for the market authorization holder to conduct two postapproval trials; one to assess the effect of the drug in cardiovascular structure and another one to
evaluate its cardiovascular safety. The second study, sponsored by GlaxoSmithKline and known
as the RECORD trial, was an open-label randomized trial of six years of duration. Some experts
and even the EMA acknowledged the weak methodology of the study and that it did not provide
enough data for testing cardiovascular safety49.
In 2004, the WHO started getting a high number of safety signals from patients taking
rosiglitazone and decided to alert GSK, who in response, conducted two meta-analyses
including all 37 trials until that date using rosiglitazone, on cardiovascular risk (Figure 4). The
first result was a hazard ratio of 1.29 (0.99, 1.89) which eventually became statistically
significant when in 2006 it was updated including now 42 trials, finding a hazard ratio of 1.31
(1.01, 1.70)50. The company informed the FDA and the EMA in 2006, but these results
remained unpublished and kept in secret to the whole medical community and patients.
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In 2007, Steven Nissen published a meta-analysis showing a hazard ratio for rosiglitazone of
1.43 (1.03, 1.98) for myocardial infarction and 1.64 (0.98, 2.74) for death51(Figure 4). His
access to all the data from all the trials involving rosiglitazone was just fortuitous and due to a
court case in New York where GSK settled to publish all its recent clinical studies data online,
on a case where GSK was found guilty of suppressing clinical trial results of children and
adolescents taking the antidepressant paroxetine, which showed an increase risk for suicide.
This meta-analysis published by Nissen brought big public attention to the drug’s safety profile
and both the FDA and the EMA recommended new warnings about its risk on myocardial
infarction and cardiac ischemia, but voted to keep the drug on the market.
In 2009, the results from the RECORD trial were published, showing no significant increased
risk of myocardial infarction52(Figure 4). The FDA assembled an advisory committee meeting
to be held in 2010, with the aim of exonerating the drug, but eventually, in the meeting several
concerns about the methodology of the trials were issued. Thomas Marciniak, an FDA
investigator, particularly highlighted the unblinded design of the study, missed outcomes,
insufficient collection of information, failure to refer cases for adjudication, and the high
number of patients lost to follow-up49. Consequently, a majority of the committee voted either
to restrict the drug or to withdraw it from the market. While in Europe in 2010 it resulted in the
complete ban of the drug, the FDA in the US decided to require the company to implement a
risk evaluation and mitigation strategy (REMS) for the drug and leave it available as a last
resource option. This led to a huge decrease in the use of rosiglitazone globally53,54(Figure 4).
However, the story did not finish there, since the FDA also agreed to let the company
submitting the RECORD trial for “readjudication” by an external research institute at Duke
University. GSK submitted then the same documentation of the original trial analysis for a
reanalysis by the third party, the Duke Clinical Research Institute. Duke agreed eventually with
the conclusions first published, a similar risk of cardiovascular events for the drug and
placebo50. However, doubts remain about this process of readjudication; the FDA official
Marciniak claimed that the institute was operationally and financially supported by GSK and
could not be considered independent, and that the institute did not have access to all the study
reports and patients information that would have been required for a proper evaluation of the
trials55. In spite of all this, the FDA announced on November 25th 2013 that it would remove
most of its restrictions on the drug and that it would not require patients any longer to register in
the REMS program for its use 56. The drug went off patent in 2012.
5.3 Pioglitazone
Pioglitazone, the third PPARγ agonist, was approved in the US in 1999 and in Europe in 2000.
Once again, this drug has been surrounded by a big controversy over its safety profile.
Its approval, like the other glitazones of its group, was based on a reduction of HbA1c of about
1% and a relatively acceptable safety profile shown in the premarketing studies 57. However,
again, its long-term cardiovascular effect was unknown. This comes against the fact that its
biggest selling point has always been its alleged cardioprotective effects. In order to evaluate the
cardiovascular effect of the drug, the PROspective Clinical Trial In MacroVascular Events
(PROactive) was conducted. The study results were published in 2005 and showed beneficial
effects on the lipid profile, blood pressure and glucose levels, but also an increased risk of heart
failure58(Figure 5). Despite being the only study with relevant clinical outcomes, several
methodological weaknesses limited its conclusions (e.g. the study conclusions were based on
15
Figure. 4 Number of patients with a prescription for a product containing rosiglitazone in the Netherlands during the last decade (data
obtained from http://www.gipdatabank.nl) and highlighted events and safety-related regulatory actions taken by the authorities.
the results of secondary outcomes, the control groups received placebo and not a reference drug,
patients included had prior evidence of high cardiovascular risk) 58. A big meta-analysis
conducted later in 2007 and including 99 trials with a total of 16,390 patients showed again a
significantly higher incidence of serious heart failure, while a broad definition of cardiovascular
risk including death, MI, stroke and heart failure did not have any benefit for pioglitazone
users59. Up until date, all the data suggests that its clinical efficacy reducing cardiovascular
events is not clear.
