[e-drug] FDA and Lotronex (alosetron)

[Kirsten Myhr <myhr@online.no>]

E-drug: FDA and Lotronex (alosetron)
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Lancet 2001; 357 no 9268, 19 May had the following commentary about a 
controversial drug, alosetron. The commentary ends by questioning the role 
of the regulatory authority in pharmacovigilance (postmarketing 
surveillance, adverse drug reactions monitoring). A comment from Alec 
Walker, only to be found on the web, is copied at the end.
Lotronex and the FDA: a fatal erosion of integrity
In March last year, The Lancet published the results of a randomised triel 
reporting that alosetron (Lotronex, GlaxoWellcome) "was well tolerated and 
clinically effective in alleviating pain and bowel-related symptoms" in 
women with irritable bowel syndrome.1 Michael Camilleri and colleagues 
described their findings as "important". Indeed, irritable bowel syndrome, 
although not life threatening, can be severely disabling. Lotronex was an 
early example of a new class of drug for irritable bowel, the 5-HT3 
antagonists. This apparent pharmacological breakthrough has generated an 
explosion of new research interest in functional bowel disease.2
Camilleri and colleagues also found that one in ten patients taking 
Lotronex withdrew from the trial because of constipation, but they argued 
that this symptom was not "perceived as a negative consequence" of 
treatment. They concluded that "No serious drug-related adverse events or 
deaths were reported during the study". A single case of ischaemic colitis 
was, they wrote, misdiagnosed.
Lotronex was licensed by the US Food and Drug Administration (FDA) in 
February, 2000. By November, GlaxoWellcome had voluntarily withdrawn 
Lotronex from the market. At least five people had died after taking the 
drug. Yet many within the FDA's leadership now want to bring Lotronex back. 
An advisory committee meeting set up to do so is being planned for June or 
July. This story reveals not only dangerous failings in a single drug's 
approval and review process but also the extent to which the FDA, its 
Center for Drug Evaluation and Research (CDER) in particular, has become 
the servant of industry.
New drug application 21-107 (alosetron hydrochloride) was submitted to CDER 
on June 29, 1999, and assigned priority review. 7 months later, Victor 
Raczkowski, deputy director for the FDA's Office of Drug Evaluation dealing 
with Lotronex, wrote to inform GlaxoWellcome that, in the FDA's view, 
Lotronex was "safe and effective for use as recommended". He also reminded 
the company of its commitment to "A large, long-term (1 year) population 
risk trial to assess the incidence of colitis in patients receiving 
alosetron". The FDA was clearly anxious about the drug's risk profile. The 
printed labelling accompanying Lotronex warned about the possibility of 
acute ischaemic colitis but noted that such cases "resolved over several 
days to weeks without sequelae or complications".
Glossy six-page advertisements in specialist medical journals claimed that 
Lotronex had "a favourable safety profile and [was] generally 
well-tolerated". The advertisements did, however, mention the problem of 
ischaemic colitis, although the warning emphasised that a causal connection 
between the drug and this adverse event was uncertain. By July, 2000, 
concerns about the balance of risk and benefit were being voiced.3 Between 
February and June that year, seven patients had developed serious 
complications of constipation, three of whom required surgery. Eight 
further cases of ischaemic colitis were reported. The FDA had an 
opportunity then to take stock of its earlier decision. The clinical data 
confirmed the substantial and potentially life-threatening risks hinted at 
during pre-approval review. But instead of withdrawing Lotronex and calling 
for more evidence, the FDA issued a medication guide designed to warn 
patients of escalating risks, while keeping the drug on the market.
This decision was to prove fatal. On Nov 28, GlaxoWellcome withdrew 
Lotronex from the market after the deaths of five patients taking the drug. 
There had been 49 cases of ischaemic colitis and 21 of severe constipation, 
including instances of obstructed and ruptured bowel. In addition to the 
deaths, 34 patients had required admission to hospital and ten needed 
surgery. A letter from Janet Woodcock, director of CDER, declared that the 
"FDA is committed to working with pharmaceutical sponsors to facilitate the 
development and availability of treatment options for patients with IBS". 
There was no word of sorrow or regret for the families of those who had 
died.
The course of these events can be followed through documents posted on the 
FDA's website (www.fda.gov). But what these press releases, talk papers, 
and letters do not reveal is the internal struggle and suppression of 
dissenting opinion that took place within the FDA once reports of serious 
complications and deaths began to come in. An evaluation of Lotronex's risk 
profile in the summer of 2000 found that the warning in the proposed 
medication guide was impracticable. The new guidance would be that women 
should stop taking Lotronex if they experienced "increasing abdominal 
discomfort". But since abdominal pain is a cardinal symptom of an irritable 
bowel, FDA scientists argued that it was unreasonable to expect either 
patients or their physicians to judge pain as an early warning of possibly 
fatal ischaemic colitis. This view was dismissed by FDA officials. The 
scientists who raised these issues felt intimidated by senior colleagues 
and were excluded from further discussions about Lotronex's future. 
