|European Pharmaceutical Contractor
| Three new drug applications for weight management products were filed in 2010 with the US FDA, but to date none have been approved. In addition to the drug being promising, the safety profiles must fulfil certain criteria in order to pass the test.
Over the last few years, the US Food and Drug Administration’s (FDA)
regulatory activities related to drugs for obesity have been dynamic.
In 2010 alone, the FDA’s Endocrinologic and Metabolic Drugs Advisory
Committee (EMDAC) reviewed three new drug applications (NDAs) for:
naltrexone/bupropion; lorcaserin; and phentermine/topiramate
(PHEN/TPM).These products have so far gone unapproved. Another
significant regulatory action occurred in September 2010 when the FDA
held a public meeting to review data from clinical trials for the
approved weight loss drug Meridia (sibutramine).The EMDAC members
responded critically to the results of the Sibutramine Cardiovascular
Outcomes (SCOUT) trial, with half the committee members voting to
support the removal of the drug from the US market. Within two months
of this meeting, the sibutramine sponsor, Abbott Laboratories,
voluntarily withdrew the product from the US market.
In all of their meetings last year, members of the EMDAC reviewed both
safety and efficacy data; however, safety issues, particularly
cardiovascular risk profiles,were a specific focus. All the trials
submitted as the basis for gaining FDA approval were randomised and
placebo-controlled.When examining the committee’s comments during the
public meetings, several commonalities emerge, despite the differences
in the chemical formulations of the products. Similar concerns were
highlighted years before at a 2007 public meeting on the weight loss
drug rimonabant (Sanofi-aventis). At that time, the advisory committee
unanimously refused to support approval of the product, mostly due to
the lack of available safety data on the drug, and the committee
highlighted some trial design issues, namely long-term data.
Approved, But With a Catch
The regulatory processes relating to the safety evaluation of
sibutramine also highlighted particular safety and efficacy concerns
that have emerged as primary considerations in the approval of obesity
drugs. Sibutramine was approved as Meridia in 1997 for the management
of obesity, including weight loss and weight loss maintenance, when
combined with a reduced-calorie diet.This indication is very similar to
those named in the NDAs reviewed in 2010.
At the sibutramine public meeting in 2010, EMDAC members reviewed data
from the SCOUT trial. SCOUT was part of a postapproval commitment
between the European Medicines Agency (EMA) and the manufacturer. Begun
in 2002, SCOUT was designed to show that weight loss with sibutramine
and standard care was more effective in reducing the number of
cardiovascular events when compared to weight loss from a placebo and
Following their evaluation of data from SCOUT, the EMDAC voted to
support the removal of sibutramine, citing its modest efficacy for
weight loss and evidence of cardiovascular risks.The committee also
stressed that the SCOUT data offered no evidence that weight loss
achieved by use of the drug results in any of the health benefits
associated with weight loss achieved through diet and exercise (for
example, reduction in diabetes or sleep apnea). In addition, the data
failed to identify a particular subgroup of patients benefitting from
sibutramine that would justify keeping the drug on the market.
Committee members who supported continued marketing of the drug with
revised labelling and boxed warnings stated that the failure of the
data to show health benefits was due to the trial’s design. They
stressed that consumers should not lose access to a drug due to
researchers’ failure to design a trial that identified health benefits,
and indicated that combined with an effective risk evaluation and
mitigation strategy (REMS), the drug could remain on the market safely.
EMDAC members stated repeatedly they were unable to respond to FDA
questions about sibutramine due to lack of data.The agency had asked
whether the risk for major adverse cardiac events (MACE) could be
mitigated through the monitoring of body weight, blood pressure and
pulse.While a patient’s pulse is an important factor when analysing
MACE risk, there were no data presented at the meeting to support that
monitoring of pulse would help to mitigate the cardiovascular risks
associated with sibutramine.Panel members stipulated that if the drug
were to remain on the market, tools would be needed to help identify
patients at risk before the drug was prescribed.
Back to the Drawing Board
In all EMDAC obesity drug meetings, cardiovascular risk has been a
prevailing discussion prior to and after the review of sibutramine.This
is reflected in the statements made by committee members regarding
PHEN/TPM (proposed trade name Qnexa), the first obesity drug reviewed
in 2010 as part of an NDA.This product was sponsored by Vivus, Inc and
proposed as an adjunct to diet and exercise for weight management.
However, several other common safety and efficacy issues begin to
appear when the discussions were compared.
While the committee generally supported the efficacy of PHEN/TPM, their
concerns regarding the cardiovascular implications, as well as the
potential for cognitive and teratogenic adverse effects, resulted in a
negative recommendation. All panel members agreed on the need for
long-term data given the trend of those who lost weight gaining it back
within a few years following discontinuation of therapy. The trials did
not include adequate numbers of participants with comorbid conditions
and the committee recommended modifications to trial design to account
for this deficiency.
More Information Needed
The next product reviewed in 2010 was lorcaserin (proposed trade name
Lorquess), a new molecular entity (NME) proposed as a weight management
treatment for obese patients when combined with diet and exercise. In
their review of this product, several EMDAC members called the drug
promising, however, overall the committee concluded that the data
presented did not provide enough convincing evidence of efficacy and
safety to merit approval. Population-related deficiencies in the
pivotal clinical trials were again seen as an issue.