Besides the undemonstrated cardiovascular benefits, pioglitazone has also been associated with
a higher risk for fractures and weight gain6061. However, the biggest controversy regarding its
use revolves around the likely higher risk that it confers to patients for developing bladder
cancer. When it was first approved in the US, preclinical data showed occurrence of bladder
cancer in rats58, but given the short duration of clinical trials, its association with its effects in
humans was unclear. Both the FDA and EMA asked for postmarketing studies in order to
monitor patients on the drug. With this aim, the KPNC cohort study was planned62. Following
the publication of an interim analysis of the KPNC study in 200963, a Risk Evaluation and
Mitigation Strategy (REMS) was implemented in the US, informing that few more cases of
bladder cancer occurred in patients taking pioglitazone compared to other patients taking other
antidiabetic drugs.
In 2011, pioglitazone use was suspended in France and Germany after the publication of the
results of another retrospective cohort study from the French authorities64 (Figure 5). The EMA
also confirmed a small increased risk of bladder cancer (almost a double increased risk for
pioglitazone users, especially those on higher doses, as shown in a large BMJ publication65) but
only recommended restrictions in its use in order to ensure a positive benefit-risk profile. It also
implemented risk minimizations measures and a Dear Healthcare Professional Communication
letter and an update of the risk minimization plan. Although further restrictions and warnings
were added, the EMA still considers that its benefit-risk balances remains positive as a second
and third line option66. Despite new studies, including a new meta-analysis from 201467,
confirming a clinically significant increased risk of bladder cancer for patients taking
pioglitazone for a prolonged period, the drug remains in the market and the FDA continues
evaluating the safety profile of the drug in an ongoing safety review (Figure 5).
5.4 Glucagon-like peptide-1 analogues (GLP-1 analogues)
In 2005, the first glucagon-like peptide-1 analogues (GLP-1 analogues), also known as GLP-1
receptor (GLP-1R) agonists, were approved for commercialization and introduced into clinical
practice in the US. Although they are not orally taken, but subcutaneously injected, they remain
a new interesting approach in the treatment of T2DM. The principle behind their actions is
based on the physiological effects of the type-1 glucagon-like peptide (GLP-1), a
gastrointestinal hormone that is secreted shortly after food ingestion and that leads to insulin
secretion stimulation, glucagon secretion inhibition and also slows intestinal motility and
promotes satiety among other effects68. Because of the several potentially beneficial effects for
diabetic patients that they carry, these drugs were presented as a new generation of antidiabetic
drugs with the potential of improving glucose controls without the risk of hypoglycaemia while
promoting weight loss and improving cardiovascular parameters68.
Figure 5. Number of patients with a prescription for a product containing pioglitazone in the Netherlands during the last decade (data
obtained from http://www.gipdatabank.nl) and highlighted events and safety-related regulatory actions taken by the authorities.
GLP-1 has a short half-life due to the rapid degradation by the enzyme dipeptidyl peptidase 4
(DPP-4) and rapid renal elimination69. Because of this short half-life, GLP-1 analogues resistant
to the degradations by DPP-4, as well as DPP-4 inhibitors (see section 4.7) were developed.
Exenatide was the first GLP-1 analogue approved by the FDA in 2005 and in Europe in 2007
for the treatment of DMT2. It was followed by liraglutide, which was approved in Europe in
2009 and in the US in 2010, lixisenatide, approved in Europe in 2013 and albiglutide approved
both in Europe and the US in 2014. They differ not only in their structure, but also in their
pharmacokinetic profiles, being classified as short-acting or continuous-acting68.
In terms of efficacy, RCTs have shown that all GLP-1 analogues reduce HbA1c levels by about
1%, lead to greater weight loss than most of active comparators and had a lower risk of
hypoglycaemia70. They also cause nausea as the main adverse event, although none of the
studies published so far has been long enough to evaluate long-term effects of these drugs70.