Instead, the FDA preferred to support a series of epidemiological studies 
into ischaemic colitis and constipation. An independent review of these 
research protocols revealed profound flaws in their design. A more rigorous 
research proposal from one FDA scientist was ignored.
A memorandum dated Nov 16, 2000, and disclosed through the Freedom of 
Information Act by US Public Citizen's Health Research Group, shows the 
extent of FDA scientists' concern.4 The company believed that the risk of 
Lotronex could be managed safely by looking for warning symptoms. But the 
note from FDA scientists to Lilia Talarico, director of the Division of 
Gastrointestinal and Coagulation Drug Products, explains that "Early 
warning of the dire side effects of this drug is clearly not feasible". The 
scientists state that "the sponsor [GlaxoWellcome] has not identified a 
subset of women who will respond to Lotronex therapy safely". Moreover, and 
crucially, given recent manoeuvres to reintroduce Lotronex, the report 
states that "a risk management plan cannot be successful that will 
eliminate deaths, colectomies, ischemic colitis, and complications of 
treatment that were never seen previously in the management of IBS".
This unambiguous conclusion was blurred by the time of the key Nov 28 
meeting between GlaxoWellcome and FDA officials. Rather than reject the 
company's risk- management proposal and withdraw Lotronex, the FDA offered 
several conciliatory options--eg, voluntary withdrawal of Lotronex, 
temporary suspension of marketing pending further discussion, and 
restricted marketing to specialists. Pleased and quite likely surprised by 
the FDA's desire to bargain over the terms of public access to Lotronex, 
the company pressed for a new advisory committee hearing and affirmed its 
view that risk management was feasible. The FDA's options were heavily 
criticised, the process was deemed unfair, and FDA scientists were accused 
of not taking irritable bowel syndrome seriously. There was stalemate, and 
the company blinked first.
Once GlaxoWellcome had withdrawn Lotronex, recriminations within the FDA 
began in earnest. In addition, Woodcock was swamped by e-mails from 
patients asking for the drug to be brought back. The company gave money to 
support groups for patients with irritable bowel syndrome to assist their 
research and educational programmes, according to Ramona DuBose, a 
GlaxoSmithKline spokeswoman. The FDA was brought under further pressure 
when the new Bush administration removed its Commissioner, Jane Henney, 
probably because of her support for the abortion-inducing mifepristone.
As arguments about Lotronex intensified, FDA officials took an increasingly 
hard line towards their own scientists. Yet new data acquired since the 
November withdrawal only strengthen the view that Lotronex should not be 
made widely available again. A further internal review of the incidence of 
ischaemic colitis among women taking Lotronex suggests that the company may 
have seriously underestimated the hazards of the drug. And additional 
adverse reports obtained by Public Citizen show rising numbers of cases of 
ischaemic colitis and severe constipation in women who continued to take 
Lotronex.
While the FDA held further internal discussions about how to respond to 
patients' groups and congressional pressure, private communications opened 
up between Woodcock and senior executives at the newly merged 
GlaxoSmithKline. The company was now worried that the open meeting it had 
proposed could produce a media circus, that committee members might 
disagree with a settlement made via these private communications, and that 
the entire process might be unduly prolonged. When I rang the FDA for a 
comment, I was told that the agency was "working with GlaxoSmithKline to 
discuss issues surrounding Lotronex and we are making progress". It is 
expected that the company will reluctantly agree to a few conditions for 
the reapproval of Lotronex--ie, there may be restrictions on which 
physicians can prescribe the drug and a requirement for signed 
patient-physician agreements. To ensure that the advisory committee does 
not overturn this privately determined decision, a senior representative of 
the company has asked the FDA about the composition of the committee. And 
the FDA has undertaken to work with the company to set limits to the 
meeting's agenda and questions.
This two-track process, one official and transparent, one unofficial and 
covert, is contrary to FDA's stated policy. According to Crystal Rice, an 
FDA spokeswoman, the correct procedure is for the company to write 
officially to the FDA replying to CDER's concerns and providing new data on 
safety. A full FDA review should then take place before an advisory 
committee meeting.
In the case of Lotronex, private communications appear to have subverted 
official procedures, while suppressed scientific debate has superseded a 
full and open review process. GlaxoSmithKline commented that "A team of FDA 
and GSK scientists have met on several occasions in an attempt to work out 
a risk management plan that would allow appropriate patients to receive 
benefit from the medicine while risks can be clearly understood and 
appropriately managed". This "effort is ongoing and no final decision has 
been made". The company also denied that there had been a back-channel for 
private communication between CDER officials and the sponsor. This claim 
was "untrue and very misleading", according to DuBose. "All meetings 
between GSK and the FDA have occurred primarily at the operational level 
between scientific teams". The FDA would "not comment on or discuss any 
details with regards to internal discussions between FDA and sponsors".
A further insight into the FDA's favourable attitude to industry was 
provided by a 1998 survey of FDA medical officers.5 Many of these 
physicians reported that since the 1992 Prescription Drug User Fee Act 
(PDUFA), which enabled the FDA via direct industry funding ($329 million) 
to hire almost 700 more medical officers to review new products, standards 
for drug approval have declined. Many officers felt under greater pressure 
from FDA supervisors to approve new drugs; they received inappropriate 
calls from the sponsor about the drug under review; and they believed that 
the FDA too often interfered on the company's behalf in the drug-approval 
process. The Lotronex episode may show in microcosm a serious erosion of 
integrity within the FDA, and in particular CDER, whose operating budget 
now depends greatly on industry money.