Where PHEN/TPM had included a population representative of
comorbidities seen in the target population, lorcaserin did not meet
this prerequisite. A frequent criticism made by EMDAC experts was the
lack of diversity in the Phase 3 trial population leading to the
conclusion that such a narrow population might result in efficacy of
the drug being overstated, while any potential safety risks were
understated. It was noted that while lorcaserin data did meet FDA
efficacy criteria minimally, the merits of that evidence were tempered
by the lack of realworld information on patients with significant
comorbid conditions (such as diabetes, hyperlipidaemia and
cardiovascular disease). As with PHEN/TPM, the committee recommended
studies with a broader population and, due to concerns about the risk
to cognitive function, also recommended further studies that included
subjects with major depression and other mood disorders, prior to
There was concern over lack of data on the interaction of lorcaserin
with other drugs, as weight loss drugs are frequently used in
combination with other agents.This was particularly the case regarding
concomitant use with drugs that are known, or suspected, to carry risks
for valvular heart disease (VHD). Another safety consideration was that
animal data on cancer risk were not well-correlated with that potential
Unique among the other NDAs for obesity drugs reviewed by EMDAC, the
naltrexone/bupropion product (proposed trade name Contrave) from
Orexigen Therapeutics, Inc, earned considerable support by the
committee members. The limited treatment options for the current
indication was noted by several members in the justification of their
decision, a significant point considering that the outlook for obesity
treatments had not changed over the year prior to this meeting.
Panelists who did not favour the risk-benefit profile stated that the
efficacy findings were inadequate and long-term data (beyond one year
of treatment) were lacking.
Panelists on both sides of the vote strongly supported the need for
further characterisation of the agent in an additional randomised
clinical trial to provide a thorough assessment of its cardiovascular
risk profile, and agreement on at least a study protocol prior to the
approval of Contrave.Differences were seen when discussing when those
studies should occur. Members who favoured a post-approval clinical
outcomes trial expressed concern that it would require a considerable
amount of time and resources to conduct trials pre-approval and thus
delay a much-needed drug.
One of the safety issues of interest in the Contrave review was the
various outcomes observed in the clinical programme related to blood
pressure, pulse and major cardiovascular events including
death,myocardial infarction (MI), and cerebrovascular accident (CVA).
It was because of data indicating an increased risk of MI and stroke
that the FDA requested the voluntary removal of sibutramine from the US
market.Yet, the Phase 3 trials using the same cardiovascular outcomes
for Contrave were deemed adequate by some committee members to allow
for postmarket qualification. With sibutramine, significant concern was
noted in the inability to isolate a population for which the drug was
safe, tipping the balance of risk overshadowing benefit. Without
defining the population at risk, there is no way to mitigate the risk.
The minority of EMDAC members in favour of clinical characterisation of
cardiovascular safety of Contrave prior to approval noted that drug
effects on interim or surrogate markers, such as blood pressure and
pulse,may not translate into clinically significant outcomes from
treatment (such as reduction in morbidity and mortality from obesity).
The inclusion of higher risk populations, such as ethnic minorities,
individuals with comorbidities, and those on multiple medications in
additional studies,were recommended. All of these issues were noted in
previous NDA reviews. The review of panel discussions on Contrave
highlights the differences in committee opinions for this product when
compared to those from previous drug reviews.
The undefined population and cardiovascular risk noted in other product
reviews were seen as deficiencies that warranted study prior to
approval.The reasons for differences in the committee’s ultimate
recommendation for Contrave compared to other products are not easily
determined. However, the comparison of voting patterns indicates only a
slight margin in favour of Contrave while the previous NDA reviews from
2010 had only a slight margin against supporting approval.
Regardless of the particular issues related to voting patterns by
individual committee members, the fact remains that similar issues have
emerged during public meetings on NDAs for weight management products.
A simple comparison of issues raised by committee members may explain
the ultimate recommendation for approval for these products (see Figure
1 and Table 1, page 84).
In addition to cardiovascular risk, psychiatric events and
comorbidities in the target populations were chief among the concerns.
It may be the number as well as the types of risks associated with the
product that lead a committee to a certain conclusion. In all of the
products reviewed, not only was cardiovascular risk considered, but
also the paucity of data regarding the characterisation of a target
subpopulation in the very diverse, high-risk obese and overweight
patient population. In each review, the committee recommended further
studies to meet this end. In the case of Contrave, the overall safety
profile combined with the lack of therapeutic alternatives in the wake
of the sibutramine withdrawal may have weighed in on the ultimate
decision. It remains to be seen if the committee’s opinion figures into
the final regulatory actions made by the FDA.
Read full article from PDF >>
|Rate this article
||You must be a member of the site to make a vote.
| || || || || ||
News and Press Releases
Capsugel Awarded EXCiPACT™ Certifications for Excipient Good Manufacturing Practices
Morristown, N.J., October 1, 2014 – Capsugel announced today that
it has received EXCiPACT™ certification for its sites in Bornem,
Belgium, and Colmar, France. The certification provides independent
validation that Capsugel maintains excipient Good Manufacturing
Practices (GMPs) and complies with current European Union regulations in
the manufacturing of empty, two-piece hard capsules. Capsugel is the
first hard capsule manufacturer to receive EXCiPACT™ certification.
More info >>
Sourcing Commercial Drugs for Clinical Trials: US vs. EU Understanding the Differences
Sourcing commercial drugs for clinical trials is a dynamic process. There are many factors to consider: single source or regional sourcing, strategy, price, supply availability, lead times, and documentation are just a few. In the past, there were fewer clinical trials that required commercial drug sourcing, so demand was not as high. Today, the demand for commercial drugs in clinical trials has greatly increased and, as a result, inventory is tighter, orders are monitored more closely by manufacturers, and lead times have increased. This report highlights the key differences in sourcing from the US and EU.
More info >>
Partnerships in Clinical Trials
5-6 November 2014, CCIB, Barcelona, Spain
Creators, innovators, storytellers and rising
stars will come together at the 13th
Annual Partnerships in Clinical Trials Congress, 5-6 November 2014 at the
CCIB, Barcelona, Spain to provoke change and demand solutions to advancing
clinical trial collaborations.
More info >>