Nevertheless, there are serious safety concerns surrounding their use. On the one hand, data
from preclinical studies showed an increased risk of thyroid cancer in rodents treated with
liraglutide, although the relevance of these results for humans have been questioned71. Given the
low incidence of thyroid cancer in the general population, it is not feasible to conduct a clinical
trial to detect an increased risk of this cancer in patients taking the drug71. Instead, calcitonin is
used as a biomarker for the detection of thyroid cancer and this hormone was monitored during
clinical trials, showing a slight increase in patients taking liraglutide72. Although this increase
did not represent a higher risk for thyroid cancer, the FDA has required additional studies in
animals and launched a cancer registry to monitor the annual incidence of this cancer in the next
15 years73.
Another safety concern regarding the use of GLP-1 analogues was a high number of cases of
pancreatitis in clinical trials74. Although the small numbers of cases made it difficult to draw
any firm conclusions about the causation, the concern started to arise as well from postmarketing reports submitted to the FDA in 2007 and 2008 associated with the use of exenatide
(Figure 6). This led the FDA to require the sponsor to highlight the serious potential risks in the
drug’s label and to conduct further postmarketing animal studies and epidemiological studies to
assess whether the risk becomes clinically significant for patients taking the drug73. On the other
hand, the EMA conducted a review in July 2013 on all GLP-1 based therapies (including DPP-4
inhibitors) and found some concerns regarding an increased risk of pancreatitis with the use of
these drugs, but decided that the number of events were too small to draw firm conclusions and
decided to keep monitoring the potential safety risks of these drugs without further changes in
the label or restrictions75.
Lastly, there is still the question whether these drugs might increase cardiovascular risk. Even
though a growing body of evidence suggests that they might have beneficial cardiovascular
effects, the truth is that available data from RCTs remain insufficient, as most of the studies
performed so far have focused on surrogate outcomes and have not been long enough to discard
any harmful long-term effects derived from their use76. The FDA required therefore a
postmarketing study of cardiovascular safety. It also approved a risk evaluation and mitigation
strategy (REMS) in order to inform and educate healthcare professionals about the potential
serious effects associated with this group of drugs.
5.5 Dipeptidyl Peptidase-4 (DDP-4) Inhibitors
Working in a similar way as GLP-1 analogues, dipeptidyl peptidase-4 (DPP-4) inhibitors, also
known as incretin mimetics, are another group of oral antidiabetics that work inhibiting the
degradation of several peptides known as incretins, such as the above explained GLP-1,
extending thus their biological activity, among which is the stimulation of the secretion of
insulin from the pancreas after food intake. The first agent of this class was sitagliptin, approved
by the FDA in 2006 in monotherapy or combination with other antidiabetic agents. It followed
later some other drugs from the same class; vildagliptin in 2007, saxagliptin in 2009, linagliptin
in 2011, anagliptin and teneligliptin in 2012 and alogliptin in 2013.
Their approval was primarily based on a reduction in HbA1c levels, which was similar to that of
sulfonylureas77. However, some of the advantages of these drugs are that, given their glucosedependent effect, they do not increase the risk of hypoglycaemia and they do not increase
weight7879. Furthermore, even when the long-term cardiovascular safety cannot be established
based on clinical trials, large meta-analyses of pre-marketing studies all pointed to the direction
of a reduction of cardiovascular events in patients taking a DPP-4 inhibitor8081. They also
showed an overall good safety and tolerability profile, where only dose-adjustments had to be
done for those drugs of the group which are excreted mainly via the kidneys in patients with a
decreased renal function82.
Early after approval, data from post-marketing studies started to indicate some rare cases of
severe hypersensitivity reactions and acute pancreatitis83, 83,84. Especially worrisome was the
potential association of the use of these drugs and acute pancreatitis. Between 2006 and 2009,
88 cases of acute pancreatitis were reported to the FDA’s Adverse Event Reporting System
(AERS)84. These led both the FDA and EMA in 2009 to add pancreatitis to the summary of
product characteristics as a potential side-effect and inform healthcare professionals about the
potentially serious side-effect and considerations to be taken for the prescription, such a close
monitoring for the emergence of signs and symptoms (Figure 7).