Where next for Lotronex and the FDA? The clinical evidence indicates that, 
at most, Lotronex should be reclassified as an investigational new drug, 
with additional restrictions, thus limiting its use to experimental 
settings only.4 Meanwhile, on this evidence the FDA urgently needs to 
re-establish the public's trust. First, all covert private communications 
between senior FDA officials and industry must be closed. Drug approvals 
and safety reviews should take place through accountable procedures. 
Second, greater weight should be placed on the epidemiological and 
statistical advice provided to advisory committees. Third, there should be 
an independent congressional audit of the FDA's drug-approval processes, 
including its priority reviews, since implementation of PDUFA. Fourth, 
pharmacovigilance should be removed from CDER's control. It is an 
impossible conflict for safety issues to be overseen by a centre that 
receives funding from industry to review and approve new drugs. Fifth, the 
culture within the FDA should welcome, not censure, differences of opinion 
about the impact of science on policymaking.
Finally, the FDA's new Commissioner should be an epidemiologically trained 
physician with substantial experience of conducting clinical trials, a 
person with a strong track record of institutional leadership, and, most 
importantly of all, someone who is demonstrably independent of the 
pharmaceutical industry.
Richard Horton
The Lancet, London WC1X 8RR, UK
1 Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley D, Mangel AW. 
Efficacy and safety of alosetron in women with irritable bowel syndrome. 
Lancet 2000; 355: 1035-40.
2 De Ponti F, Tonini M. Irritable bowel syndrome: new agents targeting 
serotonin receptor subtypes. Drugs 2001; 61: 317-32.
3 McColl KEL. Alosetron in irritable bowel syndrome. Lancet 2000; 356: 164. 
4 <http://www.citizen.org/hrg/PUBLICATIONS/1566.htm> (accessed on May 14, 
2001)
5 http://www.citizen.org/hrp/publications/fdasurvey.htm (accessed on May 
14, 2001)
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[Follow-up to the Editorial in Lancet 2001; 357 no 9268: 19 May. Web only]
Richard Horton asserted that senior staff at the FDA overrode internal 
recommendations about Lotronex before the drug's removal from the US market 
last year, and that they continue to do so (Horton R. Lotronex and the FDA: 
A fatal erosion of integrity). One point of dispute, according to Horton's 
commentary, revolved around safety studies.
Ingenix Pharmaceutical Services created the core epidemiologic protocols 
for the Lotronex post-marketing safety program. The studies involved 
research into the relations between irritable bowel syndrome (IBS), 
vascular insufficiency of the intestine, and serious complications of 
constipation in the years before Lotronex's introduction. They sought to 
profile the medical histories of new Lotronex users. They set out a direct 
assessment of the risks of serious complications in Lotronex users. The 
proposals responded to all the goals that had been set by the manufacturer, 
and--as we understood them--the FDA. So that readers of The Lancet can 
judge for themselves whether the work that had been proposed was 
scientifically sound, we have posted the protocol on our website at 
www.epidemiology.com/lotronex.htm.
With the posting, the protocol is a public document, and we would be 
grateful for any critique. We particularly hope to hear from FDA staff, who 
could post comments on this discussion board. They could do so through 
proxies, if they wish to remain anonymous. An obvious criticism is that the 
protocols could have been in place before the introduction of Lotronex, and 
that the background studies could have been well under way or even 
completed before the drug reached the market.
In the past regulatory authorities and manufacturers relied almost 
exclusively on direct reports of adverse reactions to marketed drugs as the 
first line of safety surveillance. A decade ago, promises of more extensive 
safety research sometimes formed a side agreement at the time of marketing 
authorization, but the follow-through was weak (Waller PC, Wood SM, Langman 
MJ, Breckenridge AM, Rawlins MD. Review of company post-marketing 
surveillance studies. BMJ 1992; 304: 1470-72). European and North American 
authorities have now begun to insist on well-elaborated protocols that are 
practical and have firm deadlines before product approval. The process of 
negotiating the protocols is still creaky
It would be a mistake to attribute the delay in setting up the background 
studies solely to a lack of foresight by Glaxo Wellcome's employees or the 
FDA's. There many examples of widely recognised conditions (such as benign 
prostatic hypertrophy, depressive disorders, and impotence) that received 
little attention when there was no effective treatment, and which were 
thrust into the limelight by the advent of new therapies. IBS may fall into 
this category. It is in any case a common disorder whose epidemiology, 
aetiology, and natural history are poorly understood. IBS experts were for 
the most part clinicians who lacked the training, even the vocabulary, to 
consider population-based studies, and in this IBS is certainly kin to many 
under appreciated conditions that will come to the fore because of new 
drugs, devices, procedures, and vaccines.
Alec Walker
e-mail:AlecWalker@aol.com


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