In 2013, both the FDA and the EMA communicated they were also evaluating unpublished new
findings of an increased risk for pancreatitis and pancreatic cancer in patients with T2DM
treated with incretin mimetics and DPP-4 inhibitors8586 (Figure 7). The EMA also informed that
the SAFEGUARD trial, a study carried out within the European Network of Centres for
Pharmacoepidemiology and Pharmacovigilance (ENCePP), is investigating drug-induced
pancreatitis for GLP-1 based drugs. Although the EMA announced shortly after that year that
the numbers of events were too small to draw firm conclusions and that the drugs of this class
still have a positive benefit-risk profile, up until date both agencies are still evaluating this
potential safety issue with new and ongoing studies75.
With regards to cardiovascular outcomes, one study published in October 2013 and called
EXAMINE, which only included patients with T2DM who had a recent acute coronary
syndrome, showed that the rates of major cardiovascular events were not higher in patients
taking alogliptin compared with placebo87. However, early this year 2014 and following a
publication of a study in the New England Journal of Medicine also in October 201388, the FDA
communicated that it is currently investigating a possible association between the use of
saxagliptin and an increased risk of heart failure89. The study did not report an increased rate of
death or other cardiovascular outcomes, but showed a 27% increased risk for heart failure that
came from the SAVOR-TIMI 53 study, a placebo-controlled clinical trial designed to evaluate
20
the safety and efficacy of the drug regarding cardiovascular outcomes in patients with T2DM at
risk for cardiovascular events. Furthermore, the FDA informed that this analysis is part of a
broader ongoing evaluation of all T2DM drug therapies and cardiovascular risk89.
6. Current challenges in the evaluation of diabetes medication
There are several issues surrounding the complex process of evaluating the benefit-risk profile
of oral antidiabetic drugs.
6.1 Surrogate outcomes
The treatment of diabetes has been focused on the control of glucose levels in order to prevent
complications from the disease. In this sense, when drugs such as rosiglitazone and pioglitazone
were approved, the only regulatory requirement for market authorization was focused mainly on
a surrogate outcome: glycated haemoglobin (HbA1c). The assumption was that results based on
HbA1c control would transform into improvement in health outcomes, like a reduction of the
risk of cardiovascular disease or death. However, experience has shown that drugs have many
effects and in many occasions, this assumption does not hold; we cannot infer how a drug
affects clinically significant health outcomes, like mortality or quality of life, based on the
beneficial effect on one single biomarker.
Clearly there are several advantages when surrogate endpoints are used in clinical development
instead of real clinical outcomes; clinical trials become shorter in time, smaller in size and more
cost-effective90,91. This is more attractive to pharmaceutical companies and it gives the false
reassurance that we can accelerate the approval of effective medicines for society in order to
meet public health needs. However, the problem comes when this assumption is taken for
granted and regulatory agencies do not demand further evidence on long-term effects, like in the
case of rosiglitazone. It is becoming clearer that stronger evidence has to be demanded from
authorities in order for an antidiabetic drug to get approval. In addition, proper post-marketing
studies with high standard methodology must be undertaken right from the beginning of the use
of the drugs in the real healthcare setting, in order to continuously evaluate the safety and
effectiveness of these medicines.
In light of the glitazones controversy, the FDA started in 2008 a new guidance with
recommendations for the conduct of clinical trials testing new antidiabetic drugs, including
measures to take for the evaluation of cardiovascular safety92. Although these recommendations
represent a progress in the process of assessing cardiovascular safety for new antidiabetic
therapies, they still are nonbinding recommendations for industry and not a legal requirement
for getting approval. Furthermore, it suggested that phase III clinical trials of new antidiabetic
drugs should show that the increased cardiovascular risk is not higher than 80% 93. This excess
risk remains incredibly high when compared to the likely decrease of 10% in the risk of
myocardial infarction for a 1% reduction in HbA1c94. Given the uncertain long-term effects
experienced with drugs designed for a tight glucose control, it would be needed not just proof of
cardiovascular safety, but of cardiovascular benefit in the long term, since this remains the most
important goal of diabetes therapy.
21
Figure 6. Number of patients with a prescription for a product containing a GLP-1 analogue in the Netherlands during the last decade (data
obtained from http://www.gipdatabank.nl) and highlighted events and safety-related regulatory actions taken by the authorities.
6.2 Data availability
The case of rosiglitazone exemplifies the importance that complete clinical trial data access has
on the assessment of the safety of drugs currently on the market: In response to the high number
of spontaneous reports that the WHO was getting associating rosiglitazone with heart problems,
the manufacturer GSK conducted two meta-analyses with their own data in 2005 and 2006,
which confirmed the increased cardiac risk. However, even though both GSK and FDA were
aware of the information, the results were not published until 2008. Interestingly, in the
meantime, a fortuitous release of all study level data by the manufacturer as part of a legal
settlement of a court case in the US, GSK was required to commit to publish all clinical trial
results on a public website. This allowed Nissen to perform the meta-analysis that first showed
an increased risk for myocardial infarction and death in patients taking rosiglitazone and
eventually led to the suspension of the drug in Europe and severe prescribing restrictions in the
US. Had this information been available from the beginning, regulators might have been more
cautious about their decisions, but also, doctors and patients could have made informed
decisions about the benefits and risks of the drug.
Even when some progress is currently being made in this area of clinical data access, mainly on
account of the big “All trials” campaign95, started by Ben Goldacre and where up until date over
79,000 people and 480 organizations from around the world have joined, clinical trial data
availability still remains an issue when assessing the benefit-risk profile of drugs.
6.3 Alternative treatments
There are several oral agents available to control glucose levels. Some of them have been on the
market for a long time and we have a lot of clinical experience with them, e.g. metformin was
approved by the FDA in 1994 and it remains the first-line pharmacological therapy of choice in
patients with T2DM, having shown to prevent cardiovascular complications of the disease 96.
Given the wide variety of drugs already on the market that lower blood sugar, is it really
necessary to approve more drugs – unless they can show long-term improvement of outcomes
or clear benefits over other alternatives?
It is important to note that, given the worldwide burden of diabetes and the use of these drugs by
millions of patients, even a small increased risk for a serious adverse effect becomes
significantly important. Regulatory agencies should take into account available alternatives on
the market for a given public health need, for which there is long-term experience and similar
benefits in order to make sure that patients do not take avoidable risks when starting on
treatment with a new antidiabetic drug for which the long-term effects are uncertain. With all
the drugs available at the moment, it would be reasonable that regulators start asking for more
robust and definitive evidence of long-term benefits, even if that implies delaying the approval
of other several new drugs in the pipeline expected to appear in the next years.
Figure 7. Number of patients with a prescription for a product containing any of the approved DPP-4 inhibitors in the Netherlands during the last
decade (data obtained from http://www.gipdatabank.nl) and highlighted events and safety-related regulatory actions taken by the authorities.
6.4 Methodological quality of studies
The case of rosiglitazone is rather exceptional. Even though the drug had been on the market for
more than ten years, with billions of dollars of sales and so much real patient experience with
the drug, most of the studies were not specifically designed to assess cardiovascular problems
and thus the data on this is unpredictably inaccurate. There is also the problem that regulators
had tolerated high rates of loss to follow-up in several studies evaluating the effects of the drug
on surrogate outcomes49. Unless proper post-marketing studies, with the highest level of
methodology are set and carried out right after the approval of the new oral antidiabetic drugs
that are coming to the market, it would be not possible to evaluate their most accurate benefitrisk profile.
6.5 Drug companies and regulatory agencies’ performance
Although there have been improvements in manufacturers’ commitment to conduct postmarketing studies in the last years, a recent study published in JAMA found that more than 40%
of these studies had not been started in 2011, according to FDA figures 97. This remains a great
challenge nowadays, given that the real benefit-risk profile of a drug, especially concerning
safety issues, can only be determined by large, long-term studies usually only conducted after
approval for commercialization. It is also obvious that drug companies have every interest in
delaying as much as possible the time of publication of the final results of these studies, in order
to maximize profits until that time in case any negative outcome comes up from these studies.
However, it is also complicated to decide what actions to take should companies not adhere to
such commitments. As Eichler H-G. points out, if no actions are taken, it could undermine the
system, while suspension or restriction of the authorization based on a lack of new evidence
would be difficult to support, especially in the view of patients and healthcare providers5.
There is also the problem that controversial cases such as the one of rosiglitazone can be seen
by the public as a regulatory failure by the authorities and, as Nissen suggests, these agencies
might react with the aim of clearing their image from any implications of bad decision
making50. In a letter published at the BMJ, researchers Garattini S. and Bertele V. explain that
there is a current sort of conflict of interest when the same regulatory agency is responsible for
both the drug approval and post-marketing pharmacovigilance of medicines, and propose to
create a new independent safety evaluation agency with the main role of post-marketing
pharmacovigilance 98. Such a new agency, they explain, could carry out different tasks such as
auditing companies’ commitments to post-marketing studies, taking the appropriate regulatory
decisions, gathering all collected safety information and making decisions based on the
evaluation of this information. Although there are not any current known efforts aimed in this
direction, it seems a good initiative that should be considered in the near future.
6.6 Patients’ preference
Patient preference is another factor to take into account when evaluating the benefits and risks
of an antidiabetic drug. Patient preference, mainly based on medication-related side-effects such
as weight-gain and cardiovascular risk, has been shown to be associated with medication
adherence and therefore plays a big role in the success of the therapy in many diabetes
patients99. Furthermore, another study found that net treatment benefits of antidiabetic therapies
varied widely depending most importantly on the patient’s view of the burden of the specific
treatment considered100. A new approach, where patient values are taken into consideration,
appears thus to the best new model in order to make the best decision on the proper diabetes
management for the patient.
6.7 New targets in diabetes
In spite of the glycemic control achievable today through reduction of HbA1c levels, the risk of
diabetes complications remains too high. It is becoming clear that new and better approaches in
diabetes treatment must be identified in order to improve diabetes care and reduce
complications of the disease. Some researchers have proposed a new hypothesis whereby
overall blood glucose variability, with its variations over time into hyper- and hypoglycaemia,
might represent a risk factor for complications not captured by the standard measurement of
HbA1c levels101. There is still little data available to support this hypothesis and there is no
common method yet to quantify glycemic fluctuations, but new studies will analyze this
possible role that it might play in association with the development and progression of diabetes
complications.
7. Conclusions
The analysis of the different benefit-risk assessment scenarios of the new oral antidiabetics seen
in this review and the safety-related regulatory actions taken by the authorities highlights the
complexity of the whole process while giving us some points for reflection.
- It will always be a difficult task to judge how much evidence is enough, but one thing is clear:
once a drug has come into the market, it might take years until many case reports are gathered
or a proper meta-analysis is conducted, upon which the authorities might take regulatory action,
even when the first safety signal came up years before. While postmarketing case reports are
usually enough evidence for the regulatory agencies to make a safety warning or a label change
of a drug, only methodologically sound studies, especially meta-analyses, seemed to lead to
further regulatory action, such as prescription restrictions or market withdrawal.
- The focus on surrogate end points, such as the reduction of glycated haemoglobin, as a
benchmark for marketing approval of antidiabetic agents has been proven to be inadequate.
While glucose control remains the main objective of diabetes therapy, cardiovascular safety has
become the new objective of novel therapeutic approaches, in order to avoid situations like the
one seen with the rosiglitazone case. The new guidance for industry published by the FDA in
2008 highlights this need, recommending drug makers the use of cardiovascular endpoints
during the clinical development of new antidiabetic agents and the planning of large postmarketing cardiovascular outcome studies when a large uncertainty remains at time of approval.
- Given the current wide range of options within the antidiabetic field and all the experience
with safety concerns that emerged during the last years, it would not be rational to give free way
to new antidiabetic agents that have not proven to be beneficial in the long term or have any
unique advantages over existing medications. However, we should not forget that given the
intrinsic characteristics of pre-marketing clinical trials and the differences with the real
healthcare practice situation, very rare adverse drug reactions and long-term adverse effects will
most likely not become a thing of the past, especially within the antidiabetic field, where drugs
are taken chronically by patients for very long periods of time. In order to properly assess any
changes of the benefit-risk profile of new antidiabetic drugs, methodologically sound postmarketing studies, especially pharmacoepidemiological studies making the best use of
electronic healthcare records, should be conducted right after approval, combining all available
26
evidence from clinical trials and post-marketing studies, ensuring when possible that these
studies are independent from pharmaceutical companies.
- With this same aim, current efforts to ensure publication of all existing evidence of all
available drugs by pharmaceutical companies and regulatory agencies to the medical
community and the general public must be supported. Only with all the evidence, proper clinical
evaluations will be possible so that the right regulatory decision at the right moment is taken in
order to ensure a positive benefit-risk profile of the drugs.
- With regard to the safety profiles of pioglitazone and the most recently approved GLP-1
analogues and DPP-4 inhibitors, important concerns about potential serious adverse effects
associated with their long-term use remain. Even when the benefit-risk balance of these drugs
remains to be judged as positive, clinicians and patients should weigh their benefits and risks
compared with the available alternatives, in order to make an informed shared decision to
manage diabetes the best way that could fit every patient.
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